Curcumin attenuates smoking and drinking activated NF-κB/IL-6 inflammatory signaling axis in cervical cancer.

BACKGROUND: High-risk strains of HPV are known to cause cervical cancer. Multiple clinical studies have emphasized that smoking and drinking are critical risk factors for cervical cancer and its high-grade precursors. In this study, we investigated if smoking and/or drinking augment the molecular mechanisms of cervical carcinogenesis and defined a potential therapeutic approach for their attenuation. METHODS: The impact of benzo[a]pyrene (B[a]P) and/or ethanol (EtOH) exposure on cervical cancer cells was assessed by measuring changes in their cell migration and invasion characteristics. Expression of HPV16 E6/E7, NF-κB, cytokines, and inflammation mediators was determined using qRT-PCR, immunoblotting, ELISA, luciferase reporter assay, and confocal microscopy. Herein, we used curcumin (Cur), and PLGA nanoparticle formulation of curcumin (PLGA-Cur) and determined effectiveness of free Cur and PLGA-Cur formulation on smoking and drinking activated NF-κB/IL-6 mediated inflammatory signaling pathways using in vitro cervical cancer models. RESULTS: Treatments with B[a]P and/or EtOH altered the expression of HPV16 E6/E7 oncogenes and EMT markers in cervical cancer cells; it also enhanced migration and invasion. In addition, B[a]P and/or EtOH exposure promoted inflammation pathways through TNF-α and NF-κB signaling, leading to IL-6 upregulation and activation of VEGF. The molecular effects caused by B[a]P and/or EtOH exposure were effectively attenuated by curcumin (Cur)/PLGA-Cur treatment. CONCLUSIONS: These data suggest a molecular link between smoking, drinking, and HPV infectivity in cervical carcinogenesis. In addition, attenuation of these effects by treatment with Cur/PLGA-Cur treatment, implies the role of curcumin in cervical cancer prevention and treatment.

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors.

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Incorporating Halal Into Healthy and Equitable Dietary Patterns to Address Food and Nutrition Security Among K-12 and University Students: A Perspective.

Food and nutrition insecurity exist at an alarming rate in the US educational system, ranging from 17% among K-12 students up to 58.8% among university students. Many Muslim American students face food and nutrition insecurity due, in part, to a lack of acknowledgment of student adherence to halal dietary guidelines and the availability of certified halal options at school. This has implications for health, learning, and social outcomes. In this perspective paper, we provide short-term, mid-term, and long-term recommendations to address food and nutrition insecurity among halal-observant students to advance healthy dietary patterns.

MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway.

Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.

Oropharyngeal Squamous Cell Carcinoma Outcomes by p16INK4a Antigen Status in a Veteran Population.

Background: The correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest. We aimed to study immunoexpression of the p16INK4a (p16) antigen, a surrogate marker for high-risk HPV infection, in oropharyngeal SCC among veterans to estimate HPV-related cancer and survival. Secondary aims included stratification of race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, and age at diagnosis. Methods: A retrospective electronic health record review was performed between January 1, 2000, and December 31, 2008, at a tertiary-level US Department of Veterans Affairs (VA) medical center for veterans who were treated for oropharyngeal SCC, had follow-up for a minimum of 2 years, and for whom paraffin-embedded tissue was available. Paraffin-embedded tissue was analyzed for p16 expression. Results: We identified 66 veterans who met the inclusion criteria. p16 expression was observed in 29% of the patients. All patients were male with no difference in age at diagnosis between the groups. Among patients with p16-negative status, 60% were African American, whereas among patients with p16-postive status, 32% were African American (P = .04). Among patients with p16-postive status, 22% were tobacco-naïve, and 18% were alcohol-naïve vs 0% and 4%, respectively, of patients with p16-negative status (P = .005 and P = .12, respectively). Two-year survival was the same for both groups (P = .52). Conclusions: We observed p16 expression in 29% of VA patients with oropharnygeal SCC, which was less than observed in non-VA populations. At presentation, both groups demonstrated a predilection for tonsil location and late stage without significant difference in age or disease-specific survival. Disparities in racial distribution and tobacco use between patients with and without p16-positive status appear like that reported in non-VA populations; however, the frequently reported younger age at presentation, lower stage, and improved prognosis were not observed.

