The Accuracy of a Handheld Ultrasound Device for Neuraxial Depth and Landmark Assessment: A Prospective Cohort Trial.

This study investigated the accuracy of a wireless handheld ultrasound with pattern recognition software that recognizes lumbar spine bony landmarks and measures depth to epidural space (Accuro, Rivanna Medical, Charlottesville, VA) (AU). AU measurements to epidural space were compared to Tuohy needle depth to epidural space (depth to loss of resistance at epidural placement). Data from 47 women requesting labor epidural analgesia were analyzed. The mean difference between depth to epidural space measured by AU versus needle depth was -0.61 cm (95% confidence interval, -0.79 to -0.44), with a standard deviation of 0.58 (95% confidence interval, 0.48-0.73). Using the AU-identified insertion point resulted in successful epidural placement at first attempt in 87% of patients, 78% without redirects. (C) 2017 International Anesthesia Research Society

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Trends in the Prevalence of Intraoperative Adverse Events at 2 Academic Hospitals After Implementation of a Mandatory Reporting System.

BACKGROUND: Anesthesia information management systems (AIMSs) have been effectively used to improve quality in anesthesia care, and have enabled the development of mandatory quality assurance (QA) reporting systems for adverse events (AEs). While this approach has been shown to increase event reporting over time, the long-term effect of such a system on quality is unknown. We investigated the trends in AE reporting over time after implementing AIMS-based mandatory reporting systems at 2 academic medical centers. METHODS: At Thomas Jefferson University Hospital, AEs were retrieved after implementation of a mandatory QA process in 2013. These AEs were categorized as preventable and unpreventable. The rates of overall preventable and unpreventable AEs were analyzed over time. At Vanderbilt University Medical Center, the rates of AEs were analyzed after establishing a mandatory QA process in 2002. Data were binned by quarter, and trends over time were analyzed using the Mann-Kendall test. RESULTS: At Thomas Jefferson University Hospital, over a period of 2 years after implementation of a mandatory QA process, the documented AE rate decreased from 1.23% to 0.64% (P

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Medical Statistics: For Beginners, 1st ed.

No abstract available

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Understanding Infusion Pumps.

Infusion systems are complicated electromechanical systems that are used to deliver anesthetic drugs with moderate precision. Four types of systems are described-gravity feed, in-line piston, peristaltic, and syringe. These systems are subject to a number of failure modes-occlusion, disconnection, siphoning, infiltration, and air bubbles. The relative advantages of the various systems and some of the monitoring capabilities are discussed. A brief example of the use of an infusion system during anesthetic induction is presented. With understanding of the functioning of these systems, users may develop greater comfort. (C) 2017 International Anesthesia Research Society

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Superenhancers Drive Neuroblastoma Differentiation States [Neuroblastoma]

Superenhancer-associated transcriptional networks promote neuroblastoma heterogeneity.

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Transcription Elongation Factors Are Potential Targets in Glioblastoma [Glioblastoma]

JMJD6 promotes transcription pause-release and elongation and glioblastoma cell survival in vivo.

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Epacadostat Shows Value in Two SCCHN Trials [News in Brief]

In the ECHO-202/KEYNOTE-037 and ECHO-204 trials reported at the 2017 Annual Meeting of the American Society of Clinical Oncology, patients with squamous cell carcinoma of the head and neck responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. An IDO1 inhibitor, epacadostat also demonstrated promising activity in combination with the PD-1 checkpoint inhibitors in other solid tumors, including melanoma, urothelial carcinoma, renal cell carcinoma, and non–small cell lung cancer.

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GPX4 Blocks Ferroptosis to Drive the Survival of Chemoresistant Cells [Drug Resistance]

The lipid peroxidase GPX4 is critical for the survival of therapy-resistant ZEB1⁺ cancer cells.

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Integrative Genomics Characterize Medulloblastoma Subtypes [Medulloblastoma]

Integrative genomic analysis characterized the genomic landscapes of medulloblastoma subtypes.

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Savolitinib Heads for Phase III Trial in PRCC [News in Brief]

A phase II trial of savolitinib, a MET inhibitor, found that the drug induced partial responses in some patients with papillary renal cell carcinoma and was well tolerated, prompting drug makers Chi-Med and AstraZeneca to launch a phase III study.

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Disrupting the APC-Asef Interaction Suppresses Cancer Cell Migration [Drug Design]

Structure-based design yields peptidomimetic APC–ARM pocket inhibitors that block Asef binding.

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Nivolumab Plus Ipilimumab Has Antitumor Activity in Metastatic RCC [Clinical Trials]

Nivolumab plus ipilimumab achieves durable responses and has manageable safety in metastatic RCC.

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FOXA1-Dependent Enhancer Reprogramming Promotes Metastasis [Metastasis]

Recurrent enhancer changes accompany the metastatic transition in pancreatic cancer models.

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Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers [Research Articles]

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell–cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody–drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models—a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.

Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030–45. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 920

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Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors [Research Briefs]

Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2. HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.

Significance: The mechanisms of clinical resistance to PARPi in DNA repair–deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999–1005. ©2017 AACR.

See related commentary by Domchek, p. 937.

See related article by Kondrashova et al., p. 984.

See related article by Goodall et al., p. 1006.

This article is highlighted in the In This Issue feature, p. 920

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Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma [Research Briefs]

High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.

Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984–98. ©2017 AACR.

See related commentary by Domchek, p. 937.

See related article by Quigley et al., p. 999.

See related article by Goodall et al., p. 1006.

This article is highlighted in the In This Issue feature, p. 920

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Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition [Research Articles]

Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06–0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (²P < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer.

Significance: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with "second hit" mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. Cancer Discov; 7(9); 1006–17. ©2017 AACR.

See related commentary by Domchek, p. 937.

See related article by Kondrashova et al., p. 984.

See related article by Quigley et al., p. 999.

This article is highlighted in the In This Issue feature, p. 920

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A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors [Research Briefs]

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion–positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion–positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.

Significance: LOXO-195 abrogated resistance in TRK fusion–positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963–72. ©2017 AACR.

See related commentary by Parikh and Corcoran, p. 934.

This article is highlighted in the In This Issue feature, p. 920

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New Horizons for Precision Medicine in Biliary Tract Cancers [Review]

Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.

Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943–62. ©2017 AACR.

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Mesenchymal Stromal Cell Therapy: After the Gold Rush.

No abstract available

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Long-term Functioning of Allogeneic Islets in Subcutaneous Tissue Pretreated with a Novel Cyclic Peptide without Immunosuppressive Medication.

