Issue Information

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British Society for Matrix Biology Autumn 2017 Meeting: Translating the Matrix

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The POU5F1 gene expression in colorectal cancer: a novel prognostic marker

Abstract

Purpose

The POU5F1 gene, which encodes the POU domain, class 5, transcription factor 1 (also known as Oct-4), is expressed in embryonic stem cells where it regulates pluripotency and proliferation. Few studies have examined the expression and significance of POU5F1 in cancer tissues. The aim of this study was to clarify its significance in colorectal cancer (CRC).

Methods

The study included 95 patients who underwent surgery for CRC from 2009 to 2011. The correlations between the POU5F1 gene expression and the clinical parameters were assessed in these patients. The serum TP53 expression levels were also examined by an enzyme-linked immunosorbent assay.

Results

Patients with a high POU5F1 expression were significantly more likely to have a poor prognosis than those with a low expression. In contrast, patients with a low POU5F1 expression had a better disease-free survival after curative surgical resection than those with a high expression (P = 0.007). Multivariate analyses showed that the POU5F1 expression (P = 0.003) and lymph node metastasis (P < 0.001) were significantly correlated with the disease-free survival. The prognosis was significantly related to the serum TP53 levels, according to the POU5F1 expression.

Conclusion

The POU5F1 expression was suggested to be a prognostic factor in patients with CRC.

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Clinicopathological features and EBV infection status of lymphoma in children and adolescents in South China: a retrospective study of 662 cases

The clinicopathological features and Epstein-Barr virus (EBV) infection status of lymphoma in children and adolescents in South China is under-researched. South China is a well-known high-incidence area of EBV...

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Intravesicular taxane-induced dermatotoxicity in a 78-year-old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma

Patients treated with intravesical bacillus Calmette-Guerin therapy for urothelial carcinoma often become refractory and experience recurrent disease, thus necessitating alternative intravesical treatment modalities if the patient is to be spared the morbidities associated with radical cystectomy. Intravesical treatment with taxane-based chemotherapy, such as docetaxel, has gained traction in urologic oncology, proving to be an effective salvage therapy in such patients. Systemic taxane-based chemotherapeutic regimens have long been used in several advanced malignancies, and their systemic side effects and associated histologic correlates have been extensively documented. In contrast to adverse effects associated with systemic administration, intravesical taxane administration has thus far proven to be well-tolerated, with little to no systemic absorption. To our knowledge, features of taxane-induced systemic effects have not been reported in this setting. Herein, we report a case of a patient with recurrent urothelial carcinoma treated with intravesical docetaxel, along with primary cutaneous anaplastic large cell lymphoma, who developed characteristic dermatotoxic histologic findings associated with intravenous taxane administration. As such histopathologic findings often represent close mimickers of neoplastic and infectious etiologies, knowledge of the potential for systemic manifestations of taxane therapy in patients treated topically may prevent potentially costly diagnostic pitfalls.

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Colliding, Colonizing, or Combining?: Four Cases Illustrating the Unique Challenges of Melanoma arising in conjunction with Basal Cell Carcinoma

Biphasic lesions comprised of melanocytic and epithelial components are rare entities believed to arise either as a collision of two histologically distinct lesions in the same anatomic location or as a singular progenitor tumor differentiating along two differing lineages. Regardless of mechanism of origin, these tumors present unique challenges in pathologic interpretation and in determining appropriate measurements, which assigns subsequent prognosis to the patient.

We present 4 tumors of melanoma co-existing with basal cell carcinoma and discuss relevant literature regarding these biphasic entities. Patients consisted of 3 males and 1 female, ranging in age from 62–93, with lesions located on the shoulder, frontal scalp, forearm, and nose. Three of four lesions demonstrated melanoma cells limited to basal cell carcinoma tumor lobules, without evidence of direct dermal invasion by melanoma cells, raising question of whether or not these tumors should be classified as in situ or invasive melanoma.

These cases highlight the complexity that such lesions pose to dermatopathologists, in terms of their uncertain origin and variable microscopic appearance. In the absence of data regarding outcomes for these tumors (given their rarity), it is important to utilize a case-by-case approach with careful clinical correlation and appropriate use of ancillary techniques.

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How to take better photomicrographs: a step-wise approach

Digital photomicrographs are often used to illustrate cutaneous diseases; however, there exists no formal protocol on how to best capture these images. We present a nine-step photomicrographing protocol for dermatopathologists, using standard overhead cameras or smartphones alongside image editing packages. A notable difference in image quality is observed when using our detailed photomicrographing protocol compared to routinely procured photomicrographs.

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Multi-centre phase IV trial to investigate the immunogenicity of a new liquid formulation of recombinant human growth hormone in adults with growth hormone deficiency

Abstract

Purpose

To investigate whether a new liquid formulation of recombinant human growth hormone (r-hGH) induces the production of binding antibodies (BAbs) in adults with congenital or adult-onset growth hormone deficiency (GHD).

Methods

Men or women aged 19–65 years with adult growth hormone deficiency who were r-hGH-naïve or had stopped treatment ≥ 1 month before screening were treated with between 0.15 and 0.30 mg/day r-hGH liquid formulation for 39 weeks. The primary endpoint was the proportion of patients who developed BAbs at any time. Secondary endpoints were the proportion of patients with BAbs who became positive for neutralising antibodies, the effects on biomarkers of r-hGH exposure, safety, and adherence to treatment downloaded from the easypod™ connect software.

Results

Seventy-eight patients (61.5% men) with mean age 44.5 years (range 21–65) started and 68 (87.2%) completed the 39-week treatment period. 82.1% were treatment naïve; all were negative for BAbs to r-hGH at baseline. The median (interquartile range) duration of treatment [273 (267.0–277.0) days] was consistent with patients receiving the required doses, and mean treatment adherence measured using easypod™ connect was 89.3%. The proportion of patients who developed BAbs was 0% (95% confidence interval 0–4.68%) and biomarker profiles were consistent with exposure to r-hGH. 92.3% of patients reported ≥ 1 adverse event during treatment. Most events were mild or moderate and no new safety concerns were detected.

Conclusions

The low immunogenicity profile of the liquid formulation was consistent with that for the freeze-dried formulation, and no new safety concerns were reported.

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Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer

Opinion statement

Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well-designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice.