Role Of Cd8+ Tumour-Infiltrating Lymphocytes In Predicting Regional Lymph Node Metastasis In Lip And Oral Cavity Squamous Cell Carcinoma.

BACKGROUND: Lip and oral squamous cell carcinoma maintains a significant disease burden in Pakistan. The latest research on cancer focuses more on the role of body's immune response in tumour progression and spread rather than on the nature of neoplastic cells. Tumour-infiltrating lymphocytes constitute a major part of the tumour microenvironment and infiltration of tumour stroma by cytotoxic T-cells are known to limit the tumour progression in various malignancies, such as colorectal and stomach cancers. In our study, we aim to establish the prognostic role of CD8+ tumour-infiltrating lymphocytes in lip and oral squamous cell carcinoma. METHODS: Clinico-pathological data and paraffin-embedded blocks were obtained for 100 cases of lip and oral squamous cell carcinoma. These cases were selected through non-probability, convenience sampling at the Histopathology department of A.F.I.P., Rawalpindi. Fresh sections from the tumour proper were taken and CD8 immuno-marker was applied. Data was recorded, entered and analysed with S.P.S.S. version 27.0 and Microsoft Excel. Qualitative variables were represented as frequency/percentages and quantitative variables were represented as mean and standard deviation. Chi-squared test was applied to test association between categorical data. A p-value of <0.05 was taken as significant. RESULTS: Increased CD8 T.I.L. density was significantly associated with pN stage (p-value= .000) and early clinical stage (p-value= .014). No significant association with other clinico-pathological parameters was established. CONCLUSIONS: CD8 T.I.L. density is a reliable marker for predicting absence or presence of cervical nodal metastasis in lip and oral S.C.C. Its predictive role in determining overall survival rate should be evaluated in future studies.

The next phase in patient safety education: Towards a standardized, tools-based pathology patient safety curriculum: A call to action from the Association of Pathology Chairs' Residency Program Directors Section Training Residents in Patient Safety Workgroup.

Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum.

Spontaneous Pneumomediastinum in COVID-19 Pneumonia: A Rare Occurence.

Spontaneous pneumomediastinum with COVID pneumonia is a rare occurrence with or without accompanying subcutaneous emphysema or pneumothorax. The aim of this study was to establish relation of this complication to severity of lung disease and its clinical outcome. The study was conducted for a period of seven months from April to October 2020 in the CT Department of Armed Forces Institute of Radiology and Imaging (AFIRI), Rawalpindi, Pakistan. All COVID positive patients having spontaneous pneumomediastinum on high resolution CT (HRCT) chest were included (n=14). These patients were assessed for severity of lung disease as per CT severity score (CTSS), and were followed up for their clinical outcome. All patients with spontaneous pneumomediastinum had moderate to severe degree of COVID pneumonia; mortality in patients with pneumomediastinum was 50%; and was seen in those patients who had greater severity of lung disease as per the CTSS. Key Words: Spontaneous, Pneumomediastinum, COVID, Pneumothorax, Subcutaneous, Emphysema.

Ancillary findings on high resolution CT chest associated with typical features of COVID-19 pneumonia (Observational descriptive study at a tertiary care hospital).