Background: There exists a need for a minimally invasive method of islet transplantation without immunosuppressive drugs for the treatment of type 1 diabetes. Methods: In diabetic ACI rats, an agarose rod containing the cyclic oligopeptide SEK-1005 (agarose-SEK rod) was implanted at 2 dorsal subcutaneous sites. Then these rods were removed, and 1500 islets isolated from F344 rats were transplanted into each of the pockets. Results: Ten days after implantation of agarose-SEK rods, vascularized pockets were present. Nonfasting blood glucose levels confirmed long-term survival of the allogeneic islet grafts, without immunosuppressive therapy, in 8 of 10 recipients. Flow cytometry and gene expression analyses were performed to investigate the mechanisms underlying graft acceptance. Agarose-SEK rod implantation led to the formation of granulomatous tissue containing regulatory T cells that suppressed immune reactions against the allogeneic islet grafts. Conclusions: These results indicate that the use of an agarose-SEK rod to prevascularize a subcutaneous site may be a useful method for achieving successful allogeneic islet transplantation without immunosuppression. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Reply: What Is the Ideal Neophallus? Response to Frey et al. (2017): An Update on Genital Reconstruction Options for the Female-to-Male Transgender Patient: A Review of the Literature.

No abstract available

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What Is the Ideal Neophallus? Response to Frey et al. (2017): An Update on Genital Reconstruction Options for the Female-to-Male Transgender Patient: A Review of the Literature.

No abstract available

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Identification and segmentation of myelinated nerve fibers in a cross-sectional optical microscopic image using a deep learning model

Publication date: 1 November 2017
Source:Journal of Neuroscience Methods, Volume 291
Author(s): Tatsuhiko Naito, Yu Nagashima, Kenichiro Taira, Naohiro Uchio, Shoji Tsuji, Jun Shimizu
BackgroundThe morphometric analysis of myelinated nerve fibers of peripheral nerves in cross-sectional optical microscopic images is valuable. Several automated methods for nerve fiber identification and segmentation have been reported. This paper presents a new method that uses a deep learning model of a convolutional neural network (CNN). We tested it for human sural nerve biopsy images.MethodsThe method comprises four steps: normalization, clustering segmentation, myelinated nerve fiber identification, and clump splitting. A normalized sample image was separated into individual objects with clustering segmentation. Each object was applied to a CNN deep learning model that labeled myelinated nerve fibers as positive and other structures as negative. Only positives proceeded to the next step. For pretraining the model, 70,000 positive and negative data each from 39 samples were used. The accuracy of the proposed algorithm was evaluated using 10 samples that were not part of the training set. A P-value of <0.05 was considered statistically significant.ResultsThe total true-positive rate (TPR) for the detection of myelinated fibers was 0.982, and the total false-positive rate was 0.016. The defined total area similarity (AS) and area overlap error of segmented myelin sheaths were 0.967 and 0.068, respectively. In all but one sample, there were no significant differences in estimated morphometric parameters obtained from our method and manual segmentation.Comparison with existing methodsThe TPR and AS were higher than those obtained using previous methods.ConclusionsHigh-performance automated identification and segmentation of myelinated nerve fibers were achieved using a deep learning model.



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An operant-based detection method for inferring tinnitus in mice

Publication date: Available online 31 August 2017
Source:Journal of Neuroscience Methods
Author(s): Hongyan Zuo, Debin Lei, Shobhana Sivaramakrishnan, Benjamin Howie, Jessica Mulvany, Jianxin Bao
BackgroundSubjective tinnitus is a hearing disorder in which a person perceives sound when no external sound is present. It can be acute or chronic. Because our current understanding of its pathology is incomplete, no effective cures have yet been established. Mouse models are useful for studying the pathophysiology of tinnitus as well as for developing therapeutic treatments.New MethodWe have developed a new method for determining acute and chronic tinnitus in mice, called sound-based avoidance detection (SBAD). The SBAD method utilizes one paradigm to detect tinnitus and another paradigm to monitor possible confounding factors, such as motor impairment, loss of motivation, and deficits in learning and memory.ResultsThe SBAD method has succeeded in monitoring both acute and chronic tinnitus in mice. Its detection ability is further validated by functional studies demonstrating an abnormal increase in neuronal activity in the inferior colliculus of mice that had previously been identified as having tinnitus by the SBAD method.Comparisonwith Existing Methods The SBAD method provides a new means by which investigators can detect tinnitus in a single mouse accurately and with more control over potential confounding factors than existing methods.ConclusionThis work establishes a new behavioral method for detecting tinnitus in mice. The detection outcome is consistent with functional validation. One key advantage of mouse models is they provide researchers the opportunity to utilize an extensive array of genetic tools. This new method could lead to a deeper understanding of the molecular pathways underlying tinnitus pathology.



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HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Purpose: Resistance to anti-HER2 therapies in HER2⁺ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2⁺ breast cancer can reactivate the HER network under potent HER2-targeted therapies.

Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER⁺/HER2⁺ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition.

Results: Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2–irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivo.

Conclusions: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. Clin Cancer Res; 23(17); 5123–34. ©2017 AACR.

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The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis

Purpose: To develop an approach for the investigation of different subtypes of circulating tumor cells (CTC) and other cells to evaluate their potential prognostic value of prostate cancer.

Experimental Design: Malignancy of CTCs undergoing epithelial-to-mesenchymal transition (EMT) was confirmed by repeated FISH. Subgroups of CTCs in 81 patients with prostate cancer (43 castration resistant and 38 untreated localized) were correlated to disease aggressiveness parameters. AUC analysis was applied to compare the performance for metastasis prediction between serum PSA level alone and a combined risk score using both PSA and EMTing CTC count. Circulating megakaryocytes and cancer patient survival association was performed using Cox model.

Results: The majority of vimentin (VIM)⁺/CD45^– cells were malignant, with genomic alterations in several genomic regions. The number of cytokeratin (CK)^–/VIM⁺/CD45^– CTCs correlated with disease burden, tumor aggressiveness, and poorer survival. Meanwhile, CK⁺/VIM⁺/CD45^– CTCs were associated with metastases better than other subtypes of CTCs in these limited samples. Combination of PSA level and the number of CK⁺/VIM⁺/CD45^– CTCs enhanced the prediction of cancer metastases [AUC, 0.921; 95% confidence interval (CI), 0.858–0.985]. The number of circulating megakaryocytes was potentially associated with good patient survival in advanced prostate cancer (HR, 0.849; 95% CI, 0.628–1.146, per cell increase), and the difference between the number of mesenchymal CTCs and megakaryocytes strongly correlated to poor survival (HR, 10.17; 95% CI, 2.164–47.789, if score ≥2.0).

Conclusions: This CTC analysis approach and the potential association of megakaryocytes with cancer prognosis may greatly enhance our ability to investigate the cancer metastasis process and to predict/monitor cancer progression. Clin Cancer Res; 23(17); 5112–22. ©2017 AACR.

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Retraction: Polymorphisms of the CYP1B1 Gene as Risk Factors for Human Renal Cell Cancer

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Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer

Purpose: Patients with metastatic colorectal cancer suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct β-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses.

Experimental Design: Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.

Results: We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.