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Controlled release of chlorhexidine from a HEMA-UDMA resin using a magnetic field

Publication date: Available online 26 February 2018
Source:Dental Materials
Author(s): Dong Luo, Saroash Shahid, Samiul Md. Hasan, Robert Whiley, Gleb B. Sukhorukov, Michael J. Cattell
ObjectivesTo functionalize novel chlorhexidine (CHX) particles with iron oxide (Fe3O4) nanoparticles and control their release kinetics in a dental resin using an external magnetic field.MethodsFe3O4 nanoparticles were synthesized and incorporated into spherical CHX particles and the powder was freeze dried. Resin disc specimens were produced using a UDMA-HEMA resin mixed with freeze dried spherical Fe3O4-CHX particles (5wt.%), which were placed into a Teflon mould (10mm diameter×1mm depth) and covered with a Mylar strip. A MACS magnet was left in contact for 0min (Group 1), 5min (Group 2) or 10min (Group 3) and the resin discs subsequently light cured (Bluedent LED pen, Bulgaria) for 60s per side. The resin discs were immersed in deionized water at various time points up to 650h. UV–Vis absorbance was used to determine the CHX content. CHX released for each time point was determined. The functionalized CHX particles and resin discs were characterized using TEM, TGA, EDX and SEM.ResultsFe3O4 nanoparticles (20nm) incorporated into the spherical CHX particles led to a mean (SD) particle size reduction from 17.15 (1.99)μm to 10.39 (2.61)μm. The presence of Fe3O4 nanoparticles in the spherical CHX particles was confirmed with SEM, EDX, and TGA. SEM of Group 1 resin discs (no magnetic exposure) showed functionalized CHX spheres were homogeneously distributed within the resin discs. For resin discs which had magnetic exposure (5 or 10min) the particles started to cluster nearer the surface (Group 2: 43.7%, Group 3: 57.3%), to a depth of 94μm. UV–Vis absorbance revealed Group 1 resin discs had a cumulative CHX release of 4.4% compared to 5.9% for Group 2 and 7.4% for Group 3 resin discs, which had magnetic exposure (5, 10min).SignificanceFe3O4 nanoparticle functionalized CHX spheres demonstrated a magnetic field responsive property. A magnetic field responsive release of CHX may be useful in clinical situations where the drug can be directed to give a tailored release at the site of infection.



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Primary synovial sarcoma (SS) of larynx: An unusual site

Publication date: Available online 26 February 2018
Source:Oral Oncology
Author(s): Irappa Madabhavi, Vishalkumar Bhardawa, Mitul Modi, Apurva Patel, Malay Sarkar
Soft tissue sarcomas (STSs) are heterogeneous disorders comprises myriad subtypes originated from mesenchymal stem cells. Synovial sarcomas (SSs) are belligerent malignant tumours included in this group affecting extremities of patients' age ranging between 15 and 35 years. SS taking place in head and neck region is rare event and primary laryngeal involvement is even rarer happening. There are 20 odd published cases documented in world literature so far. Here we are presenting primary laryngeal SS occurred in 31 year old male patient initially mimicking laryngeal carcinoma as patient was chronic smoker and classic symptom of hoarseness of voice.



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Editorial Board/Aims & Scope

Publication date: March 2018
Source:Oral Oncology, Volume 78





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New research directions for areca nut/betel quid and oral submucous fibrosis for holistic prevention and treatment

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Sachin C. Sarode, Prashanth Panta, Gargi S. Sarode, Amol R. Gadbail, Shailesh M. Gondivkar, Shankargouda Patil




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RETRACTED: Systemic therapy in the management of metastatic or advanced salivary gland cancers

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Aymen Lagha, Nesrine Chraiet, Mouna Ayadi, Sarra Krimi, Bassem Allani, Hela Rifi, Henda Raies, Amel Mezlini




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Comparative iTRAQ analysis of protein abundance in the human sinoatrial node and working cardiomyocytes

Abstract

Our objective was to assess the changes in protein abundance in the human sinoatrial node (SAN) compared with working cardiomyocytes to identify SAN-specific protein signatures. Four pairs of samples (the SAN and working cardiomyocytes) were obtained postmortem from four human donors with no evidence of cardiovascular disease. We performed protein identification and quantitation using two-dimensional chromatography-tandem mass spectrometry with isobaric peptide labeling (iTRAQ). We identified 451 different proteins expressed in both the SAN and working cardiomyocytes, 166 of which were differentially regulated (110 were upregulated in the SAN and 56 in the working cardiomyocytes). We identified sarcomere structural proteins in both tissues, although they were differently distributed among the tested samples. For example, myosin light chain 4, myosin regulatory light chain 2-atrial isoform, and tropomyosin alpha-3 chain levels were twofold higher in the SAN than in working cardiomyocytes, and myosin light chain 3 and myosin regulatory light chain 2-ventricular/cardiac muscle isoform levels were twofold higher in the ventricle tissue than in SAN. We identified many mitochondrial oxidative phosphorylation, β-oxidation, and tricarboxylic acid cycle proteins that were predominantly associated with working cardiomyocytes tissue. We detected upregulation of the fatty acid omega activation pathway proteins in the SAN samples. Some proteins specific for smooth muscle tissue were highly upregulated in the SAN (e.g. transgelin), which indicates that the SAN tissue might act as the bridge between the working myocardium and the smooth muscle. Our results show possible implementation of proteomic strategies to identify in-depth functional differences between various heart sub-structures.

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Quantitative axial myology in two constricting snakes: Lampropeltis holbrooki and Pantherophis obsoletus

Abstract

A snake's body represents an extreme degree of elongation with immense muscle complexity. Snakes have approximately 25 different muscles on each side of the body at each vertebra. These muscles serially repeat, overlap, interconnect, and rarely insert parallel to the vertebral column. The angled muscles mean that simple measurements of anatomical cross-sectional area (ACSA, perpendicular to the long-axis of the body) serve only as proxies for the primary determinant of muscle force, physiological cross-sectional area (PCSA, area perpendicular to the muscle fibers). Here, I describe and quantify the musculature of two intraguild constrictors: kingsnakes (Lampropeltis holbrooki) and ratsnakes (Pantherophis obsoletus) whose predation performance varies considerably. Kingsnakes can produce significantly higher constriction pressures compared with ratsnakes of similar size. In both snakes, I provide qualitative descriptions, detail previously undescribed complexity, identify a new lateral muscle, and provide some of the first quantitative measures of individual muscle and whole-body PCSA. Furthermore, I compare measurements of ACSA with measurements of PCSA. There was no significant difference in PCSA of muscles between kingsnakes and ratsnakes. There is, however, a strong relationship between ACSA and PCSA measurements. I could not identify a significant difference in musculature between kingsnakes and ratsnakes that explains their different levels of constriction performance. Unmeasured components of muscle function, such as endurance and force production, might account for differences in performance between two species with similar muscle structure.

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Value-Based Care in Hematopoietic Cell Transplantation and Cellular Therapy: Challenges and Opportunities

Abstract

Purpose of Review

Improved tolerability and outcomes after hematopoietic cell transplantation (HCT), along with the availability of alternative donors, have expanded its use. With this growth, and the development of additional cellular therapies, we also aim to increase effectiveness, efficiency, and the quality of the care provided. Fundamentally, the goal of value-based care is to have better health outcomes with streamlined processes, improved patient experience, and lower costs for both the patients and the health care system. HCT and cellular therapy treatments are multiphase treatments which allow for interventions at each juncture.

Recent Findings

We present a summary of the current literature with focus on program structure and overall system capacity, coordination of therapy across providers, standardization across institutions, diversity and disparities in care, patient quality of life, and cost implications.

Summary

Each of these topics provides challenges and opportunities to improve value-based care for HCT and cellular therapy patients.