OBJECTIVE: To determine the frequency of ancillary pulmonary signs and their relation to the severity of disease seen on high-resolution computed tomography of chest in patients of coronavirus disease-2019 pneumonia. METHODS: The observational descriptive study was conducted at the Armed Forces Institute of Radiology and Imaging, Rawalpindi, Pakistan, from March to July 2020, and included in place of comprised all coronavirus disease-2019 patients who were found positive on reverse transcription-polymerase chain reaction-and were referred to have high-resolution computed tomography of chest. Ancillary pulmonary findings in addition to typical features of coronavirus disease-2019 pneumonia were recorded. These included vacuole sign, halo sign, reverse halo sign, subpleural white line, subpleural translucent line, microvascular dilatation, fibrotic streaks and bronchiectasis. Relative frequency of these signs were determined for mild versus and severe disease, as determined by the computed tomography severity score. Data was analysed using SPSS 26. RESULTS: Of the 1645 patients, 1286(78.2%) were males and 359(21.8%) were females. The overall mean age was 47.5±15.7 years (range: 1-92). High-resolution computed tomography was normal in 418(25.4%) patients, typical findings for coronavirus disease-2019 were seen in 1110(67.5%), indeterminate in 113(16.9%) and atypical in 4(0.2%). Vacuole sign, subpleural white line, subpleural translucent sign, microvascular dilatation and fibrotic streaks were more commonly seen in severe disease (p<0.001), while discrete pulmonary nodule was identified more in the milder form (p<0.05). Halo and reverse halo signs as well as bronchiectatic changes demonstrated no significant propensity to the degree of disease severity (p>0.05). CONCLUSIONS: Coronavirus disease-2019 pneumonia demonstrated various ancillary pulmonary features on high resolution computed tomography of the chest in addition to typical findings more commonly described; radiologists should be aware of these signs and their relation to disease severity.

Targeted Next-generation Sequencing for Reliable Detection of Genetic Status in Breast Cancer.

OBJECTIVE: To test the germline oncogenic mutations in BRCA1 and BRCA2 genes, associated with triple-negative breast cancer (TNBC) patients under study, by targeted sequencing of their DNA with next-generation sequencing (NGS) platform. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Histopathology Department, Armed Forces Institute of Pathology (AFIP) Rawalpindi, Pakistan from May to June 2020. METHODOLOGY: Peripheral blood of 14 women (aged ≤60) with triple negative breast carcinoma (TNBC) was taken with the consent of performing germline genetic testing. Targeted NGS was performed for all coding regions and splicing sites of BRCA1 and BRCA2 genes, using AmpliSeq for Illumina BRCA Panel and Illumina MiSeq sequencer (placed at AFIP). Analysis and interpretation of the sequencing results have been done by using Illumina bioinformatics tools and external databases. RESULTS: Two hundred and fifty-four variants were detected in BRCA1 and BRCA2 genes, having variant quality score of 100 in all cases under study. As a result, two pathogenic variants and three variants of uncertain significance were interpreted in this germline pipeline. Cases with pathogenic variants had early onset breast cancer with age less than 35. CONCLUSION: Germline variants in BRCA were detected in the known cases of TNBC, which will not only identify the most prevalent mutations in this region; but will also make them a candidate to receive targeted therapies, which was previously not possible without genetic testing. Moreover, this study further validates the importance of early BRCA genetic screening in young patients, who have positive family history of breast carcinoma. Key Words: Breast cancer, Triple negative, Next-generation sequencing, BRCA1, BRCA2.

Smoking and COVID-19: Adding Fuel to the Flame.

The coronavirus disease 2019 (COVID-19) pandemic, an infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has led to more than 771,000 deaths worldwide. Tobacco smoking is a major known risk factor for severe illness and even death from many respiratory infections. The effects of smoking on COVID-19 are currently controversial. Here, we provide an overview of the current knowledge on the effects of smoking on the clinical manifestations, disease progression, inflammatory responses, immunopathogenesis, racial ethnic disparities, and incidence of COVID-19. This review also documents future directions of smoking related research in COVID-19. The current epidemiological finding suggests that active smoking is associated with an increased severity of disease and death in hospitalized COVID-19 patients. Smoking can upregulate the angiotensin-converting enzyme-2 (ACE-2) receptor utilized by SARS-CoV-2 to enter the host cell and activate a 'cytokine storm' which can lead to worsen outcomes in COVID-19 patients. This receptor can also act as a potential therapeutic target for COVID-19 and other infectious diseases. The COVID-19 pandemic sheds light on a legacy of inequalities regarding gender, racial, and ethnic health disparities associated with active smoking, thus, smoking cessation may help in improving outcomes. In addition, to flatten the COVID-19 curve, staying indoors, avoiding unnecessary social contact, and bolstering the immune defense system by maintaining a healthy diet/living are highly desirable.

Social Media Engagement at Academic Conferences: Report of the Association of Pathology Chairs 2018 and 2019 Annual Meeting Social Media Committee.