Conclusions: Altogether, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS–mutated colorectal patients, for which there is a crucial unmet medical need. Clin Cancer Res; 23(17); 5267–80. ©2017 AACR.

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Expression and Therapeutic Potential of SOX9 in Chordoma

Purpose: Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma.

Experimental Design: SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescent assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound-healing assay and a Transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell-cycle arrest, as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by an MTT assay.

Results: Tissue microarray and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell-cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells.

Conclusions: Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma. Clin Cancer Res; 23(17); 5176–86. ©2017 AACR.

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Immune Correlates of GM-CSF and Melanoma Peptide Vaccination in a Randomized Trial for the Adjuvant Therapy of Resected High-Risk Melanoma (E4697)

Purpose: E4697 was a multicenter intergroup randomized placebo-controlled phase III trial of adjuvant GM-CSF and/or a multiepitope melanoma peptide vaccine for patients with completely resected, high-risk stage III/IV melanoma.

Experimental Design: A total of 815 patients were enrolled from December 1999 to October 2006 into this six-arm study. GM-CSF was chosen to promote the numbers and functions of dendritic cells (DC). The melanoma antigen peptide vaccine (Tyrosinase_{368-376 (370D)}, gp100_{209-217 (210M)}, MART-1_27-35) in montanide was designed to promote melanoma-specific CD8⁺ T-cell responses.

Results: Although the overall RFS and OS were not significantly improved with the vaccine or GM-CSF when compared with placebo, immunomodulatory effects were observed in peripheral blood and served as important correlates to this therapeutic study. Peripheral blood was examined to evaluate the impact of GM-CSF and/or the peptide vaccine on peripheral blood immunity and to investigate potential predictive or prognostic biomarkers. A total of 11.3% of unvaccinated patients and 27.1% of vaccinated patients developed peptide-specific CD8⁺ T-cell responses. HLA-A2⁺ patients who had any peptide-specific CD8⁺ T-cell response at day +43 tended to have poorer OS in univariate analysis. Patients receiving GM-CSF had significant reduction in percentages of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) at day +43. In a subset of patients who received GM-CSF, circulating myeloid-derived suppressor cells (MDSC), and anti-GM-CSF–neutralizing antibodies (Nabs) were also modulated. The majority of patients developed anti-GM-CSF Nabs, which correlated with improved RFS and OS.

Conclusions: The assessment of cellular and humoral responses identified counterintuitive immune system changes correlating with clinical outcome. Clin Cancer Res; 23(17); 5034–43. ©2017 AACR.

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Dual Inhibition of HDAC and Tyrosine Kinase Signaling Pathways with CUDC-907 Inhibits Thyroid Cancer Growth and Metastases

Purpose: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer–related deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDAC) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response.

Experimental Design: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its antiproliferative effect in vitro and in vivo.

Results: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G₂–M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase-3/7 activity and decreased survivin levels and decreased cellular migration and invasion. CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Finally, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.

Conclusions: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer. Clin Cancer Res; 23(17); 5044–54. ©2017 AACR.

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Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors

Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested.

Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.

Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1–blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression.

Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. Clin Cancer Res; 23(17); 5149–61. ©2017 AACR.

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Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum–derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.

Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.

Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.

Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074–81. ©2017 AACR.

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WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non-Small Cell Lung Cancer

G1–S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2–M checkpoint for adaptation to stress and DNA repair, making G2–M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2–M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non–small cell lung cancer (NSCLC) and is commonly comutated with oncogenic KRAS mutations. We investigated the preclinical effects of AZD1775 in the context of KRAS/LKB1 in NSCLC. Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in LKB1-deficient NSCLC cells. In vitro, LKB1 deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type LKB1 cells. In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, combined AZD1775 and cisplatin extended overall survival compared with cisplatin alone. Our data suggest that lack of phosphorylation of LKB1 by ATM was involved in AZD1775-mediated cytotoxicity. Collectively, these findings provide a clinical application for AZD1775 with DNA-damaging agents in KRAS/LKB1 NSCLC. Cancer Res; 77(17); 4663–72. ©2017 AACR.

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Angela M.H. Brodie, PhD, FAACR: In Memoriam (1934-2017)

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SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710–22. ©2017 AACR.

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Resistance to the Antibody-Drug Conȷugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity

Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1–resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness. Cancer Res; 77(17); 4639–51. ©2017 AACR.

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Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas?

The epithelial-to-mesenchymal transition (EMT) is a reversible process comprised of various subprograms via which epithelial cells reduce their intercellular adhesions and proliferative capacity while gaining a mesenchymal phenotype with increased migratory and invasive properties. This process has been well described in several carcinomas, which are cancers of epithelial origin, and is crucial to metastatic tumor cell dissemination and drug resistance. In contrast, the precise role of EMT-related processes in tumors originating from mesenchymal tissues, such as bone and soft-tissues sarcomas, is still largely unclear. In fact, although the existence of the EMT in sarcomas appears paradoxical because these cancers are, by definition, mesenchymal ab initio, accumulating evidence suggests that many sarcomas can undergo EMT-related processes, which may be associated with aggressive clinical behavior. These processes may be especially operative in certain sarcoma subtypes, such as carcinosarcomas displaying a biphenotypic morphology with characteristics of both mesenchymal and epithelial tumors. In this review, we discuss findings regarding the potential existence of EMT-related processes in sarcomas and propose that sarcomas can reside in a metastable state, enabling them to become either more mesenchymal or epithelial under specific conditions, which likely has important clinical implications. Cancer Res; 77(17); 4556–61. ©2017 AACR.

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Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN{gamma} Signaling

Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. Cancer Res; 77(17); 4562–6. ©2017 AACR.

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APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM. ATR inhibition in APOBEC3A-expressing cells resulted in a surge of abasic sites at replication forks, revealing an ATR-mediated negative feedback loop during replication. The surge of abasic sites upon ATR inhibition associated with increased accumulation of single-stranded DNA, a substrate of APOBEC3A, triggering an APOBEC3A-driven feed-forward loop that ultimately drove cells into replication catastrophe. In a panel of cancer cell lines, ATRi selectively induced replication catastrophe in those harboring high APOBEC3A and/or APOBEC3B activities, showing that APOBEC3A and APOBEC3B activities conferred susceptibility to ATRi. Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567–78. ©2017 AACR.

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Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint

Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here, we report that A3A is highly expressed in subsets of pediatric and adult acute myelogenous leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell-cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small-molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A expression in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy. Cancer Res; 77(17); 4579–88. ©2017 AACR.

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Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589–601. ©2017 AACR.

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Identification of Interacting Stromal Axes in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673–83. ©2017 AACR.

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PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer

Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response. Cancer Res; 77(17); 4613–25. ©2017 AACR.

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Highlights from Recent Cancer Literature

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Inclusion of a Genetic Risk Score into a Validated Risk Prediction Model for Colorectal Cancer in Japanese Men Improves Performance

We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case–control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535–41. ©2017 AACR.