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Intraoperative Evaluation of Prophylactic Hysterectomy and Salpingo-oophorectomy Specimens in Hereditary Gynecologic Cancer Syndromes

Abstract

Aims

Prophylactic total hysterectomy (TH) and bilateral salpingo-oophorectomy (BSO) have become routine procedures in women at genetic risk for gynecologic malignancies. Intraoperative pathology diagnosis of an occult malignancy provides the opportunity for immediate surgical staging and helps avoiding a second surgery. However, no standard guidelines exist for optimal intraoperative evaluation (IOE) of these specimens. We performed a retrospective analysis of prophylactic TH and BSO cases to assess the presence of gross findings, frozen and permanent section sampling practices, frozen section diagnoses and diagnostic discrepancies.

Methods and results

All prophylactic TH and BSO cases between 1990-2017 were retrieved from our departmental archives. A total of 413 cases were included in the study: 27 with Lynch syndrome (LS), 222 with germline BRCA 1 or 2 mutations, and 164 cases with strong family or personal history (non-Lynch/ non-BRCA). Only less than half of all cases (159 of 413; 38.5%) were sent for IOE: fifteen of 27 (56%) LS cases, 93 of 222 (42%) BRCA cases and 51 of 164 (31%) non-Lynch/ non-BRCA cases. A total of 19 patients (4.6% of patients combining all 3 groups) had a final diagnosis of malignancy or pre-malignancy on permanent sections. Of these 19 cases, 8 had a corresponding gross lesion (42%) and could have been diagnosed on frozen section; however, only one of them underwent IOE.

Conclusions

Our results highlight the potential benefits and challenges of IOE in this setting and may provide a basis for future practice recommendations.

This article is protected by copyright. All rights reserved.

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Hydroxyl Radical Generation and Contaminant Removal from Water by the Collapse of Microbubbles Under Different Hydrochemical Conditions

Abstract

The present study addresses the mechanism of hydroxyl radical (·OH) generation by the collapse of microbubbles in water solution. The influence of gas supply and flow rate, solution pH, and ionic strength on the aeration efficiency, free radical generation, and contaminant removal (take methylene blue as an example) are elucidated. The results showed that the degradation rate of methylene blue by ·OH increased with flow rate as well as in acidic or alkaline solutions compared to that in neutral conditions. ·OH was shown to be produced by the reaction between protons and oxygen radicals generated by the decomposition of O₂ rather than water molecules. A greater concentration of O₂ or H⁺ thus promoted the reaction, resulting in effective removal at a high flow rate or low pH. Nevertheless, there was considerable methylene blue removal at high pH, driven by the production of the dye cation through the dissociation of methylene blue and the high electronegativity of bubbles at high pH, thus enhancing interface adsorption and degradation, as well as by the high ionic strength of the solution helping to generate ultrafine bubbles and maintaining them through ionic shielding. The current work provides useful insights into the application of microbubble as a promising technique.

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Associations between human fungiform papillae and responsiveness to oral stimuli: effects of individual variability, population characteristics, and methods for papillae quantification

Abstract

Fungiform papillae on human tongue are the proxy structures designated to oral stimuli detection and transduction. However, the role of their density (fungiform papillae/cm²) in explaining oral sensitivity is still controversial. While early studies generally found that the responsiveness to oral stimuli increased as the number of papillae increased, recent large-scale studies failed to confirm this finding.The present paper reviews relevant studies dealing with the relationship between fungiform papillae density and responsiveness to oral sensations including: fundamental tastes, 6-n-propyl-2-thiouracil (PROP) and sensations from trigeminal stimulation.Manual methods and automated methods for papillae detection and quantification are reviewed and their advantages and limitations highlighted. The main factors affecting fungiform papillae density and functionality (age, gender, pathologic impairments) are also considered. Possible bias related to methodological issues in counting technique (equipment used, area and location of the tongue to count, procedures to validate the count), population sample (demographics) and sensory response collection (threshold or supra-threshold stimuli, intensity scaling) are illustrated.The lack of information related to the variability in taste pores density and the possible impairments due to nerve damages, may obscure the relationship between FPD and oral responsiveness.

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Osteotomies and autografted artificial dermal substitute over bone marrow in a bone-deep burn in an elder patient: An alternative to amputation

Abstract

In this report, we describe the case of an elder patient who suffered a third-degree fire burn with extensive bone affection and exposure of both tibias. The usual treatment strategy for this type of case would have been amputation, or the performance of a multiple free flap surgery. Notwithstanding taking into account the age and the functional objectives for this patient, the multiple free flap option was disregarded. Therefore, we performed an original limb salvage procedure which consisted in bilateral anterior tibial cortex osteotomies and direct grafting over bone marrow, applying skin grafts over a monolayer artificial dermal substitute (Integra®), covered by a negative pressure therapy device. The wound was successfully and early covered, preventing the patient from the long hospital stay and derived complications that other coverage strategies would have carried.

Level of Evidence: Level V, therapeutic study.

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Management of nipple-areola complex ischemia after breast reduction: A systematic literature review and algorithm proposal

Abstract

Background

Rare and dreaded, necrosis of the nipple-areola complex (NAC) is one of the major complications of breast reduction surgery. Our objective was to establish a management algorithm summarizing the different possible treatments reported in the literature.

Methods

The data extracted from the articles selected for this literature review covered surgical techniques, frequency of NAC necrosis, type of necrosis, and management proposed for women who have had this surgery for macromastia.

Results

In the 54 articles finally selected, the mean frequency of NAC necrosis was 5.1%. The risk factors for necrosis were the weight of the tissue resected, smoking, obesity, the surgical technique used, and stretch marks. The treatments proposed were listed according to four categories of issues: patient-specific susceptibility, type of breast, surgical technique, and its technical performance.

Conclusions

No consensus exists about the management of NAC necrosis, which remains a complication feared by surgeons. We propose a management algorithm that simplifies the therapeutic indications.

Level of Evidence: Not ratable

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Near-infrared fluorescence image-guidance in plastic surgery: A systematic review

Abstract

Background

Near-infrared fluorescence (NIRF) imaging technique, after administration of contrast agents with fluorescent characteristics in the near-infrared (700–900 nm) range, is considered to possess great potential for the future of plastic surgery, given its capacity for perioperative, real-time anatomical guidance and identification. This study aimed to provide a comprehensive literature review concerning current and potential future applications of NIRF imaging in plastic surgery, thereby guiding future research.

Methods

A systematic literature search was performed in databases of Cochrane Library CENTRAL, MEDLINE, and EMBASE (last search Oct 2017) regarding NIRF imaging in plastic surgery. Identified articles were screened and checked for eligibility by two authors independently.

Results

Forty-eight selected studies included 1166 animal/human subjects in total. NIRF imaging was described for a variety of (pre)clinical applications in plastic surgery. Thirty-two articles used NIRF angiography, i.e., vascular imaging after intravenous dye administration. Ten articles reported on NIRF lymphography after subcutaneous dye administration. Although currently most applied, general protocols for dosage and timing of dye administration for NIRF angiography and lymphography are still lacking. Three articles applied NIRF to detect nerve injury, and another three studies described other novel applications in plastic surgery.

