Radiation therapy will always alter skin in breast cancer treatment

No abstract available

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Intestinal-type adenocarcinoma of the sinonasal tract: an update

Purpose of review Intestinal-type adenocarcinoma (ITAC) is one of the most frequent sinonasal tumors, especially in European countries. The purpose of this article is to review the most recent literature, with special emphasis on biological and genetic profile and treatment guidelines. Recent findings Results on large series support transnasal endoscopic surgery as the technique of choice in the large majority of patients with ITAC. Adjuvant radiotherapy is recommended in advanced-stage and high-grade lesions. More robust data are required to confirm that early-stage, low-grade lesions can be treated with exclusive surgery. The efficacy of new chemotherapy and biotherapy regimens and the added value of heavy particle radiotherapy are currently under evaluation. With a 5-year overall survival ranging between 53 and 83%, which is mainly impacted by local recurrences, ITAC requires a more detailed understanding of its biology. Genetic and biological studies have identified alterations in the molecular pathways of EGFR, MET, and H-RAS which might be considered as potential targets for biotherapy. Summary Surgery still plays a key role in the treatment of ITAC, but multidisciplinary management is mandatory. Although further validation is needed, the role of nonsurgical treatment strategies is rising, in agreement with the progresses made in the biological profiling of the disease. Correspondence to Piero Nicolai, MD, Unit of Otorhinolaryngology, Spedali Civili of Brescia, University of Brescia, Piazza Spedali Civili, 1, 25123 Brescia, Italy. Tel: +39 0303995319; fax: +39 030395212; e-mail: pieronicolai@virgilio.it Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Strength Training Effects on Muscular Regeneration after ACL Reconstruction

ABSTRACTPurposeProtracted quadriceps muscle atrophy is observed after anterior cruciate ligament reconstruction (ACL-R). The aim of this study was to assess if quadriceps strength training with eccentric overload (CON/ECC+) is more efficient to induce muscle regeneration after ACL-R than conventional concentric/eccentric (CON/ECC) strength training.MethodsBiopsies from the vastus lateralis muscle were obtained from 37 recreational athletes after 12 weeks of regular rehabilitation following ACL-R and again after 12 weeks with twice a week either conventional CON/ECC (n = 16) or CON/ECC+ (n = 21) one-legged supervised leg-press training. Immunohistochemical analyses were used to determine satellite cell number (SC, Pax7+), activated SCs (Pax7+/MyoD+), fibers expressing myosin heavy chain (MHC) I, II and neonatal, fiber cross sectional area (FCSA). Magnetic resonance imaging was performed to measure quadriceps cross sectional area (MCSA) and isokinetic testing for the measurement of quadriceps strength.ResultsCON/ECC+ induced a significantly (p = 0.002) greater increase in MCSA than CON/ECC. There also was a significant increase in the FCSAs of all fiber types and in quadriceps strength, however, without significant difference between training groups. Only CON/ECC+ training lead to a significant (p

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Walls or Bridges: “No Gobbledygook”: The International Psycho-Oncology Society 2017 Sutherland Award Lecture

Abstract

Illness, health and wellness happens in social contexts. The present political environment is highly divisive and plays to the most primitive fears of people. Never have the stakes been so high. History is replete with putative leaders who create walls that separate people in ways that inevitably leads to dehumanization, suffering and eventually violence. Timely and openly shared psychosocial insights by experts in mental health into the evil consequences of "wall builders" are essential to the physical, mental and spiritual health of individuals and nations. For health care professionals (in particular) to ignore the dangers posed by the ill equipped self-serving leaders who now dominate the news and exploit the dark psyche of the world stage, would be at the very least unethical and at worst collusion in repeating the sins of the past. This article first recognizes the impact of leaders who, at great personal costs, have built bridges (with relentless compassion and courage) where only chasms existed before. Although international politics may seem like a universe away, in which people may (erroneously) feel powerless to influence change, our home health care settings can be dramatically improved and humanized by the application of universally accepted humanistic values. Health care, as it is practiced today, is an anachronism at multiple levels. Supportive care in general and psychosocial values specifically offer a more inclusive and realistic alternative. Based on an inclusive staff leadership model, a strategic, hands-on, practical and compassionate approach to creating and implementing supportive care programs of excellence is described. Finally, potentially fruitful areas in which supportive care and psychosocial values can provide leadership as bridges to more accessible, affordable and humanistic care are provided for contemplation.

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Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer: is it ready for primetime?

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Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study

Abstract

Background

Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent anti-mitotic agent, monomethyl auristatin E (MMAE), which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug-conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients.

Patients and Methods

Platinum-resistant OC patients were randomized to receive LIFA (2.4 mg/kg, intravenously, every 3 weeks [Q3W]), or pegylated liposomal doxorubicin (PLD) (40 mg/m², intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary endpoint was progression-free survival (PFS) in intent to treat (ITT) and NaPi2b-high patients.

Results

Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 (95% CI, 0.46–1.31; p=0.34) with a median PFS of 5.3 vs. 3.1 months (LIFA vs. PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40–1.26; p=0.24) with a median PFS of 5.3 vs. 3.4 months (LIFA vs. PLD arm, respectively) in NaPi2b-high patients. The objective response rate (ORR) was 34% (95% CI, 22–49%, LIFA) vs. 15% (95% CI, 7–28%, PLD) in the ITT population (p=0.03), and 36% (95% CI, 22–52%, LIFA) vs.14% (95% CI, 6–27%, PLD) in NaPi2b-high patients (p=0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA vs. 2 (4%) PLD patients had grade ≥ 2 neuropathy.

Conclusion

Lifastuzumab vedotin Q3W was well-tolerated and improved ORR with a modest, non-statistically significant improvement of PFS compared to PLD in platinum-resistant OC. While the response rate for the MMAE-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADC's in OC.

Clinical trials.gov

NCT01991210

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Results of a multi-institutional, randomized, non-inferiority, phase 3 trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group study (JCOG0701)

Background

We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC).

Patients and Methods

In this multi-institutional, randomized, phase 3 trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1 − 2N0M0, age 20 − 80, Eastern Cooperative Oncology Group (ECOG) performance status of 0 − 1, and adequate organ function. Patients were randomly assigned to receive either SF of 66 − 70 Gy (33 − 35 fractions), or AF of 60 − 64.8 Gy (25 − 27 fractions). The primary endpoint was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%.

Results

Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4 − 85.4) for SF and 81.7% (95% CI 75.4 − 87.0) for AF (difference 1.8%, 91% CI 5.1%−8.8%; one-sidedP = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year OS between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1(0.5%)) in the SF/AF arms.

Conclusion

Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared to SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. UMIN000000819

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Outcomes of Donation After Cardiac Death Liver Grafts from Donors ≥ 50 years of Age: A Multi-center Analysis

ABSTRACTIntroductionAs the population in the United States continues to age, an increase in the number of potential DCD donors with advanced chronological age can be expected. The aim of this study was to analyze a multi-institutional experience in liver transplantation using DCD donor age ≥50 years.MethodsAll DCD LT performed at Mayo Clinic Florida, Mayo Clinic Rochester and Mayo Clinic Arizona from 2002-2016 were included. Recipients of DCD LT were divided into 2 groups: those with donor age ≥50 years(N=155) and those with donor age

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Inequalities in zoster disease burden: a population-based cohort study to identify social determinants using linked data from the UK Clinical Practice Research Datalink

Abstract

Background

Zoster vaccination was introduced in England in 2013, where tackling health inequalities is a statutory requirement. However, specific population groups with higher zoster burden remain largely unidentified.