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Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties

Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of "metastatic inefficiency." Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. Cancer Prev Res; 10(9); 514–24. ©2017 AACR.

See related editorial by Hynds and Janes, p. 491

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When the Damage Is Done: Selecting Patients for Head and Neck Cancer Chemoprevention Trials

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Signals from the Adipose Microenvironment and the Obesity-Cancer Link--A Systematic Review

Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer. Epidemiologic, clinical, and preclinical data suggest that within the growth-promoting, proinflammatory microenvironment accompanying obesity, crosstalk between adipose tissue (comprised of adipocytes, macrophages and other cells) and cancer-prone cells may occur via obesity-associated hormones, cytokines, and other mediators that have been linked to increased cancer risk and/or progression. We report here a systematic review on the direct "crosstalk" between adipose tissue and carcinomas in humans. We identified 4,641 articles with n = 20 human clinical studies, which are summarized as: (i) breast (n = 7); (ii) colorectal (n = 4); (iii) esophageal (n = 2); (iv) esophageal/colorectal (n = 1); (v) endometrial (n = 1); (vi) prostate (n = 4); and (vii) ear-nose-throat (ENT) cancer (n = 1). Findings from these clinical studies reinforce preclinical data and suggest organ-dependent crosstalk between adipose tissue and carcinomas via VEGF, IL6, TNFα, and other mechanisms. Moreover, visceral white adipose tissue plays a more central role, as it is more bioenergetically active and is associated with a more procancer secretome than subcutaneous adipose tissue. Efforts to eavesdrop and ultimately interfere with this cancer-enhancing crosstalk may lead to new targets and strategies for decreasing the burden of obesity-related cancers. Cancer Prev Res; 10(9); 494–506. ©2017 AACR.

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Circulating RANKL and RANKL/OPG and Breast Cancer Risk by ER and PR Subtype: Results from the EPIC Cohort

Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case–control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n = 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (P_het = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01–1.63); P_trend = 0.20], but not ER– disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER–PR– disease [5th vs. 1st quintile RR = 0.60 (0.31–1.14); P_trend = 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk. Cancer Prev Res; 10(9); 525–34. ©2017 AACR.

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High Level of Tobacco Carcinogen-Derived DNA Damage in Oral Cells Is an Independent Predictor of Oral/Head and Neck Cancer Risk in Smokers

Exposure to tobacco-specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) is recognized to play an important role in the development of oral/head and neck squamous cell cancer (HNSCC). We recently reported higher levels of TSNA-associated DNA adducts in the oral cells of smokers with HNSCC as compared with cancer-free smokers. In this study, we further investigated the tobacco constituent exposures in the same smokers to better understand the potential causes for the elevated oral DNA damage in smokers with HNSCC. Subjects included cigarette smokers with HNSCC (cases, n = 30) and cancer-free smokers (controls, n = 35). At recruitment, tobacco/alcohol use questionnaires were completed, and urine and oral cell samples were obtained. Analysis of urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and N'-Nitrosonornicotine (NNN; TSNA biomarkers), 1-hydroxypyrene (1-HOP, a PAH), cotinine, 3'-hydroxycotinine, and the nicotine metabolite ratio (NMR) were performed. Cases and controls differed in mean age, male preponderance, and frequency of alcohol consumption (but not total alcoholic drinks). Univariate analysis revealed similar levels of NNN, 1-HOP, and cotinine between groups but, as reported previously, significantly higher DNA adduct formation in the cases. Multiple regression adjusting for potential confounders showed persistent significant difference in DNA adduct levels between cases and controls [ratio of geometric means, 20.0; 95% CI, 2.7–148.6). Our cohort of smokers with HNSCC demonstrates higher levels of TSNA-derived oral DNA damage in the setting of similar exposure to nicotine and tobacco carcinogens. Among smokers, DNA adduct formation may act as a predictor of eventual development of HNSCC that is independent of carcinogen exposure indicators. Cancer Prev Res; 10(9); 507–13. ©2017 AACR.

See related editorial by Johnson and Bauman, p. 489

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Multiparametric Detection of Antibodies against Different EBV Antigens to Predict Risk for Nasopharyngeal Carcinoma in a High-Risk Population of China

In this study, we aimed to use the combined detection of multiple antibodies against Epstein–Barr virus (EBV) antigens to develop a model for screening and diagnosis of nasopharyngeal carcinoma (NPC). Samples of 300 nasopharyngeal carcinoma patients and 494 controls, including 294 healthy subjects (HC), 99 non-nasopharyngeal carcinoma cancer patients (NNPC), and 101 patients with benign nasopharyngeal lesions (BNL), were incubated with the EUROLINE Anti-EBV Profile 2, and band intensities were used to establish a risk prediction model. The nasopharyngeal carcinoma risk probability analysis based on the panel of VCAgp125 IgA, EBNA-1 IgA, EA-D IgA, EBNA-1 IgG, EAD IgG, and VCAp19 IgG displayed the best performance. When using 26.1% as the cutoff point in ROC analysis, the AUC value and sensitivity/specificity were 0.951 and 90.7%/86.2%, respectively, in nasopharyngeal carcinoma and all controls. In nasopharyngeal carcinoma and controls without the non-nasopharyngeal carcinoma and BNL groups, the AUC value and sensitivity/specificity were 0.957 and 90.7%/88.1%, respectively. The diagnostic specificity and sensitivity of the EUROLINE Anti-EBV Profile 2 assay for both nasopharyngeal carcinoma and early-stage nasopharyngeal carcinoma were higher than that of mono-antibody detection by immune-enzymatic assay and real-time PCR (EBV DNA). In the VCA-IgA–negative group, 82.6% of nasopharyngeal carcinoma patients showed high probability for nasopharyngeal carcinoma, and the negative predictive value was 97.1%. In the VCA-IgA–positive group, 73.3% of healthy subjects showed low probability. The positive predictive value reached 98.2% in this group. The nasopharyngeal carcinoma risk probability value determined by the EUROLINE Anti-EBV Profile 2 might be a suitable tool for nasopharyngeal carcinoma screening. Cancer Prev Res; 10(9); 542–50. ©2017 AACR.

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TOC

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Proton Pump Inhibitor-related Mortality: Let Us Not Be Dead Wrong

We need to be very wary when research might be misinterpreted easily in ways that might scare patients and physicians away from appropriate medication use.