Conclusions

Future standard implementation of novel intraoperative optical techniques, such as NIRF imaging, could significantly contribute to perioperative anatomy guidance and facilitate critical decision-making in plastic surgical procedures. Further investigation (i.e., large multicenter randomized controlled trials) is mandatory to establish the true value of this innovative surgical imaging technique in standard clinical practice and to aid in forming consensus on protocols for general use.

Level of Evidence: Not ratable

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Targeting Polo-like Kinase 1 by a Novel Pyrrole-imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth in vivo

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the Plk1 promoter. PIP3 could specifically inhibit the cell cycle regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, while normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy.

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p110{alpha} inhibition overcomes stromal cell-mediated ibrutinib resistance in mantle cell lymphoma

Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated down-regulation of phosphoinositide-3-kinase (PI3K)/AKT signaling. Importantly, the stromal cell-mediated ibrutinib resistance was overcome in vitro by inhibiting AKT activity using the PI3K catalytic p110α subunit specific inhibitor BYL719. This was seen both for MCL cell lines and primary MCL cells. Furthermore, inhibition of p110α activity by BYL719 potentiated the ability of ibrutinib to inhibit MCL tumor growth in vivo in a mouse xenograft model. The stromal cell-mediated ibrutinib resistance was found to be due to a direct interaction with MCL cells and involves the integrin VLA-4, since disrupting stromal cell-MCL cell interaction using a VLA-4 blocking antibody abrogated the ibrutinib resistance. This suggests that combined treatment with ibrutinib and a p110α inhibitor, alternatively by disrupting stromal cell-MCL cell interaction, may be a promising therapeutic strategy to overcome stromal cell-mediated ibrutinib resistance in MCL.

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Inhibition of the histone H3K27 demethylase UTX enhances tumor cell radiosensitivity

The processes mediating the repair of DNA double strand breaks (DSBs) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and H2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast to results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization.

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Anti-HER2 scFv-directed extracellular vesicle-mediated mRNA-based gene delivery inhibits growth of HER2-positive human breast tumor xenografts by prodrug activation

This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease namely HER2+ve human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EVs) were used for mRNA-based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed. It contains high affinity anti-HER2 scFv antibody (ML39) and is capable of latching on to EV surface. Cells transfected with EVHB-encoding plasmid generated EVs displaying this protein ("directed EVs"). Transfection of a separate batch of cells with the new plasmid, XPort/HChrR6, generated EVs containing HChrR6 mRNA; incubation with pure EVHB enabled these to target the HER2 receptor, generating "EXO-DEPT" EVs. EXO-DEPT treatment specifically enabled HER2-overexpressing BT474 cells to convert CNOB into MCHB in actinomycin D independent manner, showing successful and specific delivery of HCHrR6 mRNA. EXO-DEPTs --but not undirected EVs-- plus CNOB caused near-complete growth-arrest of orthotopic BT474 xenografts in vivo, demonstrating for the first time EV-mediated delivery of functional exogenous mRNA to tumors. EXO-DEPTs may be generated from patient's own dendritic cells to evade immune rejection, and without plasmids and their potentially harmful genetic material, raising the prospect of clinical use of this regimen. This approach can be employed to treat any disease overexpressing a specific marker.

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Nigericin exerts anticancer effects on human colorectal cancer cells by inhibiting Wnt/{beta}-catenin signaling pathway

Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in CRC cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration and invasion, and induce the apoptosis of CRC cells. Our results of western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in CRC cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin over-expression CRC cells. Western blot, SuperTOPflash luciferase reporter and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anti-cancer effects on CRC cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in CRC progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin towards cancer cells, and suggest possible clinical application in CRC.

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Anti-tumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 Insertions

EGFR exon 20 insertions (Ex20Ins) account for 4-10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterised osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signalling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The anti-tumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC.

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The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer

BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT CRC subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT CRC cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT CRC.

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Targeting PRPK Function Blocks Colon Cancer Metastasis

The biological functions of the p53 related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients, and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stages III or IV), as compared to earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo. An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis.

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"A tricin derivative from Deschampsia antarctica Desv. inhibits colorectal carcinoma growth and liver metastasis through the induction of a specific immune response"

In colorectal carcinoma (CRC) patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic CRC have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina™ is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina™ in CRC models. We used human and murine CRC cell lines for investigating proliferation, apoptosis and cell cycle effects of Antartina™ therapy in vitro. Avatar and immunocompetent CRC animal models were applied for evaluating the effects of Antartina™ in vivo. Immune response against CRC model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T cell sub-population, and by tumor rechallenge experiments. Antartina™ inhibits in vitro human CRC cell proliferation; however, in vivo experiments in Avatar CRC model Antartina™ display a limited antitumor effect. In an immunocompetent CRC mice model Antartina™ potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina™ induced a potent specific cytotoxic T cell response against CRC, and a long-lasting antitumor immunity. Interestingly, Antartina™ increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina™ has the ability to induce antitumor immunity against CRC and can be used to develop new tools for the treatment of CRC.

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EGF Receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors

Germ cell tumors (GCTs) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and non-seminoma forms of GCT exhibit distinct differentiation states, clinical behavior and response to treatment, however the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase (MAPK) pathways were differentially active in the two classes of GCT. Here we show that non-seminomatous germ cell tumors (NSGCTs, including embryonal carcinoma, yolk sac tumor and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Lastly, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways.

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MCT4 Expression is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Monocarboxylate transporters (MCTs) are transmembrane proteins which control the lactate metabolism and associated with poor prognosis in solid tumors including colorectal cancer (CRC). Here we aimed to investigate the biological and clinical role of MCTs in CRC and to assess the potential of therapeutic application. A total of 16 human CRC cell lines, 11 patient-derived cells from malignant ascites (PDC), and 39 matched pairs of primary CRC and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo. siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by immunohistochemistry (IHC) and used for survival analysis. Expression of MCTs was demonstrated in CRC cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo. An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MTC4 was markedly increased in PDCs and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for CRC with peritoneal carcinomatosis and serve as a prognostic indicator.

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Preclinical activity of abemaciclib alone or in combination with anti-mitotic and targeted therapies in breast cancer

The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple negative breast cancer (TNBC) cell lines with intact Rb-signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2-, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved anti-tumor activity. CDK4/6 inhibition with abemaciclib combined with anti-mitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic-biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as mono-therapy or as a combination partner in selected ER+/HER2-, HER2+/ER+ and TNBCs.

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Characterization of ABBV-221, a Tumor-Selective EGFR Targeting Antibody Drug Conjugate

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR highlighting the need for therapies with activity against tumors with non-amplified EGFR overexpression. Additionally, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR targeting ADC comprised of an affinity matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and anti-tumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR amplified GBM PDX model and is highly effective alone and in combination with standard of care (SOC) temozolomide in an EGFRvIII positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase 1 clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR.