Objective

To evaluate health inequalities in zoster disease burden prior to zoster vaccine introduction in England.

Methods

This population-based cohort study utilised anonymised UK primary care data linked to hospitalisation and deprivation data. Individuals aged ≥65 years without prior zoster history (N=862,470) were followed from 01/09/2003-31/08/2013. Poisson regression was used to obtain adjusted rate ratios (ARR) for the association of socio-demographic factors (ethnicity, immigration status, individuals' area-level deprivation, care home residence, living arrangements) with first zoster episode. Possible mediation by co-morbidities and immunosuppressive medications was also assessed.

Results

There were 37,014 first zoster episodes, with incidence of 8.79 (95% confidence interval (CI):8.70-8.88) per 1,000 person-years at risk. In multivariable analyses, factors associated with higher zoster rates included care home residence (10% higher versus those not in care homes), being female (16% higher versus males), non-immigrants (~30% higher than immigrants) and White ethnicity (for example, twice the rate compared to those of Black ethnicity). Zoster incidence decreased slightly with increasing deprivation (ARR most versus least deprived=0.96 (95%CI:0.92-0.99) and among those living alone (ARR 0.96 (95%CI:0.94-0.98). Mediating variables made little difference to the ARR of social factors but were themselves associated with increased zoster burden (ARR varied from 1.11-3.84).

Conclusions

The burden of zoster was higher in specific socio-demographic groups. Further study is needed to ascertain whether these individuals are attending for zoster vaccination.

This article is protected by copyright. All rights reserved.

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Using Rasch Analysis to Evaluate the Reliability and Validity of the Swallowing Quality of Life Questionnaire: An Item Response Theory Approach

Abstract

The Swallowing Quality of Life questionnaire (SWAL-QOL) is widely used clinically and in research to evaluate quality of life related to swallowing difficulties. It has been described as a valid and reliable tool, but was developed and tested using classic test theory. This study describes the reliability and validity of the SWAL-QOL using item response theory (IRT; Rasch analysis). SWAL-QOL data were gathered from 507 participants at risk of oropharyngeal dysphagia (OD) across four European countries. OD was confirmed in 75.7% of participants via videofluoroscopy and/or fiberoptic endoscopic evaluation, or a clinical diagnosis based on meeting selected criteria. Patients with esophageal dysphagia were excluded. Data were analysed using Rasch analysis. Item and person reliability was good for all the items combined. However, person reliability was poor for 8 subscales and item reliability was poor for one subscale. Eight subscales exhibited poor person separation and two exhibited poor item separation. Overall item and person fit statistics were acceptable. However, at an individual item fit level results indicated unpredictable item responses for 28 items, and item redundancy for 10 items. The item-person dimensionality map confirmed these findings. Results from the overall Rasch model fit and Principal Component Analysis were suggestive of a second dimension. For all the items combined, none of the item categories were 'category', 'threshold' or 'step' disordered; however, all subscales demonstrated category disordered functioning. Findings suggest an urgent need to further investigate the underlying structure of the SWAL-QOL and its psychometric characteristics using IRT.

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Effects of Early- and Late-Arriving Room Reflections on the Speech-Evoked Auditory Brainstem Response

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Predictive Accuracy of Sweep Frequency Impedance Technology in Identifying Conductive Conditions in Newborns

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Survey of Current Practice in the Fitting and Fine-Tuning of Common Signal-Processing Features in Hearing Aids for Adults

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The Parsing Syllable Envelopes Test for Assessment of Amplitude Modulation Discrimination Skills in Children: Development, Normative Data, and Test‐Retest Reliability Studies

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Test‐Retest Reliability of Dual-Recorded Brainstem versus Cortical Auditory-Evoked Potentials to Speech

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Higher Asymmetry Ratio and Refixation Saccades in Individuals with Motion Sickness

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Cervical Vestibular Evoked Myogenic Potential in Hypoglossal Nerve Schwannoma: A Case Report

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Blocking the Feedback Loop between Neuroendocrine Differentiation and Macrophages Improves the Therapeutic Effects of Enzalutamide (MDV3100) on Prostate Cancer

Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.

Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.

Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.

Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708–23. ©2017 AACR.

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Surviving Ovarian Cancer: An Affair between Defective DNA Repair and RB1

Detailed clinical and molecular evaluation of large cohorts of exceptional survivors provides an unprecedented opportunity to identify mechanisms underlying long-term survival that can drive future therapeutic approaches and biomarker development. Exceptional survivors of high-grade serous ovarian cancer demonstrate concurrent disruption of homologous recombination DNA repair and retinoblastoma protein. Clin Cancer Res; 24(3); 508–10. ©2017 AACR.

See related article by Garsed et al., p. 569

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Systemic Antitumor Immunity by PD-1/PD-L1 Inhibition Is Potentiated by Vascular-Targeted Photodynamic Therapy of Primary Tumors

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors, including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition.

Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies and then examined treatment responses, including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed.

Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases, and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8⁺:regulatory T cell (Treg) and CD4⁺FoxP3-:Treg ratios in primary renal tumors and increased T-cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts.

Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone. Clin Cancer Res; 24(3); 592–9. ©2017 AACR.

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Breast Cancer Immunotherapy: Facts and Hopes

Immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of programmed cell death-1/programmed death ligand-1 (PD-1/PD-L1) antagonists in small numbers of patients with metastatic breast cancer. Clinical activity appears more likely if the tumor is triple negative, PD-L1⁺, and/or harbors higher levels of tumor-infiltrating leukocytes. Responses to atezolizumab and pembrolizumab appear to be durable in metastatic triple-negative breast cancer (TNBC), suggesting that these agents may transform the lives of responding patients. Current clinical efforts are focused on developing immunotherapy combinations that convert nonresponders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy. Identifying biomarkers that can predict the potential for response to single-agent immunotherapy, identify the best immunotherapy combinations for a particular patient, and guide salvage immunotherapy in patients with progressive disease are high priorities for clinical development. Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving us closer to effective immunotherapy for almost all patients with breast cancer. Clin Cancer Res; 24(3); 511–20. ©2017 AACR.

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Intratumoral HPV16-Specific T Cells Constitute a Type I-Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer

Purpose: Human papillomavirus (HPV)–associated oropharyngeal squamous cell cancer (OPSCC) has a much better prognosis than HPV-negative OPSCC, and this is linked to dense tumor immune infiltration. As the viral antigens may trigger potent immunity, we studied the relationship between the presence of intratumoral HPV-specific T-cell responses, the immune contexture in the tumor microenvironment, and clinical outcome.

Experimental Design: To this purpose, an in-depth analysis of tumor-infiltrating immune cells in a prospective cohort of 97 patients with HPV16-positive and HPV16-negative OPSCC was performed using functional T-cell assays, mass cytometry (CyTOF), flow cytometry, and fluorescent immunostaining of tumor tissues. Key findings were validated in a cohort of 75 patients with HPV16-positive OPSCC present in the publicly available The Cancer Genome Atlas database.

Results: In 64% of the HPV16-positive tumors, type I HPV16-specific T cells were present. Their presence was not only strongly related to a better overall survival, a smaller tumor size, and less lymph node metastases but also to a type I–oriented tumor microenvironment, including high numbers of activated CD161⁺ T cells, CD103⁺ tissue-resident T cells, dendritic cells (DC), and DC-like macrophages.