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Calendar Listings

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Instructions for Contributors

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Editorial Board

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Calendar

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Preface to the proceedings of the Workshop on Eosinophils in Allergy and Related Diseases 2016

Publication date: September 2017
Source:Allergology International, Volume 66, Supplement
Author(s): Kohei Yamauchi




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Enhanced Microalgal Growth and Effluent Quality in Tertiary Treatment of Livestock Wastewater Using a Sequencing Batch Reactor

Abstract

Effect of harvesting and hydraulic retention time (HRT) on the performance of a sequencing batch reactor (SBR), growing a green alga Botoryococcus braunii, was investigated. In this continuous tertiary treatment, relieving limitations of light, inorganic carbon, nitrogen, and phosphorous can make photoautotrophy active through the rapid fixation of the building blocks into microalgal biomass together with heterotrophy promoted by organics and self-shading effect. Analysis of the results reveals that the control over CO₂ supply and the extension of solid retention time (SRT) are the keys to maintaining higher biomass productivity and better treatability in the mixotrophic SBR. Among HRTs tested, the shortest HRT of 2 days could demonstrate the best removal efficiencies of ammonia (98.8%) and total phosphorus (96.2%) while keeping the highest specific growth rate of 0.23 day⁻¹. Those results provide understanding on the impact of settling sequence, which extends SRT to 5~7 days and prevents significant limitations of light and essential building blocks. With the interplay between photoautotrophic and heterotrophic metabolisms of microalgae, this study identifies how the mixotrophic SBR perform resource recovery during tertiary treatment of livestock wastewater, and how limitation is associated with the effluent quality in the SBR.

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Conditioning of Synthetic Sludge and Anaerobically Digested Sludge Using Chitosan, Organic Polyelectrolytes and Inorganic Metal Cations to Enhance Sludge Dewaterability

Abstract

Anaerobic digestion (AD) and dewatering are the most common and widely applied sludge treatment methods in wastewater treatment plants (WWTPs). However, sludge dewatering has been recognised as one of the most expensive and least understood processes. Therefore, this study investigated the dewatering performance of synthetic sludge in comparison with anaerobically digested sludge when conditioned with chitosan, organic polyelectrolytes and inorganic metal cations. Capillary suction time (CST), turbidity, electrical conductivity, zeta potential, cake solids content and particle size were used to assess sludge dewatering performance and to determine the optimum conditioner dose. The effectiveness of sludge conditioning was evaluated by batch experiments using a series of 250-mL jar test beakers. Both synthetic sludge and AD sludge exhibited similar trend but little different extent of dewaterability when conditioned with low molecular weight (MW) chitosan. The low MW and medium MW chitosans, commercial cationic polyelectrolytes and trivalent metal cations (Al³⁺, Fe³⁺) demonstrated as effective conditioning agents with good sludge dewaterability. When assessing the dewaterability measurement parameters using synthetic sludge, the optimal dosage was found at the range of 15 to 20 g-chitosan/kg-dry sludge where the values of CST, turbidity and cake solids content were attained between 6.6 and 11.0 s, 35.4–40.6 NTU, and 24.3–25.3%, respectively. The application of cationic polyelectrolytes and trivalent metal cations generally improved the sludge dewaterability via charge neutralisation and polymer bridging. This study also demonstrated that less complex chemically controlled synthetic sludge can be used for studying the final properties of complex real digested sludge.

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Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

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Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

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Impact of dysfunction of the facial nerve after superficial parotidectomy: a prospective study

Publication date: Available online 31 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): V.E. Prats-Golczer, E. Gonzalez-Cardero, J.A. Exposito-Tirado, E. Montes-Latorre, L.M. Gonzalez-Perez, P. Infante-Cossio
To evaluate the impact of dysfunction of the facial nerve after superficial parotidectomy for pleomorphic adenoma of the superficial lobe, we prospectively analysed the data of 79 patients using the Facial Disability Index (FDI) and the Short-Form 36-Item (SF-36) questionnaires up to 12 months postoperatively. The function of the facial nerve was grading on the House-Brackmann Scale. Results at 1 week and 1, 3, 6, and 12 months were compared with preoperative (baseline) measurement. The maximum reduction in FDI scores coincided with the highest facial paresis values at one week. Physical values on the FDI significantly decreased during the first three months (p=.039 at 3 months) and psychosocial values improved significantly from then onwards (p=.001 at 12 months). At 12 months, there were signs of full recovery compared with the preoperative baseline, and it was even exceeded in some psychosocial items. The SF-36 questionnaire showed no significant differences at any time during the study. The FDI was a useful instrument with which to understand the impact of facial disability and wellbeing associated with physical, social, and emotional aspects after superficial parotidectomy. Unlike the SF-36 questionnaire, the FDI offers clinicians a tool with which to counsel patients and better inform them about the anticipated results of operation before superficial parotidectomy.



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Corrigendum to “New approach to improve the keratinised peri-implant soft tissues in patients with intraoral osteocutaneous reconstruction using a free flap” [Br J Oral Maxillofac Surg 55 (September (7)) (2017) 732–33]

Publication date: Available online 31 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): N. Patel, D. Patel, J. Kwok




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Performance on a clinical quadriceps activation battery is related to a laboratory measure of activation and recovery after total knee arthroplasty

Publication date: Available online 31 August 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Michael Bade, Tamara Struessel, Roger Paxton, Joshua Winters, Carol Baym, Jennifer Stevens-Lapsley
ObjectiveTo determine the relationship between performance on a clinical quadriceps activation battery (QAB) with 1) activation measured by doublet interpolation and 2) recovery of quadriceps strength and functional performance following total knee arthroplasty (TKA).DesignThis was a planned secondary analysis of a randomized controlled trialSettingUniversity research laboratoryParticipantsOne hundred sixty-two patients (aged 63 ± 7 (mean ± sd) years; 89 females) undergoing TKA participated.Outcome MeasuresPatients were classified as HIGH (QAB ≥ 4/6) or LOW (QAB ≤3/6) based upon performance on the QAB measured 4 days after TKA. Differences between groups in activation and recovery at 1, 2, 3, 6, and 12 months after TKA were compared using a repeated measures maximum likelihood model.ResultsThe LOW QAB group demonstrated poorer quadriceps activation via doublet interpolation (p=0.01), greater quadriceps strength loss (p=0.01), and greater functional performance decline (all p<0.001) at 1 month after TKA compared to the HIGH QAB group. Differences between LOW and HIGH QAB groups on all measures did not persist at 3 and 12 months (all p>0.05).ConclusionPoor performance on the QAB early after TKA is related to poor quadriceps activation and poor recovery in the early postoperative period. Patients in the LOW QAB group took 3 months to recover to the same level as the HIGH QAB group. The QAB may be useful in identifying individuals who need specific interventions to target activation deficits or different care pathways in the early postoperative period to speed recovery after TKA.



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School honors Dr. Roy C. Page

The School of Dentistry's Department of Periodontics has renamed its research laboratory to honor one of the school's most illustrious faculty members and researchers, Dr. Roy C. Page.

The post School honors Dr. Roy C. Page appeared first on UW School of Dentistry.

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Epigenetic silencing of miR-493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1)

The potential mechanisms regarding how methylation of microRNA(miRNA) CpG Island could regulate cancer cell chemo-resistance remains unclear. This study aims to explore the epigenetic dysregulation mechanism o...