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Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long term growth inhibition in estrogen receptor positive breast cancer

The cyclin dependent kinase (CDK) -retinoblastoma (RB) -E2F pathway plays a critical role in the control of cell cycle in estrogen receptor positive (ER+) breast cancer. Small molecule inhibitors of CDK4/6 have shown promise in this tumour type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data has suggested cooperation between the phosphatidylinositol 3-kinase (PI3K)/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation and E2F mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F dependent transcription, which translates into more durable growth arrest and a delay to the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6 and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor resistant cell lines re-activate the CDK-RB-E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy.

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Analysis of Tissue and Circulating Tumor DNA by Next Generation Sequencing of Hepatocellular Carcinoma: Implications for Targeted Therapeutics

Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. However, biopsy is not routinely performed in HCC. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. We performed 32 ctDNA NGS analyses on 26 patients; 10 of these patients had tissue NGS (236 to 626 genes). ctDNA was evaluated using an assay that detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion alterations in 54 to 70 genes. The ctDNA demonstrated that 23 of 26 patients (88.5%) had ≥ 1 characterized alteration, and all these individuals had ≥ 1 potentially actionable alteration. The most frequently mutated gene was TP53 (16 of 26 patients, 61.5%). There were 47 unique characterized molecular alterations amongst 18 total gene alterations (variants of unknown significance (VUSs) excluded). ctDNA and tissue NGS frequently showed different profiles, perhaps due to length of time between tissue and blood samples (median = 370 days (range, 29 to 876 days)). Serial ctDNA evaluation in an illustrative patient treated with capecitabine demonstrated emergence of a new TP53 alteration after progression. In conclusion, ctDNA profiling is feasible in advanced HCC, and serial assessment using ctDNA NGS can reveal genomic changes with time. NGS of ctDNA provides a minimally invasive alternative for identifying potentially actionable gene alterations and potential molecular targeted therapies. Dynamic changes in molecular portfolio associated with therapeutic pressure in difficult-to-biopsy patients can be observed.

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Impact of chemical-induced mutational load increase on immune checkpoint therapy in poorly responsive murine tumors

A recurring historical finding in cancer drug development is encouraging anti-tumor effects observed in tumor-bearing mice which fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26 and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26 and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Though tumor PD-L1 expression was upregulated in in vivo chemotherapy exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically 'hot' or 'cold' tumors with a high mutational load - to which certain chemotherapy agents may contribute - on immunotherapy outcomes.

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Wilms’ tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability

Wilms' tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. The regulation of cell cycle is mainly dependent on cycl...

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The viable circulating tumor cells with cancer stem cells feature, where is the way out?

With cancer stem cells (CSCs) became the research hotspot, emerging studies attempt to reveal the functions of these special subsets in tumorigenesis. Although various approaches have been used in CSCs researc...

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Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16INK4a inactivation

The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. Howev...

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Colonoscopy-induced Hemoscrotum

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Symptomatic large ampullary gastric heterotopia

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Unusual findings in Peutz-Jeghers syndrome: endoscopic and histological appearance of gastric hamartomatous polyposis with foveolar dysplasia

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Narrow-band imaging of a gastric carcinoma with lymphoid stroma associated with Epstein-Barr virus

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STAT5A/B BLOCKADE SENSITIZES PROSTATE CANCER TO RADIATION THROUGH INHIBITION OF RAD51 AND DNA REPAIR

Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double strand DNA break repair in PC, and whether Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic survival assays, followed by assays specific to Homologous Recombination (HR) DNA repair and Non-Homologous End-Joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacological Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues.

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Phase 1 study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment naive and previously treated basal cell carcinoma

Purpose: To determine a recommended Phase 2 dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a Phase 1, multicenter, open-label study of oral LY2940680. The maximum tolerated dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naive and previously hedgehog (Hh) inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n=25; dose confirmation, n=19; and BCC dose expansion, n=40). Common treatment-emergent adverse events were dysgeusia (41 [48.8%]), fatigue (40 [47.6%]), nausea (38 [45.2%]), and muscle spasms (34 [40.5%]). Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested all doses were biologically active (inhibition median of 92.3% [80.9% to 95.7%]). All clinical responses (per RECIST 1.1) were in patients with BCC (n=47); the overall and estimated response rate was 46.8% (95% CI: 32.1-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh-treatment-naive (11/16) patients. Conclusions:LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh-treatment-naive patients.

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Patient-customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients

The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10/24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.

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hPCL3s promotes hepatocellular carcinoma metastasis by activating {beta}-catenin signaling

Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2) with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has however not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic beta-catenin destruction complex, inhibited beta-catenin degradation, and activated beta-catenin/T-cell factor (TCF) signaling. Downstream of the beta-catenin cascade, interleukin 6 (IL-6) mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the beta-catenin/IL-6 pathway.

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A soft microenvironment protects from failure of midbody abscission and multinucleation downstream of the EMT-promoting transcription factor Snail

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or transforming growth factor-beta (TGFbeta), known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.

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IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (T-IC) within the tumor bulk. Therefore, targeting liver T-IC may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced T-IC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.

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A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma—the ESO-shanghai 1 trial protocol

Abstract

Background

Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.

Method

Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m²/d, d1–3, plus 5-fluorouracil 1800 mg/m², continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m², continuous infusion for 96 h plus paclitaxel 50 mg/m², d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m², continuous infusion for 72 h, plus paclitaxel 175 mg/m² d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.

Discussion

The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.

Trial registration

ClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012.

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A new tissue segmentation method to calculate 3D dose in small animal radiation therapy

Abstract

Background

In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Z_eff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Z_eff) in small animal dose calculation.

Methods

The method is based on the relationship found between CBCT number and ρ*Z_eff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZ_eff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZ_eff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations.

Results

The study of the impact of ρZ_eff variation over the range of materials, from ρZ_eff = 2 g.cm^− 3 (lung) to 27 g.cm^− 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZ_eff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance.

Conclusions

Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZ_eff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.

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Undifferentiated headache: broadening the approach to headache in children and adolescents, with supporting evidence from a nationwide school-based cross-sectional survey in Turkey

Headache is a leading disabler in adults worldwide. In children and adolescents, the same may be true but the evidence is much poorer. It is notable that published epidemiological studies of these age groups h...

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Comparing spiking and slow wave activity from invasive electroencephalography in patients with and without seizures

Seizures have long been defined as paroxysmal events typified by abnormally excessive or synchronous brain activity (Fisher et al., 2005). Seizures can occur in healthy brain, or can be the result of disease. By definition, epilepsy requires an increased probability of seizures. Seizure threshold is a clinically useful concept expressing a time-varying probability of seizures. Despite clinical relevance, there remains no clear way of quantitatively assessing seizure probability. As a result, epilepsy patients often undergo long therapy titrations or never have their therapy appropriately optimized.