Conclusions: The viral antigens trigger a tumor-specific T-cell response that shapes a favorable immune contexture for the response to standard therapy. Hence, reinforcement of HPV16-specific T-cell reactivity is expected to boost this process. Clin Cancer Res; 24(3); 634–47. ©2017 AACR.

See related commentary by Laban and Hoffmann, p. 505

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Validation of Immunohistochemical Assays for Integral Biomarkers in the NCI-MATCH EAY131 Clinical Trial

Biomarkers that guide therapy selection are gaining unprecedented importance as targeted therapy options increase in scope and complexity. In conjunction with high-throughput molecular techniques, therapy-guiding biomarker assays based upon immunohistochemistry (IHC) have a critical role in cancer care in that they inform about the expression status of a protein target. Here, we describe the validation procedures for four clinical IHC biomarker assays—PTEN, RB, MLH1, and MSH2—for use as integral biomarkers in the nationwide NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) EAY131 clinical trial. Validation procedures were developed through an iterative process based on collective experience and adaptation of broad guidelines from the FDA. The steps included primary antibody selection; assay optimization; development of assay interpretation criteria incorporating biological considerations; and expected staining patterns, including indeterminate results, orthogonal validation, and tissue validation. Following assay lockdown, patient samples and cell lines were used for analytic and clinical validation. The assays were then approved as laboratory-developed tests and used for clinical trial decisions for treatment selection. Calculations of sensitivity and specificity were undertaken using various definitions of gold-standard references, and external validation was required for the PTEN IHC assay. In conclusion, validation of IHC biomarker assays critical for guiding therapy in clinical trials is feasible using comprehensive preanalytic, analytic, and postanalytic steps. Implementation of standardized guidelines provides a useful framework for validating IHC biomarker assays that allow for reproducibility across institutions for routine clinical use. Clin Cancer Res; 24(3); 521–31. ©2017 AACR.

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Utility of Radionuclide Bone Scintigraphy in Complex Regional Pain Syndrome

Abstract

Purpose of Review

To describe the current understanding of the role of three-phase bone scintigraphy (TPBS) in the diagnosis and management of complex regional pain syndrome (CRPS), discuss its advantages and limitations, and present three examples of TPBS patterns typically seen in CRPS patients.

Recent Findings

CRPS is a debilitating disorder frequently presenting with pain to ordinarily non-painful stimuli, redness, swelling, following fractures, stroke, myocardial infarction, surgery, or even minor trauma, and its diagnosis, based on clinical criteria and supportive imaging findings, is difficult. Of the available adjunctive diagnostic imaging modalities, radionuclide bone scintigraphy using a TPBS protocol is the most sensitive and specific for detecting abnormalities commonly seen with this condition—classically, increased periarticular uptake on delayed phase of TPBS, with variable increased uptake on perfusion phases, depending on chronicity. Recent studies have (1) demonstrated a more heterogeneous correlation of TPBS findings with CRPS diagnosis using the current Budapest criteria than in studies using older criteria, (2) pointed to the utility of novel quantitative scintigraphic techniques, and (3) highlighted the value of the early perfusion phases of TPBS in predicting treatment response.

Summary

TPBS remains a valuable imaging adjunct to clinical diagnosis of CRPS. In combination with a multi-modal analgesic approach, TPBS can be used to follow disease course and potentially treatment response, although prospective trials are needed to further delineate its role.

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Medical Cannabis for Neuropathic Pain

Abstract

Purpose of Review

Many cultures throughout history have used cannabis to treat a variety of painful ailments. Neuropathic pain is a complicated condition that is challenging to treat with our current medications. Recent scientific discovery has elucidated the intricate role of the endocannabinoid system in the pathophysiology of neuropathic pain. As societal perceptions change, and legislation on medical cannabis relaxes, there is growing interest in the use of medical cannabis for neuropathic pain.

Recent Findings

We examined current basic scientific research and data from recent randomized controlled trials (RCTs) evaluating medical cannabis for the treatment of neuropathic pain. These studies involved patients with diverse etiologies of neuropathic pain and included medical cannabis with different THC concentrations and routes of administration. Multiple RCTs demonstrated efficacy of medical cannabis for treating neuropathic pain, with number needed to treat (NNT) values similar to current pharmacotherapies.

Summary

Although limited by small sample sizes and short duration of study, the evidence appears to support the safety and efficacy of short-term, low-dose cannabis vaporization and oral mucosal delivery for the treatment of neuropathic pain. The results suggest medical cannabis may be as tolerable and effective as current neuropathic agents; however, more studies are needed to determine the long-term effects of medical cannabis use. Furthermore, continued research to optimize dosing, cannabinoid ratios, and alternate routes of administration may help to refine the therapeutic role of medical cannabis for neuropathic pain.

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High Dose of A Conjugated Linoleic Acid Mixture Increases Insulin Resistance in Rats Fed Either A Low Fat or A High Fat Diet

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-118348

Obesity and related diseases are becoming more prevalent. Conjugated linoleic acid (CLA) might be a useful coadjutant treatment helping to decrease fat mass. However, the precise impact of CLA is unclear because the decreased body fat mass is followed by an increase in insulin resistance. This study aimed to evaluate some of the consequences of a high dose of CLA in rats fed a normal low fat or a high fat diet for 30 days. Male Wistar rats were separated into 4 groups (each n = 10): Control group receiving 7% fat (soybean oil); CLA group receiving 4% soybean oil and 3% CLA mixture; animal fat (AF) group, receiving 45% fat (lard); and animal fat plus CLA (AF+CLA) group, receiving 42% lard and 3% CLA mixture. The CLA mixture contained 39.32 mole% c9,t11-CLA and 40.50 mole% t10,c12-CLA. After 30 days, both CLA groups (CLA and AF+CLA groups) developed insulin resistance, with an increase in glucose in the fasting state and in an insulin tolerance test. The CLA group had increased liver weight and percentage of saturated fatty acids in liver and adipose tissue. Feeding the high fat diet resulted in increased hepatic triacylglycerol accumulation and this was exacerbated by dietary CLA. It is concluded that a high dose of CLA mixture increases insulin resistance and exacerbates hepatic steatosis when combined with a high fat diet.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Early Stage Graves’ Disease is Uniformly Accompanied by Orbital Immune Activity even in Patients who Fail to Develop Orbithopathy during Follow-up

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-125065

Purpose Graves' orbitopathy (GO) is a complication of Graves' disease (GD), the development of which cannot be predicted at the time of diagnosis of GD. Our aims were (i) to test if orbital 99mTc-labelled diethylenetriamine pentaacetic acid single-photon emission computer tomography (DTPA SPECT) can predict development of GO later during the course of the disease and (ii) to study whether orbital immune activity can be detected in GD patients who do not develop GO during follow-up. Methods Fifty-four orbits of 27 patients with newly diagnosed GD were entered into the case-control study. Individuals showing signs of GO at enrolment were excluded. During the two-year follow-up, eye signs were recorded every 3 months. Orbital DTPA uptakes on SPECT images were measured when entering the study and at the end of the follow-up period, or when clinical signs of GO developed, whichever occurred first. Results During the follow-up, 6 patients (22%) were diagnosed with GO. There was no significant difference between the initial DTPA uptakes of the patients with or without later developing GO (10.45±1.72 MBq/cm3 vs. 9.18±1.18 MBq/cm3 respectively). However, the DTPA uptakes of both GD groups (ie. with and without GO) were higher than that of the control group (7.45±1.36 MBq/cm3, p<0.05). Conclusions We have shown that GD is accompanied by moderate orbital immune activity in GD patients without GO, irrespective of later development of GO. Why this orbital autoimmunity remains subclinical in the majority of the cases, and progresses into clinically detectable GO in others, remains unclear.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0044-100722

Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models. Intraperitoneal injection (i.p.) of TIIA for 3 weeks in PDN rats significantly improved mechanical allodynia and thermal hyperalgesia. Patch clamp recordings showed that the excitability of dorsal root ganglion (DRG) nociceptive neuron was increased in diabetic state, and TIIA treatment effectively recovered the subnormality, which was achieved by preventing augments of both Tetrodotoxin-sensitive (TTX-resistant) and Tetrodotoxin-sensitive (TTX-S) sodium currents. Further, the protein expressions of voltage-gated sodium channels (VGSCs) α-subunits Nav1.3, Nav1.7 and Nav1.9 increased in DRG of diabetic rats and were normalized by TIIA application. In conclusion, this study provides evidence that the TIIA attenuated PDN by effecting VGSCs activities and expressions, indicating that the TIIA could be a promising agent for PDN treatment.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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The PCOS Patients differ in Lipid Profile According to their Phenotypes

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-121264

Polycystic ovary syndrome (PCOS) affects 4–18% of women of reproductive age. The number of reports exploring the lipid profiles among PCOS patients and number of studied patients are limited. The aim of our study was to assess the lipid profile separately in lean and non-lean women with polycystic ovary syndrome divided according to hyperandrogenemia, defined as free androgen index (FAI)≥5. The second aim was to compare the lipid profiles among lean and non-lean PCOS patients with respect to hyperandrogenemia and regularity of menstruation cycles. We evaluated 232 patients from Department of Endocrinological Gynecology, Jagiellonian University Medical College in Krakow diagnosed with PCOS. The population consisted of 166 lean and 66 non-lean women. We observed higher levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) in lean patients with FAI<5 than in lean patients with FAI≥5. There were no differences in lipid profile between non-lean patients with FAI≥5 and non-lean patients with FAI<5. Among lean patients higher total cholesterol levels were observed in those with irregular menstruation cycles and FAI<5 than in patients with FAI≥5 and regular cycles. There were no differences in lipid profiles between four phenotypes among non-lean PCOS patients. Conclusions The results of our study showed differences in lipid profile between lean PCOS patients according to their phenotype based on androgens' level. This effect was abandoned by fat tissue mass in non-lean ones. Further studies should be conducted to explore these associations.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial–mesenchymal transition and cancer stem-like cell phenotypes. Notably, dinaciclib resensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon, and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.Significance: Dual targeting of MYC-regulated homologous recombination and PARP-mediated DNA repair yields potent synthetic lethality in triple-negative breast tumors and other aggressive tumors characterized by MYC overexpression. Cancer Res; 78(3); 742–57. ©2017 AACR.

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Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target. USP18 is the major DUB that removes IFN-stimulated gene 15 (ISG15) from conjugated proteins. Prior work discovered that engineered loss of USP18 increases ISGylation and in contrast to its gain decreases cancer growth by destabilizing growth-regulatory proteins. Loss of USP18 reduced cancer cell growth by triggering apoptosis. Genetic loss of USP18 repressed cancer formation in engineered murine lung cancer models. The translational relevance of USP18 was confirmed by finding its expression was deregulated in malignant versus normal tissues. Notably, the recent elucidation of the USP18 crystal structure offers a framework for developing an inhibitor to this DUB. This review summarizes strong evidence for USP18 as a previously unrecognized pharmacologic target in oncology. Cancer Res; 78(3); 587–92. ©2018 AACR.

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Correction: Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases

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Oncogenic Ras Isoforms Signaling Specificity at the Membrane

How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher KRAS mRNA levels. As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Kα/Akt signaling. We propose that full activation of both MAPK and PI3Kα/Akt proliferative pathways by oncogenic KRas4B—but not by HRas or NRas—may help explain why the KRas4B isoform is especially highly populated in certain cancers. We further discuss pharmacologic implications. Cancer Res; 78(3); 593–602. ©2017 AACR.

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Aptamer-Conjugated Extracellular Nanovesicles for Targeted Drug Delivery

Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins, and nucleic acids that contribute to intercellular communication. ENVs have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application, clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes; however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of approximately 107 cells grafted with lipidated ligands can generate cancer cell–targeting ENV and can be prepared in approximately 1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.Significance: A new and rapid method for production of drug-targeting nanovesicles has implications for cancer treatment by chimeric antigen receptor T cells and other therapies. Cancer Res; 78(3); 798–808. ©2017 AACR.

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T-type Ca2+ Channels: T for Targetable

In the past decade, T-type Ca2+ channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, in vitro and in vivo studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug–drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells in vitro and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer. Cancer Res; 78(3); 603–9. ©2018 AACR.

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Oncolytic Virotherapy Blockade by Microglia and Macrophages Requires STAT1/3

The first oncolytic virotherapy employing HSV-1 (oHSV-1) was approved recently by the FDA to treat cancer, but further improvements in efficacy are needed to eradicate challenging refractory tumors, such as glioblastomas (GBM). Microglia/macrophages comprising approximately 40% of a GBM tumor may limit virotherapeutic efficacy. Here, we show these cells suppress oHSV-1 growth in gliomas by internalizing the virus through phagocytosis. Internalized virus remained capable of expressing reporter genes while viral replication was blocked. Macrophage/microglia formed a nonpermissive OV barrier, preventing dissemination of oHSV-1 in the glioma mass. The deficiency in viral replication in microglial cells was associated with silencing of particular viral genes. Phosphorylation of STAT1/3 was determined to be responsible for suppressing oHSV-1 replication in macrophages/microglia. Treatment with the oxindole/imidazole derivative C16 rescued oHSV-1 replication in microglia/macrophages by inhibiting STAT1/3 activity. In the U87 xenograft model of GBM, C16 treatment overcame the microglia/macrophage barrier, thereby facilitating tumor regression without causing a spread of the virus to normal organs. Collectively, our results suggest a strategy to relieve a STAT1/3-dependent therapeutic barrier and enhance oHSV-1 oncolytic activity in GBM.Significance: These findings suggest a strategy to enhance the therapeutic efficacy of oncolytic virotherapy in glioblastoma. Cancer Res; 78(3); 718–30. ©2017 AACR.

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T-Cell Densities in Brain Metastases Are Associated with Patient Survival Times and Diffusion Tensor MRI Changes

Brain metastases are common and are usually detected by MRI. Diffusion tensor imaging (DTI) is a derivative MRI technique that can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain–tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity and fractional anisotropy (FA). The tissue samples were analyzed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21; 95% confidence interval, 0.06–0.82; P = 0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann–Whitney U, P = 0.037) as well as confounding completely the effect of FA on multivariate survival analyses. We conclude that the T-cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, noninvasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.Significance: These findings show that white matter tract integrity is degraded in areas where T-cell infiltration is highest, providing a noninvasive method to identify immunologically active microenvironments in secondary brain tumors. Cancer Res; 78(3); 610–6. ©2017 AACR.

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Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer

Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies.Significance: Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. Cancer Res; 78(3); 769–80. ©2017 AACR.