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Recombinant rabies virus expressing IL-15 enhances immunogenicity through promoting the activation of dendritic cells in mice

Abstract

Rabies remains a public health threat that kills approximately 59,000 people worldwide each year, most of which are from the developing countries of Africa and Asia where dog rabies are endemic. Therefore, developing an affordable and efficacious vaccine is crucial for rabies control in these countries. Interleukin (IL)-15, an immunoregulatory cytokine, is a pluripotent molecule with therapeutic potential, which targets many cell types and links the innate and adaptive immune system. In this study, IL-15 gene was cloned and inserted into the genome of a recombinant rabies virus (RABV) strain LBNSE (designated as LBNSE-IL15), and the effect of over-expression of IL-15 on the immunogenicity of RABV was investigated. It was found that mice vaccinated with LBNSE-IL15 could induce significantly higher level of virus-neutralizing antibody (VNA) than those immunized with LBNSE, resulting in the higher protection after challenge. Further investigation was performed to find out the possible role of IL-15 plays in the process of antibody induction, and it was found that LBNSE-IL15 could enhance the maturation of dendritic cells (DCs) in immunized mice. Furthermore, the mice immunized with LBNSE-IL15 could promote the T_FH cells differentiation and the generation of germinal center B cells and plasma cells. Together, these data indicated that IL-15 could be a potential adjuvant in enhancing the immunogenicity of RABV, contributing to the development of more-efficacious rabies vaccines.

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A study of the distribution of B-cell lymphoma/leukemia-2 in odontogenic cyst and tumors: Histochemical study

Khushboo Phull, Rashmi Metgud, Shrikant Patel

Journal of Cancer Research and Therapeutics 2017 13(3):570-575

Introduction: The odontogenic keratocyst is known for its aggressiveness, high recurrence rate, and transformation of keratinized epithelia to nonkeratinized squamous epithelium for which inflammation has been suggested to be responsible. B-cell lymphoma/leukemia-2 (Bcl-2) an anti-apoptotic protein, prolongs the life span of epithelial cells and allows proliferation, differentiation, and morphogenesis. Materials and Methods: Study was carried out comprising of 90 cases; (30 ameloblastoma, 30 keratocystic odontogenic tumor (KCOT), and 30 radicular cyst). Bcl-2 expression was determined with respect to localization, area (percentage) and intensity of stained cells in epithelium, and connective tissue stroma by counting the endothelial, round, and fusiform cells. Results: In epithelium bcl-2 expression in KCOTs was higher followed by ameloblastoma and lowest in the radicular cyst. Whereas, in connective tissue stroma bcl-2 expression was higher in KCOT and radicular cyst than ameloblastoma cases. Solid variants showed statistically higher expression as compared to the unicystic variants of ameloblastoma (P = 0.009, 0.033, 0.011, and 0.041). Conclusion: High expression of bcl-2 in KCOT supports the general agreement that some features of KCOT are those of a neoplasia. The bcl-2 expression in connective tissue cells suggests that these cells may also be important as epithelial cells in the biological behavior odontogenic keratocyst.

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Physical activity influences the immune system of breast cancer patients

Thorsten Schmidt, Marion van Mackelenbergh, Daniela Wesch, Christoph Mundhenke

Journal of Cancer Research and Therapeutics 2017 13(3):392-398

It has been suggested that physical activity in breast cancer patients can not only improve quality of life. Influences on physical and psychological levels have been evaluated, but effects on the immune system of breast cancer patients are hardly known. A PubMed search identified relevant trials and meta-analyses from 1970 to 2013. This review summarizes the results of international studies and the current discussion of effects of physical activity on the immune system of breast cancer patients. Highlighted are effects of physical activity on the immune system. Seven original articles and 14 reviews included in this review. Two original and the review articles includes other tumor entities besides breast cancer.Evaluated methods such as dose-response relationships for exercise in oncology, hardly exist. Increased immunological anti-cancer activity due to physical activity is probably mediated via an increase in number and cytotoxicity of monocytes and natural killer cells and cytokines.

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The impact of patient positioning and use of belly board on small bowel toxicity in patients receiving pelvic radiotherapy for gynecological malignancies

Milan Anjanappa, Rajeev Kavalakara Raghavan, Francis V James, Aswin Kumar, Susan Mathews, Sarin Bhaskaran, Shaiju Vasudevannair Sreedevi, Puthuveetil Govindan Jayaprakash

Journal of Cancer Research and Therapeutics 2017 13(3):519-523

Aim: To determine the efficacy of belly board device in patients receiving postoperative radiation for gynecological malignancies in terms of setup error and acute small bowel toxicity. Materials and Methods: Patients requiring postoperative radiation for gynecological malignancies were prospectively randomized to either treatment with supine position (supine arm) or prone position using belly board (prone arm). Each patient underwent computed tomography simulation in the assigned treatment position, and a three-dimensional conformal radiation was planned. Weekly two to three treatment sessions were verified using portal imaging and setup errors were noted. All patients were reviewed weekly to assess for symptoms and toxicity using a structured format. The systematic and random errors were calculated along the three axes. Results: Twenty-four patients were randomized and 22 patients were available for the final analysis. The systematic error in supine arm versus prone arm was 3.9 versus 3.5 mm, 2.1 versus 4.8 mm and 3.1 versus 3.1 mm along lateral, antero-posterior (AP) and cranio-caudal (CC) direction. The random error in supine arm versus prone arm was 5 versus 3.9 mm, 2.9 mm versus 4.4 mm and 4.3 versus 3.4 mm along lateral, AP and CC direction. The calculated planning target volume margin for supine arm was 1.3, 0.7, and 1.0 cm and margin for prone arm was 1.1, 1.5, and 1.0 cm along lateral, AP, and CC direction, respectively. One patient in supine arm developed Grade 3 toxicity. Conclusion: The systematic error and random error is more along AP direction for prone position. The acute small bowel toxicity was less using belly board.

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An update on studies on etiological factors, disease progression, and malignant transformation in oral submucous fibrosis

Samiha Bari, Rashmi Metgud, Zankhana Vyas, Aniruddh Tak

Journal of Cancer Research and Therapeutics 2017 13(3):399-405

Worldwide estimates of oral submucous fibrosis (OSMF) show a confinement to Indians and Southeast Asians. In India, the prevalence of OSMF has increased over the past four decades from 0.03% to 6.42%. The condition is well recognized for its malignant potential rate of 7-30%. The condition has a multifactorial etiology and may remain either stationary or become severe, leaving an individual physically challenged both physically and psychologically. Hence, the study aims at reviewing studies done on various etiological factors leading to its onset. Their analysis may serve as an adjunct in defining the broad spectrum of the causation of this potentially malignant disorder.