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Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis

The morphology and the distribution of interictal epileptiform discharges (IEDs) on scalp EEG provide useful information about the syndromic diagnosis of epilepsy and its localization in cases of focal epilepsy (Niedermeyer, 1999). Traditionally, IEDs are considered to have a limited specificity with regard to the underlying etiology of epilepsy. However, certain EEG patterns in the form of continuous or semi-continuous rhythmic IEDs and interictal regional polyspikes on intraoperative electrocorticography and scalp EEG have been demonstrated more commonly in patients with focal cortical dysplasia (FCD) (Ferrier et al., 2006; Gambardella et al., 1996; Noachtar et al., 2008; Palmini et al., 1995; Rosenow et al., 1998).

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Intra-operative characterisation of subthalamic oscillations in Parkinson’s disease

There is growing interest in the nature of local field potential (LFP) activities recorded from the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) undergoing neurosurgery for deep brain stimulation (DBS). This is fueled by the evidence that oscillatory activity in the beta frequency band is unduly synchronized and strong in these patients and that this relates to deficiency of dopamine in the basal ganglia (Hammond et al, 2007). Thus, the power of beta activity is correlated with the motor impairment in PD and the changes of power engendered by levodopa treatment or DBS correlate with improvements in bradykinesia and rigidity (Ray et al., 2008; Kühn et al., 2008 and 2009; Eusebio et al., 2011).

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Does Acute Radio-Frequency Electromagnetic Field Exposure Affect Visual Event-Related Potentials in Healthy Adults?

It is well established that waking electroencephalogram (EEG) power in the alpha (8-12 Hz) band (Croft et al., 2002; D'Costa et al., 2003; Curcio et al., 2005; Regel et al., 2007; Croft et al., 2010), and sleep EEG in the sleep spindle range (Borbely et al., 1999) are both affected by radio-frequency electromagnetic field (RF-EMF) exposure. These effects persist even after RF-EMF exposure cessation for sleep EEG (Huber et al., 2002; Loughran et al., 2005; Loughran et al., 2012), and also possibly for the waking EEG (Curcio et al., 2005).

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Predictive Factors for Vestibular Loss in Children With Hearing Loss

Purpose

The aim of this study was to determine if there are factors that can predict whether a child with hearing loss will also have vestibular loss.

Method

A retrospective chart review was completed on 186 children with hearing loss seen at Boys Town National Research Hospital for vestibular testing from 1999 to 2015 through neurosensory genetics clinic or cochlear implant candidacy. Each child's medical chart was reviewed to obtain the following data: vestibular loss severity (classified as normal, bilateral, or mild to moderate), degree of hearing loss (bilateral pure-tone average [PTA]), imaging abnormalities (classified as "normal" or "abnormal"), parental concerns for gross motor delay (classified as "yes, there is concern" or "no, there is not a concern"), parent report of age when their child sat (months) and walked independently (months), comorbidities (classified as "yes" if there were 1 or more comorbidities or "no" if there were no comorbidities), and score on the Developmental Profile-3.

Results

Children were grouped according to vestibular loss severity; 115 children had normal vestibular function, 31 had bilateral vestibular loss, and 40 had mild-to-moderate vestibular loss. As severity of vestibular loss increased, children (a) sat and walked later, (b) scored more poorly on the Developmental Profile-3 physical subscale, (c) had more severe hearing loss, (d) had parents who more frequently reported concern for gross motor delay, and (e) were more likely to have other comorbidities. Of these factors, age-to-sit, age-to-walk, PTA, and parental concerns for gross motor developmental delay had the greatest ability to differentiate children with vestibular loss from children with normal vestibular function. For age-to-sit, using a cutoff value of 7.25 months yielded a sensitivity of 62% and a specificity of 81%. For age-to-walk, a cutoff value of 14.5 months yielded a sensitivity of 78% and a specificity of 77%. For PTA for the neurosensory genetics group, a cutoff value of 40 dB yielded a sensitivity of 80% and a specificity of 55%; however, a cutoff value of 66 dB yielded a sensitivity of 33% and an improved specificity of 91%.

Conclusions

A referral for vestibular evaluation should be considered for children whose hearing loss is greater than 66 dB and particularly those who sit later than 7.25 months or walk later than 14.5 months or whose parents report concerns for gross motor development. Collectively, these factors appear to be more sensitive for identifying children with bilateral vestibular loss compared with children with mild-to-moderate vestibular loss. Because of the benefit of physical therapy, children identified with vestibular loss should then be referred to physical therapy for further evaluation and treatment.

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Structured Review of Dichotic Tests of Binaural Integration: Clinical Performance in Children

Purpose

The aim of the study was to evaluate the evidence of clinical utility for dichotic speech tests of binaural integration used to assess auditory processing in English-speaking children 6–14 years old.

Method

Dichotic speech test recordings and pertinent research studies were identified from iterative searches of the Internet and bibliographic databases, as well as communication with colleagues and test publishers. Test documentation and peer-reviewed literature were evaluated for evidence of reliability, accuracy, usefulness, and value.

Results

Eleven dichotic tests of binaural integration were identified for children. Evidence of test–retest reliability was found for 5 tests and demonstrated moderate to good correlation between results on repeated administration (r = .59–.92). Evidence of accuracy was identified for 5 tests but was either inconsistent with accurate performance or was not generalizable due to significant limitations in study design. No evidence was found to either support or dispute claims of usefulness or value.

Conclusions

A medical diagnostic framework is useful for evaluating dichotic tests. Although dichotic procedures show moderate reliability, the absence of a widely accepted gold standard reference test limits our ability to assess their value. Overall, the data available at the time of this review do not support the routine use of dichotic tests of binaural integration for clinical evaluation of children.

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Validation of the Chinese Sound Test: Auditory Performance of Hearing Aid Users

Purpose

The Chinese Sound Test (Hung, Lin, Tsai, & Lee, 2016) has been recently developed as a modified version of the Ling Six-Sound Test (Ling, 2012). By incorporating Chinese speech sounds, this test should be able to estimate whether the listener can hear across the Chinese speech spectrum. To establish the clinical validity of the test, this study examined the relationship between the aided audiometric thresholds and the distance thresholds.

Method

Sixty children with bilateral hearing aids were recruited. The aided sound-field thresholds at 250, 500, 1000, 2000, 4000, and 6000 Hz were compared with the distance thresholds of six sounds, /u, ə, a, i, tɕʰ, and s/, which encompass the entire Chinese speech frequency range from low to high.

Results

Partial correlation and stepwise regression analyses revealed that the Chinese testing sounds are frequency specific and that the audibility of each sound could be predicted by a specific frequency threshold.

Conclusions

The results confirm the validity of the Chinese Sound Test, indicating that the testing sounds can be reliably used to assess the perception of frequency-specific information. Crucially, these data also demonstrate that the Chinese Sound Test is a useful tool to identify red flags of poor auditory access in daily environment to monitor device malfunctions and possible hearing fluctuations.

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Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibition

Abstract

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.

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Too good to be true

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Does Parkinson's disease start in the gut?

ABSTRACT Current understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies.