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Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients

APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding β-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Furthermore, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA (The Cancer Genome Atlas) data for colorectal cancer outcomes. Transcriptional patterns exhibited evidence of activated canonical Wnt signaling in both types of adenomas, with Apc-mutant adenomas also exhibiting unique changes in pathways related to proliferation, cytoskeletal organization, and apoptosis. Apc-mutant adenomas were characterized by increased expression of the glial nexin Serpine2, the human ortholog, which was increased in advanced human colorectal tumors. Our results support the hypothesis that APC-mutant colorectal tumors are transcriptionally distinct from APC-wild-type colorectal tumors with canonical WNT signaling activated by other mechanisms, with possible implications for stratification and prognosis.Significance: These findings suggest that colon adenomas driven by APC mutations are distinct from those driven by WNT gain-of-function mutations, with implications for identifying at-risk patients with advanced disease based on gene expression patterns. Cancer Res; 78(3); 617–30. ©2017 AACR.

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Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817–29. ©2017 AACR.

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Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631–44. ©2017 AACR.

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Highlights from Recent Cancer Literature

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SIRT6 Is a Target of Regulation by UBE3A That Contributes to Liver Tumorigenesis in an ANXA2-Dependent Manner

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor-suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and to epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential, and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.Significance: These findings provide mechanistic insights into regulation of the tumor suppressive sirtuin SIRT6 and its implications for the development of hepatocellular carcinoma. Cancer Res; 78(3); 645–58. ©2017 AACR.

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VEGFR2-Mediated Reprogramming of Mitochondrial Metabolism Regulates the Sensitivity of Acute Myeloid Leukemia to Chemotherapy

Metabolic reprogramming is central to tumorigenesis, but whether chemotherapy induces metabolic features promoting recurrence remains unknown. We established a mouse xenograft model of human acute myeloid leukemia (AML) that enabled chemotherapy-induced regressions of established disease followed by lethal regrowth of more aggressive tumor cells. Human AML cells from terminally ill mice treated with chemotherapy (chemoAML) had higher lipid content, increased lactate production and ATP levels, reduced expression of peroxisome proliferator–activated receptor gamma coactivator 1α (PGC-1α), and fewer mitochondria than controls from untreated AML animals. These changes were linked to increased VEGFR2 signaling that counteracted chemotherapy-driven cell death; blocking of VEGFR2 sensitized chemoAML to chemotherapy (re-)treatment and induced a mitochondrial biogenesis program with increased mitochondrial mass and oxidative stress. Accordingly, depletion of PGC-1α in chemoAML cells abolished such induction of mitochondrial metabolism and chemosensitization in response to VEGFR2 inhibition. Collectively, this reveals a mitochondrial metabolic vulnerability with potential therapeutic applications against chemotherapy-resistant AML.Significance: These findings reveal a mitochondrial metabolic vulnerability that might be exploited to kill chemotherapy-resistant acute myeloid leukemia cells. Cancer Res; 78(3); 731–41. ©2017 AACR.

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The Power of a “Maverick” in Collaborative Problem Solving: An Experimental Investigation of Individual Perspective-Taking Within a Group

Abstract

Integrating different perspectives is a sophisticated strategy for developing constructive interactions in collaborative problem solving. However, cognitive aspects such as individuals' knowledge and bias often obscure group consensus and produce conflict. This study investigated collaborative problem solving, focusing on a group member interacting with another member having a different perspective (a "maverick"). It was predicted that mavericks might mitigate disadvantages and facilitate perspective taking during problem solving. Thus, 344 university students participated in two laboratory-based experiments by engaging in a simple rule-discovery task that raised conflicts among perspectives. They interacted with virtual partners whose conversations were controlled by multiple conversational agents. Results show that when participants interacted with a maverick during the task, they were able to take others' perspectives and integrate different perspectives to solve the problem. Moreover, when participants interacted in groups with a positive mood, groups with a maverick outperformed groups having several perspectives.

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Non-Scientific Criteria for Belief Sustain Counter-Scientific Beliefs

Abstract

Why is evolutionary theory controversial among members of the American public? We propose a novel explanation: allegiance to different criteria for belief. In one interview study, two online surveys, and one nationally representative phone poll, we found that evolutionists and creationists take different justifications for belief as legitimate. Those who accept evolution emphasize empirical evidence and scientific consensus. Creationists emphasize not only the Bible and religious authority, but also knowledge of the heart. These criteria for belief remain predictive of views about evolution even when taking into account other related factors like religion, political affiliation, and education. Each view is supported by its own internally specified criteria for what constitutes a justified belief. Changing minds may thus require changing epistemic norms.

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A Self-Organizing Approach to Subject–Verb Number Agreement

Abstract

We present a self-organizing approach to sentence processing that sheds new light on notional plurality effects in agreement attraction, using pseudopartitive subject noun phrases (e.g., a bottle of pills). We first show that notional plurality ratings (numerosity judgments for subject noun phrases) predict verb agreement choices in pseudopartitives, in line with the "Marking" component of the Marking and Morphing theory of agreement processing. However, no account to date has derived notional plurality values from independently needed principles of language processing. We argue on the basis of new experimental evidence and a dynamical systems model that the theoretical black box of notional plurality can be unpacked into objectively measurable semantic features. With these semantic features driving structure formation (and hence agreement choice), our model reproduces the human verb production patterns as a byproduct of normal processing. Finally, we discuss how the self-organizing approach might be extended to other agreement attraction phenomena.

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Modeling Reference Production as the Probabilistic Combination of Multiple Perspectives

Abstract

While speakers have been shown to adapt to the knowledge state of their addressee in choosing referring expressions, they often also show some egocentric tendencies. The current paper aims to provide an explanation for this "mixed" behavior by presenting a model that derives such patterns from the probabilistic combination of both the speaker's and the addressee's perspectives. To test our model, we conducted a language production experiment, in which participants had to refer to objects in a context that also included a visually misleading object (e.g., a crayon shaped like a Lego brick) whose function was either known to both partners, or known just to the speaker but not the addressee. Modeling results indicate that the experimental findings cannot be explained by assuming that speakers tailor a referring expression solely to their own perspective or to the perspective of their addressee. Instead, accounting for the behavioral pattern requires an approach where both perspectives influence the choice of referring expressions. Nevertheless, in our situation, speakers consider their partner's perspective more than their own.

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Frontal lobe epileptic seizures are accompanied by elevated pitch during verbal communication

Summary

The objective of our study was to assess alterations in speech as a possible localizing sign in frontal lobe epilepsy. Ictal speech was analyzed in 18 patients with frontal lobe epilepsy (FLE) during seizures and in the interictal period. Matched identical words were analyzed regarding alterations in fundamental frequency (ƒo) as an approximation of pitch. In patients with FLE, ƒo of ictal utterances was significantly higher than ƒo in interictal recordings (p = 0.016). Ictal ƒo increases occurred in both FLE of right and left seizure origin. In contrast, a matched temporal lobe epilepsy (TLE) group showed less pronounced increases in ƒo, and only in patients with right-sided seizure foci. This study for the first time shows significant voice alterations in ictal speech in a cohort of patients with FLE. This may contribute to the localization of the epileptic focus. Increases in ƒo were interestingly found in frontal lobe seizures with origin in either hemisphere, suggesting a bilateral involvement to the planning of speech production, in contrast to a more right-sided lateralization of pitch perception in prosodic processing.

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A Randomized Dose-Response Trial of Aerobic Exercise and Health-Related Quality of Life in Colon Cancer Survivors

Abstract

Objective

To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors.

Methods

Thirty-nine stage I-III colon cancer survivors were randomized to one of three groups: usual-care control, 150 min·wk^-1 of aerobic exercise (low-dose), and 300 min·wk^-1 of aerobic exercise (high-dose) for six months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal (FACT-C), Pittsburgh Sleep Quality Index (PSQI), Fear of Cancer Recurrence Inventory (FCRI), Fatigue Symptom Inventory (FSI), and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes.