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Comment on: Survey of cervical cancer survivors regarding quality of life and sexual function

Antonio Simone Laganà, Valentina Lucia La Rosa, Daniele Fanale, Salvatore Giovanni Vitale

Journal of Cancer Research and Therapeutics 2017 13(3):598-599



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Lactate – A new frontier in the immunology and therapy of prostate cancer

Iuliana Nenu, Grigore-Aristide Gafencu, Tiberiu Popescu, Gabriel Kacso

Journal of Cancer Research and Therapeutics 2017 13(3):406-411

Prostate cancer, one of the most common male malignancies with an increasing incidence in the recent years, requires the development of new methods of treatment. One of the most debated subjects is the tumor-associated macrophages (TAM). Although, the pathophysiological mechanisms are still a subject of intense research, TAM acts as procarcinogenic factors. It was also demonstrated that hypoxia-inducible factor 1 (HIF1) induces the expression of TAM genes involved in prostate carcinogenesis. Furthermore, it should be noted that the stromal extracellular lactate, the result of tumoral glycolysis process is one of the HIF1 activators. In addition, lactate inhibits the differentiation of monocytes and dendritic cells and also induces the inactivation of the cytotoxic T-lymphocytes. Through an analysis of recent studies, we conclude that lactate is a vital component of several ways of modulating the immune response at the stromal prostatic adenocarcinoma including TAM activation and cytotoxic T lymphocytes immunosuppression. Our review focuses on the impact of lactate on prostatic adenocarcinoma progression in terms of its immunology, and how this influences the therapy of this condition and the clinical outcome.

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Honey bee venom combined with 1,25-dihydroxyvitamin D3as a highly efficient inducer of differentiation in human acute myeloid leukemia cells

Homa Mohseni-Kouchesfahani, Mohammad Nabioni, Zahra Khosravi, Maryam Rahimi

Journal of Cancer Research and Therapeutics 2017 13(3):544-549

Purpose: Most cancer cells exhibit a defect in their capacity to mature into nonreplicating adult cells and existing in a highly proliferating state. Differentiation therapy by agents such as 1,25-dihydroxyvitamin D3(1,25-(OH)2 VD3) represents a useful approach for the treatment of cancer including acute myeloid leukemia. Human myeloid leukemia cell lines are induced to terminal differentiation into monocyte lineage by 1,25-(OH)2 VD3. However, usage of these findings in the clinical trials is limited by calcemic effects of 1,25-(OH)2 VD3. Attempts to overcome this problem have focused on a combination of low concentrations 1,25-(OH)2 VD3 with other compounds to induce differentiation of HL-60 cells. In this study, the effect of honey bee venom (BV) and 1,25-(OH)2 VD3, individually and in combination, on proliferation and differentiation of human myeloid leukemia HL-60 cells were assayed. Materials and Methods: In this in vitro study, toxic and nontoxic concentrations of BV and 1,25-(OH)2 VD3 were tested using Trypan blue stained cell counting and (3[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. In addition, differentiation of cells was assayed using a Wright-Giemsa staining and nitroblue tetrazolium reduction test. Data were analyzed by a one-way analysis of the variance test using SPSS software. Results: Our findings showed that both the BV and 1,25-(OH)2 VD3, in a dose and time-dependent manner, caused cell death at high concentrations and inhibited cell proliferation at lower concentrations. About 5 nM of 1,25-(OH)2 VD3 induced differentiation of HL-60 cells to monocytes after 72 h. 2.5 μg/ml of BV suppressed proliferation of HL-60 cells but had not any effects on their differentiation, whereas in combination with 5 nM of 1,25-(OH)2 VD3, it enhanced antiproliferative and differentiation potency of 1,25-(OH)2 VD3. Conclusions: These results indicate that BV potentiates the 1,25-(OH)2 VD3-induced HL-60 cell differentiation into monocytes

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Spindle cell lesions: A review on immunohistochemical markers

Surbhi , Rashmi Metgud, Smitha Naik, Shrikant Patel

Journal of Cancer Research and Therapeutics 2017 13(3):412-418

The intriguing array of spindle cell lesions occurring, especially in the head and neck region, poses a critical diagnostic challenge not only to the histopathologist but also ultimately to the clinicians for planning an appropriate treatment protocol. Overlapping spectrum of clinico-radiographic and microscopic features further compounds this problem. In such situations, the aid of ancillary techniques such as immunohistochemistry (IHC) is sought to clinch the diagnosis. This study aims to review the spindle cell neoplasms of the oral cavity with emphasis on IHC.

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Giant cell tumour of distal ulna

Shreedhar Archik, Sanjay Kumar Tripathi, Saurav Narayan Nanda, Ashlesh Choudhari

Journal of Cancer Research and Therapeutics 2017 13(3):586-588

Giant cell tumor (GCT) of distal end epiphysis ulna is a rare presentation, and only few cases are reported in the scientific literature. We report a case of GCT of distal end epiphysis ulna treated at our Tertiary Care Hospital, Mumbai.

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Optical computed tomography in PRESAGE® three-dimensional dosimetry: Challenges and prospective

Davood Khezerloo, Hassan Ali Nedaie, Bagher Farhood, Alireza Zirak, Abbas Takavar, Nooshin Banaee, Isa Ahmadalidokht, Tomas Kron

Journal of Cancer Research and Therapeutics 2017 13(3):419-424

With the advent of new complex but precise radiotherapy techniques, the demands for an accurate, feasible three-dimensional (3D) dosimetry system have been increased. A 3D dosimeter system generally should not only have accurate and precise results but should also feasible, inexpensive, and time consuming. Recently, one of the new candidates for 3D dosimetry is optical computed tomography (CT) with a radiochromic dosimeter such as PRESAGE®. Several generations of optical CT have been developed since the 90s. At the same time, a large attempt has been also done to introduce the robust dosimeters that compatible with optical CT scanners. In 2004, PRESAGE® dosimeter as a new radiochromic solid plastic dosimeters was introduced. In this decade, a large number of efforts have been carried out to enhance optical scanning methods. This article attempts to review and reflect on the results of these investigations.

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Prospects of cytological cervical cancer screening in India: Exploring adjuvant approaches

Sandeep Singh, Showket Hussain, Sorabh Badaya

Journal of Cancer Research and Therapeutics 2017 13(3):389-391



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Utility of cell block to detect malignancy in fluid cytology: Adjunct or necessity?