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RESUMO O atual entendimento sobre a fisiopatologia da doença de Parkinson (DP) sugere um papel central do acúmulo de alfa-sinucleína na patogenia da DP Esta revisão crítica revisita marcos, teorias e controvérsias a respeito da origem e progressão da sinucleinopatia, apresentando uma atualização das principais evidências sugerindo que o sistema nervoso entérico seria o local inicial deste processo. Apesar das evidências a favor desta teoria serem crescentes e instigantes, as lacunas de conhecimento a este respeito são importantes pontos para estudos futuros.

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Chronic treatment with carvacrol improves passive avoidance memory in a rat model of Parkinson's disease

ABSTRACT The present study investigated the effects of carvacrol on motor and memory deficits as well as hyperalgesia in the 6-OHDA-lesioned rat model of Parkinson's disease. The animals were subjected to unilateral microinjection of 6-OHDA into the medial forebrain bundle and treated with carvacrol (25, 50 and 100 mg/kg, ip) for six weeks after surgery. The 6-OHDA-lesioned rats showed contralateral rotations towards the lesion side, which was accompanied by learning and memory deficits in a passive avoidance test and a decrease in tail withdrawal latency in a tail flick test at the end of week 6. The results also showed that treatment with carvacrol at a dose of 25 mg/kg ameliorated memory deficits, with no effect on rotations and hyperalgesia in lesioned rats. In conclusion, carvacrol improves memory impairments in rats with Parkinson's disease; therefore, it may serve as an adjunct therapy for the alleviation of memory deficits in Parkinson's disease patients.

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RESUMO O presente estudo investigou os efeitos do carvacrol nos déficits motores e de memória, bem como na hiperalgesia, em um modelo da doença de Parkinson (DP) em ratos com lesões 6-OHDA. Os animais foram submetidos a microinjeção unilateral de 6-OHDA no feixe mediano do prosencéfalo e tratados com carvacrol (25, 50 e 100 mg / kg, ip) durante 6 semanas após a cirurgia. Os ratos com lesões 6-OHDA mostraram rotações contralaterais para o lado da lesão, que foram acompanhadas de déficits de aprendizagem e de memória em um teste de evitação passiva, e de uma diminuição da latência de retirada da cauda em um teste de cauda no final da semana 6. Os resultados também mostraram que o tratamento crônico com carvacrol a uma dose de 25 mg / kg aliviou os déficits de memória, sem efeito sobre rotações e hiperalgesia em ratos lesados. Em conclusão, o carvacrol melhora a deficiência de memória em ratos com DP e, portanto, pode servir como uma terapia complementar para aliviar os déficits de memória em pacientes com DP.

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Effect of virtual reality in Parkinson's disease: a prospective observational study

ABSTRACT Objective: To assess the effectiveness of balance exercises by means of virtual reality games in Parkinson's disease. Methods: Sixteen patients were submitted to anamnesis, otorhinolaryngological and vestibular examinations, as well as the Dizziness Handicap Inventory, Berg Balance Scale, SF-36 questionnaire, and the SRT, applied before and after rehabilitation with virtual reality games. Results: Final scoring for the Dizziness Handicap Inventory and Berg Balance Scale was better after rehabilitation. The SRT showed a significant result after rehabilitation. The SF-36 showed a significant change in the functional capacity for the Tightrope Walk and Ski Slalom virtual reality games (p < 0.05), as well as in the mental health aspect of the Ski Slalom game (p < 0.05). The Dizziness Handicap Inventory and Berg Balance Scale showed significant changes in the Ski Slalom game (p < 0.05). There was evidence of clinical improvement in patients in the final assessment after virtual rehabilitation. Conclusion: The Tightrope Walk and Ski Slalom virtual games were shown to be the most effective for this population.

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RESUMO Objetivo: Verificar a eficácia dos exercícios de equilíbrio com realidade virtual (RVi) na doença de Parkinson. Métodos: Dezesseis pacientes foram submetidos a uma anamnese, exames otorrinolaringológico e vestibular, ao Dizziness Handicap Inventory (DHI), Escala de Equilíbrio de Berg (EEB), questionário SF-36 e o Teste de Sentar e Levantar (TSL) que foram aplicados antes e após a reabilitação com RVi. Resultados: Os resultados dos escores finais do DHI e EEB foram melhores após a reabilitação. O TSL apresentou resultado significativo após a reabilitação. O SF-36 demonstrou alteração significativa da capacidade funcional para os jogos Tightrope Walk e Ski Slalom (p < 0,05) e da saúde mental para o jogo Ski Slalom (p < 0,05). O DHI e EEB apresentaram alterações significativas no jogo Ski Slalom (p < 0,05). Houve melhora clínica evidente dos pacientes após reabilitação virtual. Conclusão: Os jogos virtuais Tightrope Walk e o Ski Slalom foram os mais eficazes.

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Driving and visual deficits in stroke patients

ABSTRACT Objective: The aim of the present study was to conduct an exploratory assessment of visual impairment following stroke, and to discuss the possibilities of reintroducing patients to the activity of driving. Methods: The Useful Field of View test was used to assess visual processing and visual attention. Results: A total of 18 patients were included in the study, and were assigned to either the drive group (n = 9) or the intention group (n = 9). In the drive group, one patient was categorized as moderate-to-high risk; whereas, in the intention group, one patient was categorized as low-to-moderate risk. Additionally, two patients in the intention group were categorized as high risk. The patients did not perceive their visual deficits as a limitation. Conclusion: Visual attention is an interference factor in terms of the safe performance of driving after a stroke. All patients showed a high level of interest for the independence provided through being able to drive.

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RESUMO Objetivo: O objeto deste estudo foi realizar uma avaliação exploratória de déficits visuais decorrentes do AVC e discutir possibilidades de retorno à direção de automóveis. Métodos: Estudo descritivo e observacional. O software UFOV foi utilizado para avaliar o processamento visual e atenção visual. Resultados: Um total de 18 pacientes foram incluídos no estudo, classificados em Grupo Direção – GD (n = 9) e Grupo Pretensão – GP (n = 9). No GD, um paciente foi classificado em moderado a alto risco de acidentes, e um paciente do GP em baixo a moderado risco. Especificamente, no grupo GP dois pacientes foram classificados em alto risco de acidentes. Pacientes não reconhecem os déficits visuais como dificuldades. Conclusão: Atenção visual é um fator de interferência no desempenho seguro da direção após o AVC. Todos os pacientes mostraram alto interesse na independência oferecida pela direção de automóveis.

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Relationship between visuospatial episodic memory, processing speed and executive function: are they stable over a lifespan?

ABSTRACT The present study evaluated the association between episodic memory, executive function and processing speed in a sample with different age ranges. We tested the hypothesis that processing speed, executive function and memory are more strongly associated during childhood and old age. We evaluated 571 participants, aged six to 92 years, divided into four age groups: children/adolescents, young adults, middle-aged adults and older adults. Correlation analyses suggested that the shared variance between the processing speed and memory is strong in childhood but weak across other age ranges. Executive function, however, had a stronger association both in childhood and in old age, when compared with the intermediate stages. We conclude that the effects of processing speed and executive function on memory are not stable across human development. These functions may be compensatory mechanisms for memory functioning in childhood and old age.