Results

Over six months, the low-dose group completed 141±10 min·wk^-1 of aerobic exercise, and the high-dose group completed 247±11 min·wk^-1 of aerobic exercise. Over six months, exercise improved the physical component summary score of the SF-36 (P_trend=0.002), the FACT-C (P_trend=0.025), the PSQI (P_trend=0.049), and the FSI (P_trend=0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35–0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the FCRI, or bowel function.

Conclusion

Higher doses of aerobic exercise, up to 300 min·wk^-1, improve multiple HRQoL outcomes among stage I-III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors.

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Making Sports Accessible to Student Athletes with Hearing Loss

Time Out! I Didn't Hear You, was published in 1996 as a resource to support the participation of student athletes with hearing loss in high school athletics. This article describes a project to update the resource for all stakeholders involved in making college level athletics accessible to students with hearing loss.

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Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma

Abstract

We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan–Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60–100) and median age was 67 years (range 60–81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9–11.0) and OS was 12.7 months (95% CI 9.7–14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8–0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1–0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3–0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.

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Immunohistochemical evaluation of H3K27 trimethylation in malignant peripheral nerve sheath tumors

Publication date: Available online 31 January 2018
Source:Pathology - Research and Practice
Author(s): Hiroshi Otsuka, Kenichi Kohashi, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yuichi Yamada, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda
The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs. We evaluated immunohistochemical expression of H3K27me3 in MPNSTs with heterologous components and metachronous cases of MPNSTs. Among 145 MPNST samples, 50 (34.5%) showed complete loss of staining, and 45 (31.0%) showed partial loss of staining. Regarding the backgrounds of MPNSTs, 74 samples of neurofibromatosis type 1 (NF-1)-associated MPNST demonstrated 26 (35.1%) complete and 26 (35.1%) partial loss of H3K27me3. Among MPNSTs with heterologous component, almost all of MPNSTs with epithelioid differentiation (8/9 samples, 88.9%) retained H3K27me3, and malignant Triton tumors without epithelioid component lacked H3K27me3 at high rate (91.7%). Five of 20 metachronous MPNST cases showed significantly reduced expression of H3K27me3 between primary and later-occurring tumors, but in some cases increased expression of H3K27me3 in the clinical course (such as complete loss to partial loss) was observed. If the tumors are recurrent or metastatic, H3K27me3 expression should be reduced or at least maintained because loss of H3K27me3 is due to genetic mutation of EED or SUZ12. MPNSTs, especially those associated with NF-1, can occur in heterochronous and multiple patterns, and the identification of increased expression of H3K27me3 during a patient's clinical course can be helpful for determining whether the tumors are heterochronous, multiple or not. As heterochronous and multiple tumors may show lower malignancy compared to recurrent or metastatic tumors, favorable prognosis may be expected when H3K27me3 expression is increased.



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Downregulation of SETD8 by MiR-382 is involved in glioma progression

Publication date: Available online 31 January 2018
Source:Pathology - Research and Practice
Author(s): Zhiming Ma
BackgroundSETD8 (named PR-SET7 or KMT5a) has been reported to regulate various biological processes including carcinogenesis. However, the role of SETD8 in glioma progression has not been investigated.MethodqPCR and western blot were used to detect the expression levels of miR-382 and SETD8. MTT and wound healing assay used to detect the cell proliferation and migratory capability. A predicted target of miR-382 (SETD8) was first validated using a luciferase assay.ResultsIn this study, we found that SETD8 expression was evidently upregulated in glioma tissues and glioma cells, compared with the adjacent normal tissues and normal human astrocytes (NHA). Next, we showed that SETD8 evidently induced cell proliferation and migration in vitro and in vivo. In addition,dual-luciferase assays revealed that miR-382 directly regulates oncogenic SETD8 expression in U87 and U251 cells. Finally a statistically significant inverse correlation of miR-382 and SETD8 expression was observed in 30 glioma patients.ConclusionThese data indicated that oncogenic SETD8 was regulated by miR-382 and involved glioma progression, .revealing new therapeutic targets for glioma cancer.



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Cross-Generalization Profile to Orosensory Stimuli of Rats Conditioned to Avoid A High Fat/High Sugar Diet

Abstract

The orosensory characteristics of a diet play a role in its acceptance and rejection. The current study was designed to investigate the gustatory components that contribute to the intake of a palatable, high-energy diet (HE; 45% calories from fat, 17% calories from sucrose). Here, rats were conditioned to avoid HE diet by pairings with i.p. injections of LiCl to induce visceral malaise. Subsequently, the degree of generalization was tested to an array of taste compounds using a brief-access lick procedure (10-s trials, 30-min sessions). Compared to NaCl-injected controls, LiCl-injected rats suppressed licking response to 100% linoleic acid and 20% intralipid, and to a lesser extent 17% sucrose. There was more variability in the lick responses to sucrose among the LiCl-injected rats. Rats that tended to suppress licking responses to sucrose generalized this response to glucose, fructose and Na-saccharin but not to Polycose. In contrast, LiCl-injected rats did not significantly suppress lick responses to water, NaCl, citric acid or quinine compared to controls rats. The brief access feature of this procedure, allows for behavioral measures when postingestive factors are minimized. These findings support a role for gustatory cues in the detection of high fat/high sugar diets. Furthermore, it appears that the fat component is a more salient orosensory feature of the HE diet.

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Olfactory Adaptation is Dependent on Route of Delivery

Abstract

Odorants are perceived orthonasally (nostrils) or retronasally (oral cavity). Prior research indicates route of delivery impacts odorant perception, pleasantness, and directed behaviors thus suggesting differential processing of olfactory information. Adaptation is a form of neural processing resulting in decreased perceived intensity of a stimulus following prolonged and continuous exposure. The present study objective was to determine whether route of delivery differentially impacts olfactory adaptation and whether cross-adaptation occurs between orthonasal and retronasal pathways. Linalool (12%) or vanillin (25%) were delivered orthonasally (6 liters/min [LPM]) and retronasally (8 LPM) in air phase through a custom built olfactometer. Perceived odorant intensity was collected every 5 mins over 10-mins exposure. Immediately following the exposure period, cross-adaptation was assessed by shunting the delivery of the odorant from the nostrils to the oral cavity, or vice versa. A control study was also completed in which subjects underwent the orthonasal adaptation protocol using stimulus concentrations matched to the intensity of restronasal stimuli (e.g. 1.5% linalool and 6.25% vanillin). Following orthonasal delivery of both high and low vanillin concentrations, results showed perceived intensity decreased significantly at 5- and 10-mins. High concentrations of orthonasal linalool similarly decreased significantly whereas lower concentrations decreased but did not reach statistical significance. Linalool and vanillin delivered retronasally did not adapt as perceived intensity actually increased significantly following a 10-min exposure. In addition, evidence of cross-adaptation was not obvious following extended odorant exposure from either delivery pathway. This study suggests that olfactory processing may be affected by the route of odorant delivery.