Sumedha Dey, Dipanwita Nag, Ayandip Nandi, Ranjana Bandyopadhyay

Journal of Cancer Research and Therapeutics 2017 13(3):425-429

Aim of the Study: Cell block (CB) technique when supplemented with conventional smear, provides increased cellularity, preservation of architectural pattern with excellent morphology, and a clear background. We compare the utility of CB technique compared to conventional smear in detection of malignancy in serous effusions. Materials and Methods: An institution-based observational and analytical study was carried out over 1 year on 50 patients with effusions. The residual amount of centrifuged deposit after preparation of conventional smear was mixed with 10% alcohol-formalin solution, and CBs were prepared. Calretinin and cytokeratin 5 were used for reactive mesothelial cells and Wilms tumor 1, thyroid transcription factor 1, CDX2, and estrogen receptor were used to confirm the adenocarcinoma cells. Results: Maximum patients belonged to the age group of 61–70 years. Male:female ratio 1:1.17. Most common cause of malignant peritoneal effusion was due to ovarian malignancies in females and adenocarcinoma of stomach in males while, in case of pleural effusion, it was breast carcinoma in females and lung carcinoma in males. Thirteen suspicious cases were subjected to immunohistochemistry (IHC). In 70% cases, CB findings were consistent with the findings of conventional smears. In 20% cases, the conventional smears were suspicious for malignancy, and malignancy was confirmed by CB technique, whereas in 10% cases, both smears and CB were suspicious for malignancy and the original nature of the lesion was confirmed by the IHC. Sensitivity and specificity of CB compared to conventional smear were 88.88% and 86.98%, respectively. Conclusion: CB produced significantly better results (P = 0.0271) while detecting malignant lesions and reducing suspicious results (P = 0.0226).

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Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model

Hooman Yarmohammadi, Luke R Wilkins, Joseph P Erinjeri, Ronald D Novak, Agata A Exner, Hanping Wu, Elena N Petre, Edward Boas, Etay Ziv, John R Haaga

Journal of Cancer Research and Therapeutics 2017 13(3):533-537

Background/Aim: The aim of this study was to determine whether the addition of bumetanide (BU), a glycolytic metabolism pathway inhibitor, to arterial embolization improves tumor necrosis of N1-S1 hepatocellular carcinoma in a rat model. Materials and Methods: N1-S1 tumors were surgically implanted in the liver of 14 Sprague-Dawley rats. The rats were divided into three groups: In control group (n = 5), 1 ml of normal saline was injected intra-arterially. The tumor in the transarterial embolization group (TAE, n = 4) was embolized using 10 mg of 50–150 μ polyvinyl alcohol (PVA) particles and embolization plus BU group (TAE + BU, n = 5) were embolized with 10 mg of PVA plus 0.04 mg/kg of BU. Tumor volume was measured using two-dimensional ultrasound before intervention and twice a week afterward. Relative tumor volume after the intervention was calculated as the percentage of preinterventional tumor volume. After 4 weeks of observation, the rats were sacrificed for histopathological evaluation. Results: No statistically significant difference was detected in the preintervention tumor sizes between the three groups (P > 0.05). In the control group, the relative tumor volume increased to 142.5% larger than baseline measurements. In the TAE group, the tumor volume decreased by 18.2 ± 12.2%. The tumor volume in the TAE + BU group decrease by 90.4 ± 10.2%, which was 72.2% more than in TAE only group (P < 0.0001). Histopathological evaluation demonstrated no residual tumor in the TAE + BU group. Conclusion: Tumor necrosis significantly increased in N1-S1 tumor that received BU at the time of TAE when compared to TAE alone.

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Epidemiological profile of head and neck cancer patients in Western Uttar Pradesh and analysis of distributions of risk factors in relation to site of tumor

Mohammad Shadab Alam, Shahid Ali Siddiqui, Roshan Perween

Journal of Cancer Research and Therapeutics 2017 13(3):430-435

Background: Head and neck cancers (HNCs) are a major form of cancers in India. The spectrum varies from place to place within the country because of significant diversified risk factors. Aims and Objective: To study, epidemiology and risk factors of HNC patients from Western Uttar Pradesh and to find out the correlation between risk factors and different anatomical regions involved. Materials and Methods: All patients with histologically confirmed diagnoses of HNC between January 2011 and December 2013 were selected from hospital records. Data regarding age, gender, addiction habits, site of tumor, and other details were obtained from their clinical records, and statistical analysis was done. Results and Conclusion: HNC accounts for 21.2% of total body malignancy and 47% of all malignancies in males and 2.5% in females. Squamous cell carcinoma was the most common histological type (97%). Maximum incidence of HNC (>60%) was in 40–60 year of age. Male:female ratio was 16:1. Oral cancers were most common HNC in patients below 40 year age group, whereas carcinoma oropharynx and larynx were more common in patients above 40 year age group. Tobacco smoking was a most prevalent risk factor for carcinoma oropharynx, larynx, and hypopharynx. Tobacco chewing was a most prevalent risk factor in females, young males, and carcinoma buccal mucosa patients. Habit of tobacco consumption in HNC patients was much higher than their normal counterpart. Alcohols drinking alone was observed in <1% patient as a risk factor. In oral tongue cancer, smoking and tobacco chewing were equally prevalent. Habit of tobacco chewing and alcohol were significantly higher in carcinoma buccal mucosa than other HNC suggesting synergistic effect specific to this site.

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Serum metabolomics in oral leukoplakia and oral squamous cell carcinoma

Gokul Sridharan, Pratibha Ramani, Sangeeta Patankar

Journal of Cancer Research and Therapeutics 2017 13(3):556-561

Context: Metabolomics is a core discipline of system biology focusing on the study of low molecular weight compounds in biological system. Analysis of human metabolome, which is composed of diverse group of metabolites, can aid in diagnosis and prognosis of oral squamous cell carcinoma (OSCC). Aim: The aim of the present study is to analyze and identify serum metabolites in oral leukoplakia and OSCC as a potential diagnostic biomarker and a predictor for malignant transformation of oral leukoplakia. Subjects and Methods: Serum metabolomic profile of patients diagnosed with oral leukoplakia (n = 21) and OSCC (n = 22) was compared with normal controls (n = 18) using quadrupole time of flight-liquid chromatography–mass spectrometry. MassHunter profile software was used for metabolite identification, and statistical analysis to assess the variation of the metabolites was performed using Mass Profiler Professional software. Statistical significance between the three groups was expressed using ANOVA (P < 0.05), and intergroup comparison was done using Student's t-test (P < 0.05). Results: Significant upregulation of estradiol-17-beta-3-sulfate, L-carnitine, 5-methylthioadenosine (MTA), 8-hydroxyadenine, 2-methylcitric acid, putrescine, and estrone-3-sulfate was seen in oral leukoplakia and OSCC than in normal controls. Furthermore, significant upregulation of 5,6-dihydrouridine, 4-hydroxypenbutolol glucuronide, 8-hydroxyadenine, and putrescine was evident in OSCC group than in oral leukoplakia. Conclusion: Upregulation of L-carnitine, lysine, 2-methylcitric acid, putrescine; 8-hydroxyadenine; 17-estradiol; 5,6-dihydrouridine; and MTA suggests their diagnostic potential in oral leukoplakia and OSCC. Further, a significant upregulation of putrescine, 8-hydroxyadenine, and 5,6-dihydrouridine in OSCC than in oral leukoplakia indicates their potential role in predicting the malignant transformation of oral leukoplakia.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2iL5K3b