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RESUMO O presente estudo avalia a associação entre velocidade de processamento, funções executivas e memória em uma amostra de diferentes faixas etárias. O estudo testa a hipótese de que a velocidade de processamento, as funções executivas e a memória apresentam associação mais forte na infância e na velhice. Avaliamos 571 participantes, com idade entre seis e 92 anos, divididos em quatro grupos etários: crianças/adolescentes, adultos jovens, adultos de meia-idade e idosos. Análises de correlação sugerem que a variância compartilhada entre velocidade de processamento e memória é forte na infância e fraca nas demais idades. Já as funções executivas apresentaram associação forte com a memória tanto na infância quanto na velhice, quando comparadas aos estágios intermediários. Concluímos que os efeitos da atenção sobre a memória variam em função da idade do participante. Essas funções podem ser mecanismos compensatórios para a memória ao longo do desenvolvimento.

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Naming and verbal learning in adults with Alzheimer's disease, mild cognitive impairment and in healthy aging, with low educational levels

ABSTRACT Language assessment seems to be an effective tool to differentiate healthy and cognitively impaired aging groups. This article discusses the impact of educational level on a naming task, on a verbal learning with semantic cues task and on the MMSE in healthy aging adults at three educational levels (very low, low and high) as well as comparing two clinical groups of very low (0-3 years) and low education (4-7 years) patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) with healthy controls. The participants comprised 101 healthy controls, 17 patients with MCI and 19 with AD. Comparisons between the healthy groups showed an education effect on the MMSE, but not on naming and verbal learning. However, the clinical groups were differentiated in both the naming and verbal learning assessment. The results support the assumption that the verbal learning with semantic cues task is a valid tool to diagnose MCI and AD patients, with no influence from education.

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RESUMO A linguagem tem se mostrado uma ferramenta eficiente para diferenciar grupos de idosos saudáveis dos com deficiências cognitivas. O artigo objetiva discutir o impacto do nível educacional na nomeação, na aprendizagem verbal (AV) com pistas semânticas e no MEEM no envelhecimento saudável em três níveis de escolaridade (muito baixa: 0-3 anos, baixa: 4-7 anos e alta: >8 anos) e em dois grupos clínicos de escolaridade muito baixa e baixa (Doença de Alzheimer – DA – e Comprometimento Cognitivo Leve - CCL), comparados a controles saudáveis. Participaram 101 controles, 17 CCL e 19 DA. Comparações entre grupos saudáveis demonstraram um efeito da escolaridade no MEEM, mas não nas tarefas de nomeação e de AV. Considerando as comparações entre os grupos clínicos, tanto a nomeação quanto a AV os diferenciaram. Os resultados corroboram a pressuposição de que a tarefa de AV com pistas semânticas é válida para diagnosticar CCL e DA, não sendo influenciada pela escolaridade.

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Traumatic brain injury pharmacological treatment: recommendations

ABSTRACT This article presents the recommendations on the pharmacological treatment employed in traumatic brain injury (TBI) at the outpatient clinic of the Cognitive Rehabilitation after TBI Service of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. A systematic assessment of the consensus reached in other countries, and of articles on TBI available in the PUBMED and LILACS medical databases, was carried out. We offer recommendations of pharmacological treatments in patients after TBI with different symptoms.

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RESUMO Este artigo apresenta as recomendações sobre o tratamento farmacológico empregado para o traumatismo cranioencefálico (TCE) em pacientes ambulatoriais de Reabilitação Cognitiva pós-TCEno Serviço do HCFMUSP Foi realizada uma avaliação sistemática dos consensos publicados em outros países e dos artigos sobre TCE disponíveis nas bases de periódicos médicos como PUBMED e LILACS. Recomendamos tratamentos farmacológicos em pacientes pós-TCE com diferentes sintomas.

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A new motor screening assessment for children at risk for motor disorders: construct validity

ABSTRACT Objective: To develop a motor screening assessment and provide preliminary evidence of its psychometric properties. Methods: A sample of 365 elementary school students was assessed, with structural equation modeling applied to obtain evidence of the adequacy of the factor structure of the motor screening assessment. As well, differential item functioning was used to evaluate whether various identifiable subgroups of children (i.e., sex and grade) perform particular tasks differently. Results: Overall, girls obtained higher scores than boys while, for both sexes, the assessment scores increased with age. Furthermore, differential item function analysis revealed that the precision of the test was highest for those with moderate to low motor performance, suggesting that this tool would be appropriate for identifying individuals with movement difficulties. Conclusion: Although further tests of its psychometric properties are required, the motor screening assessment appears to be a reliable, valid, and quickly-administered tool for screening children's movements.

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RESUMO Objetivo: Desenvolver uma avaliação de triagem motora (ATM) e fornecer evidências preliminares de suas propriedades psicométricas. Métodos: 365 alunos do ensino fundamental foram avaliados. Foi utilizado modelagem de equações estruturais para evidenciar a adequação da estrutura fatorial da ATM. A função diferencial do item foi utilizada para avaliar tarefas podem funcionar de forma diferente para subgrupos (ou seja, sexo e escolaridade). Resultados: Em geral, as meninas obtiveram pontuações mais altas do que os meninos e, em ambos os sexos, os escores da avaliação aumentaram com a idade. A análise da função diferencial do item revelou que a precisão do teste foi maior para aqueles com desempenho motor baixo a moderado, sugerindo que essa ferramenta seria apropriada para identificar aqueles com dificuldades motoras. Conclusão: Embora sejam necessários novos testes de suas propriedades psicométricas, a ATM parece ser uma ferramenta confiável, válida e rápida de administrar como rastreio motor para crianças.

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Guillain, Barraquer and I

ABSTRACT The year 2016 was the centennial anniversary of the recognition of the Guillain-Barré syndrome, which was first described by George Guillain, Jean-Alexandre Barré and André Strohl. In celebration of the centennial, this historical review describes aspects of the contributions of Guillain and the Spanish neurologist, Barraquer-Bordas and a brief account of the Fourth International Neurological Congress, which brought together Guillain and Barraquer-Bordas. There were many outstanding Brazilian physicians at that meeting. Finally, the author describes his interaction with Barraquer-Bordas and provides an account of his influence in shaping a generation of Brazilian neurologists, including himself.

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RESUMO O ano de 2016 foi o aniversário do centenário do reconhecimento da síndrome de Guillain-Barré (GBS), que foi descrita pela primeira vez por George Guillain, Jean-Alexandre Barré e André Strohl. Em comemoração ao centenário, esta revisão histórica descreve aspectos das contribuições de Guillain e Barraquer-Bordas e uma breve descrição do IV Congresso Neurológico Internacional, que reuniu Guillain e o neurologista espanhol Barraquer-Bordas. Naquela reunião houve participação também de excelentes médicos brasileiros. Finalmente, o autor descreve sua interação com Barraquer-Bordas e fornece uma descrição de sua influência na formação de uma geração de neurologistas brasileiros, incluindo ele próprio.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2GMnYJ3