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Role of Biochar and Fungi on PAH Sorption to Soil Rich in Organic Matter

Abstract

The use of biochar (BC) has been suggested for remediation of contaminated soils. This study aims to investigate the role of microorganisms in sorption of PAH to BC-amended soils. Fungi, especially the wood and litter-degrading fungi, have shown the ability for humification and to degrade recalcitrant molecules, and are thus suitable model organisms. Haplic Arenosol with high organic matter content was chosen to highlight the importance of soil organic matter (SOM) in PAH sorption, possibly to form non-extractable residue. Basidiomycetous fungi Agrocybe praecox and Phanerochaete velutina grown on pine bark were inoculated in organic matter (OM)-rich Haplic Arenosol and OM-poor sandy loam with either BC or chemically activated BC (ABC) and ¹⁴C-labelled pyrene for 60 days. Fungi did not mineralize pyrene, but increased sorption up to 47–56% in BC-amended Haplic Arenosol in comparison with controls (13–25%) without a fungus irrespective of the presence of an adsorbent. In OM-poor sandy loam, only 9–12% of pyrene was sorbed to amended soil in the presence of fungus and adsorbent. The results suggest that BC and fungal amendment increased sorption of pyrene, especially to Haplic Arenosol more than by either BC or fungi alone.

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Effects of an oral bisphosphonate and three intravenous bisphosphonates on several cell types in vitro

Abstract

Objective

To analyze the influence of an oral bisphosphonate and compare the potency to intravenous bisphosphonates on various cell types as regards the rarity of bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) caused by oral bisphosphonate.

Materials and methods

A viability assay (MTT), a migration assay (Boyden chamber), and an apoptosis assay (Caspase-Glo® 3/7) were performed to analyze the effect of bisphosphonates on human fibroblasts, umbilical vein endothelial cells (HUVEC), and osteoblasts.

Results

Alendronate and intravenous bisphosphonates suppressed cell viability and migration, and induced apoptosis in all tested cell types. Alendronate had a greater impact than ibandronate on the characteristics in fibroblasts and osteoblasts but not as strong as zoledronate.

Conclusions

The incidence of BP-ONJ in oral bisphosphonate treatment is reported to be much lower than that in intravenous bisphosphonates. However, the influences of alendronate on human cells were at least as strong as ibandronate, although it was lower than zoledronate.

Clinical relevance

Alendronate showed strong enough effects to suppress human somatic cells and was comparable to certain intravenous bisphosphonates in potency. This study suggests that the lower incidence of BP-ONJ in alendronate treatment is not originated by its potency, but might be due to the low bioavailability of alendronate, lower dosing on a daily basis, and having no additional therapies.

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Assessment of condylar morphology and position using MSCT in an Asian population

Abstract

Objectives

The purpose of the present study was to investigate the volume, surface, morphometric index (MI), and position of the condyle in a normal population by applying Mimics 17.0 software. Then, the difference between left and right sides, sex, and age can be explored, which will contribute to establish the reference value of condylar morphology and position in normal individuals, and help us to study characteristics of condylar morphology and position in abnormal individuals.

Materials and methods

Three-hundred subjects were enrolled in our study from the radiology department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. They were divided into three groups according to the age: group 1 (18–24 years old), group 2 (25–34 years old), and group 3 (35–44 years old). Each group included 100 subjects (with 50 males and 50 females). They were examined using multislice computed tomography (MSCT) after that. All images of condyle were reconstructed by Mimics 17.0 software, so as to measure the volume, surface, and MI of condyle, and to analyze the position of condyle in the articular fossa by means of joint spaces.

Results

The differences of condylar volume, surface, and MI between left and right sides were not obvious (P > 0.05). The condylar volume and surface were greater in males than females (P < 0.05), while their condylar MI existed no difference (P > 0.05). No statistical differences were found in volume and surface among three age groups. However, the MI of group 1 was statistically lower than that of group 3 (P < 0.05). On the other hand, no significant differences were found between left and right condylar position (P > 0.05). Nevertheless, there were significant differences of condylar position regarding the gender and age (P < 0.05).

Conclusions

This study showed no significant differences in condylar morphology and position between left and right sides, but factors of gender and age were proven to have a certain influence on the morphology and position of the condyle. This information can be clinically useful in establishing the diagnostic criteria for condylar morphology and position in the normal Asian population.

Clinical relevance

Examination of condylar morphology and position is important for evaluating the abnormalities and bony changes that affect the temporomandibular joint (TMJ). So, this will be conducive to the diagnosis and the evaluation of therapeutic effect of temporomandibular joint diseases. Also, it is important to evaluate these indexes prior to commencing orthodontic treatment, because TMJ abnormalities play a critical role in orthodontic treatment planning.

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Metastasis seeding cells: Lone invaders or mass migrators?

Lymph node metastases are among the best predictors of recurrence and of cancer related death in early stage colorectal cancers. Yet, despite their clinical and biological relevance, it remains elusive how lymph node metastases develop and whether metastatic seeding is a major bottleneck that restrains genetic heterogeneity of metastatic disease.

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Re-activation of cAMP pathway by PDE4D inhibition represents a novel druggable axis for overcoming tamoxifen resistance in ER-positive breast cancer

Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer (BC); however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance. Experimental Design: Whole transcriptome sequencing, downstream pathway analysis and drug repositioning approaches were used to identify novel modulators (here: PDE4D) of tamoxifen resistance. Clinical data involving tamoxifen-treated ER-positive BC patients were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance. Results: PDE4D, which hydrolyzes cAMP, was significantly overexpressed in both MCF-7 and T47D tamoxifen resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated BC patients (n=469, P=0.0036 for DMFS; n=561, P= 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n=132, P=0.049). Inhibition of PDE4D by either siRNAs or pharmacological inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded-protein-response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, aspirin was predicted to be a tamoxifen sensitizer using a drug re-positioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo. Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis.

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A combination of SAHA and Quinacrine is effective in inducing cancer cell death in upper gastrointestinal cancers

Purpose: We aimed to investigate the therapeutic efficacy of single agent and the combination of quinacrine (QC) and suberoylanilide hydroxamic acid (SAHA) in wt- and mut-p53 upper gastrointestinal cancer (UGC) cell models. Experimental design: ATP-Glo, clonogenic survival, Annexin V, comet, DNA double-strand breaks (DSB), quantitative real-time PCR (qPCR), and Western blot analysis assays were utilized. Results: Using clonogenic cell survival, ATP-Glo cell viability, Annexin V, and sub-G0 population analysis, we demonstrate that a combination of QC and SAHA significantly decreased colony formation and increased cancer cell death (range: 4 - 20 fold) in 6 UGC cell models, as compared to single agent treatments, irrespective of the p53 status (P < 0.01). The combination of QC and SAHA induced high levels of DSB DNA damage (>20 fold, P < 0.01). Western blot analysis showed activation of caspases 3, 9 and -H2AX in all cell models. Of note, while QC treatment induced expression of wt-p53 protein, the combination of QC and SAHA substantially decreased the levels of both wt-P53 and mut-P53. Furthermore, cell models that were resistant to cisplatin (CDDP) or gefitinib treatments were sensitive to this combination. Tumor xenograft data confirmed that a combination of QC and SAHA is more effective than a single agent treatment in abrogating tumor growth in vivo (P <0 .01). Conclusion: Our novel findings show that the combination of QC and SAHA promotes DNA damage and is effective in inducing cancer cell death, irrespective of p53 status and resistance to CDDP or gefitinib in UGC models. 

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Antitumor T cell reconditioning: improving metabolic fitness for optimal cancer immunotherapy

With the rapid rise of immunotherapy for cancer treatment, attention has focused on gaining a better understanding of T cell biology in the tumor microenvironment.  Elucidating the factors underlying changes in their function will allow for the development of new therapeutic strategies that could expand the patient population benefiting from immunotherapy, as well as circumvent therapy resistance. Cancers go beyond avoiding immune recognition and inducing T cell dysfunction through co-inhibitory molecules. Recent work has demonstrated that the tumor microenvironment elicits metabolic changes in T cells that dampen their ability to respond and manipulating these metabolic changes can strengthen an antitumor immune response. Here we review the metabolic status of various types of T cells, the energetic state of the tumor microenvironment, and proposed modalities for improvement of immunotherapy through metabolic remodeling.

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Long noncoding RNA LINC01234 functions as a competing endogenous RNA to regulate CBFB expression by sponging miR-204-5p in gastric cancer

Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function and mechanism of LINC01234 in gastric cancer (GC). Experimental Design: Firstly, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the GC cells proliferation and apoptosis, and its regulation of miR-204-5p by acting as a ceRNA. The animal model was used to support the in vitro experimental findings. Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234 induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor β (CBFB). Conclusions: LINC01234 is significantly over-expressed in GC, and LINC01234-miR-204-5p-CBFB axis plays a critical role in GC tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy.

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TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3

Aberrant epidermal growth factor receptor (EGFR) signaling is a common driver of glioblastoma (GBM) pathogenesis, however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells (GSCs). Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.

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Lysophosphatidic Acid Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response

Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase (NOX) and generation of reactive oxygen species (ROS), resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 (GLUT1) and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer.

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The Effect of Light Exposure on Insomnia anssd Nocturnal Movement in Parkinson’s Disease:An Open Label, Retrospective, Longitudinal Study

Publication date: Available online 31 January 2018
Source:Sleep Medicine
Author(s): Jessica T. Martino, Christopher B. Freelance, Gregory L. Willis
Insomnia, hypersomnia and REM Sleep Behavior Disorder (RSBD) during sleep are major problems for patients suffering from Parkinson's disease (PD) but they are also used to predict its onset. While these secondary symptoms detract from the quality of life in PD patients, few treatment options are available due to limited efficacy or risk of complicating the treatment regimen. Light therapy (LT) has been suggested as a strategy for sleep disorders but it has only been implemented recently for use in PD. An open label, retrospective study was undertaken where PD patients had been undergoing LT, using polychromatic light, for four months to 15 years prior. It was found that one hr. exposure to light, just prior to retiring, significantly improved insomnia and reduced RSBD in as little as one month after commencing LT. In addition, the improvement was maintained as long as LT was continued over a four to six year period. The efficacy of LT in alleviating these sleep related conditions was not compromised by time since diagnosis or age of the patient. These results intimate the value of long term application of non-invasive techniques such as LT for treating sleep disorders in PD and justify further controlled trials on the long term efficacy of LT.



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Prevalence of restless legs syndrome in Parkinson’s disease: a systematic review and meta-analysis of observational studies

Publication date: Available online 31 January 2018
Source:Sleep Medicine
Author(s): Xinglong Yang, Bin Liu, Hao Shen, Shimei Li, Quanzhen Zhao, Ran An, Fayun Hu, Hui Ren, Yanming Xu, Zhong Xu
ObjectiveRestless legs syndrome (RLS) and Parkinson's disease (PD) are common neurological disorders that respond to dopaminergic therapy. RLS prevalence among people with PD varies widely (0-38%) in the literature, complicating efforts to understand whether the two diseases might be associated.MethodThe databases Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were searched for observational and case-control studies of RLS prevalence in PD. Eligible studies were meta-analyzed using Stata 12.0.ResultsPooled RLS prevalence in PD among various patient populations was 14%, and prevalence in Asia (12%) was slightly lower than outside Asia (16%). Prevalence was higher among patients who had previously received PD treatment (15%) than among drug-naïve patients (11%). Prevalence of RLS was higher in female PD patients (13%) than in male patients (11%). RLS prevalence was much higher among PD patients than among healthy controls (OR 2.86, 95% CI 2.10-3.90; p<0.001).ConclusionThis meta-analysis may provide the first reliable pooled estimate of RLS prevalence in PD, and strong evidence that RLS risk is higher among PD patients than among healthy individuals.



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Factors Associated with Insomnia and Complementary Medicine Use in Children: Results of a National Survey

Publication date: Available online 31 January 2018
Source:Sleep Medicine
Author(s): Ezra M. Cohen, Michelle L. Dossett, Darshan H. Mehta, Roger B. Davis, Yvonne C. Lee
ObjectivesSleep difficulties are a serious health problem in children, and interest in using complementary and alternative medicine (CAM) therapies to treat sleep is growing. We aimed to identify: a) the prevalence of sleep difficulties in children, and b) the prevalence and patterns of CAM use among children with trouble sleeping.MethodsWe used the 2012 National Health Interview Survey (NHIS) dataset to estimate the prevalence of sleep difficulties and CAM use in children ages 6 to 17 years. Prevalence estimates were weighted to reflect the survey's sampling design. We used logistic regression to explore associations between sleep difficulties, psychosocial factors, comorbidities and CAM use.Results6.4% of children in the 2012 NHIS dataset reported regular difficulty sleeping in the last year, corresponding to an estimated 1.5 million children in the US. Older age, poorer health status, more school days missed, and multiple comorbidities were all associated with sleep difficulties (p ≤ 0.001). Among children with sleep difficulties, 29% used at least one CAM therapy. Of the CAM therapies surveyed, non-vitamin, non-mineral supplements were the most commonly used (14.6%), followed by manipulation therapies (9.2%) and mind-body techniques (8.8%). Parental education and CAM use were most strongly associated with child CAM use (p ≤ 0.001).ConclusionsCAM therapies, particularly non-vitamin, non-mineral supplements, are commonly used among children with sleeping problems. More research is needed to characterize the safety and efficacy of CAM therapies for sleep in this population.



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Restless legs syndrome: A rarity in the Nigerian pregnant population?

Publication date: Available online 31 January 2018
Source:Sleep Medicine
Author(s): Michael B. Fawale, Ismaila I. Alani, Abubakar A. Kullima, Morenikeji A. Komolafe, Omotade A. Ijarotimi, Samuel Anu Olowookere, Rotimi Oluyombo, Tewogbade Adeoye Adedeji
ObjectivesThe prevalence of RLS in pregnancy is higher when compared with the general population however it remains unknown among indigenous black Africans. Available data indicate that RLS is uncommon in sub-Saharan Africa. We embarked on this study to determine the prevalence and characteristics of RLS in an antenatal clinic sample of Nigerian pregnant women compared with a primary care sample of non-pregnant women.MethodsA total of 310 pregnant women and non-pregnant women filled out a questionnaire which incorporated the 2014 minimal criteria of the International Restless Legs Syndrome Study Group. Demographic and clinical data, including sleep duration and samples for blood hemoglobin concentration and urinalysis were obtained.ResultsThe mean ages of the pregnant and non-pregnant women were 24.9 ± 5.6 years and 23.6 + 5.4 years, respectively (p = 0.003). There was no case of RLS found among pregnant women while five (1.6%) of the non-pregnant women fulfilled the criteria for RLS. Overall, the prevalence report of RLS symptoms was associated with lower mean habitual nocturnal sleep duration (p < 0.05) coffee (p = 0.013) and kola nut (0.023) consumption, report of leg cramps (p < 0.001) and proteinuria (p = 0.047), Report of leg cramps and proteinuria were independently associated with RLS.ConclusionThe prevalence of restless legs syndrome is low among women of child-bearing age in the Nigerian population and may be lower in pregnancy. Report of leg cramps and proteinuria are independently associated with RLS.



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