The use of social media at academic conferences is expanding, and platforms such as Twitter are used to share meeting content with the world. Pathology conferences are no exception, and recently, pathology organizations have promoted social media as a way to enhance meeting exposure. A social media committee was formed ad hoc to implement strategies to enhance social media involvement and coverage at the 2018 and 2019 annual meetings of the Association of Pathology Chairs. This organized approach resulted in an 11-fold increase in social media engagement compared to the year prior to committee formation (2017). In this article, the social media committee reviews the strategies that were employed and the resultant outcome data. In addition, we categorize tweets by topic to identify the topics of greatest interest to meeting participants, and we discuss the differences between Twitter and other social media platforms. Lastly, we review the existing literature on this topic from 23 medical specialties and health care fields.

Protein kinase D1 regulates subcellular localisation and metastatic function of metastasis-associated protein 1.

BACKGROUND: Cancer progression and metastasis is profoundly influenced by protein kinase D1 (PKD1) and metastasis-associated protein 1 (MTA1) in addition to other pathways. However, the nature of regulatory relationship between the PKD1 and MTA1, and its resulting impact on cancer metastasis remains unknown. Here we present evidence to establish that PKD1 is an upstream regulatory kinase of MTA1. METHODS: Protein and mRNA expression of MTA1 in PKD1-overexpressing cells were determined using western blotting and reverse-transcription quantitative real-time PCR. Immunoprecipitation and proximity ligation assay (PLA) were used to determine the interaction between PKD1 and MTA1. PKD1-mediated nucleo-cytoplasmic export and polyubiquitin-dependent proteosomal degradation was determined using immunostaining. The correlation between PKD1 and MTA1 was determined using intra-tibial, subcutaneous xenograft, PTEN-knockout (PTEN-KO) and transgenic adenocarcinoma of mouse prostate (TRAMP) mouse models, as well as human cancer tissues. RESULTS: We found that MTA1 is a PKD1-interacting substrate, and that PKD1 phosphorylates MTA1, supports its nucleus-to-cytoplasmic redistribution and utilises its N-terminal and kinase domains to effectively inhibit the levels of MTA1 via polyubiquitin-dependent proteosomal degradation. PKD1-mediated downregulation of MTA1 was accompanied by a significant suppression of prostate cancer progression and metastasis in physiologically relevant spontaneous tumour models. Accordingly, progression of human prostate tumours to increased invasiveness was also accompanied by decreased and increased levels of PKD1 and MTA1, respectively. CONCLUSIONS: Overall, this study, for the first time, establishes that PKD1 is an upstream regulatory kinase of MTA1 status and its associated metastatic activity, and that the PKD1-MTA1 axis could be targeted for anti-cancer strategies.

Clinical significance of MUC13 in pancreatic ductal adenocarcinoma.

BACKGROUND: Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. METHODS: MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. RESULTS: MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P < 0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS = 9.7, P < 0.0001) as compared to low expression in tumor adjacent tissues (MCS = 4, P < 0.001) along with faint or no expression in normal pancreatic tissues (MCS = 0.8; AUC >0.8; P < 0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P < 0.05), invasion of cancer to peripheral tissues (P < 0.5) and poor patient survival (P < 0.05; prognostic AUC = 0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. CONCLUSION: This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test.

Prostatic adenocarcinoma oncocytic variant: Case report and literature review.

The oncocytic variant of prostatic adenocarcinoma is exceptionally rare with only 4 cases reported in the English literature. Little is known about the clinical behavior of this variant of prostatic adenocarcinoma, because of the exceptionally low number of reported cases. The 2016 World Health Organization Classification of Tumors of Prostate does not recognize the oncocytic variant, again likely related to the exceptional paucity of reported cases. Here, we report the fifth case of the oncocytic variant of acinar type prostatic adenocarcinoma in an asymptomatic 64-year-old Caucasian American male with elevated serum prostate specific antigen (7.33 ng/mL; normal range 0-4.00 ng/mL) during routine blood screening for diabetes mellitus. At subsequent transrectal prostate biopsy, the right side of prostate was infiltrated by adenocarcinoma with tumor cells forming variably differentiated glands, including some poorly differentiated. Tumor cell nuclear:cytoplasmic ratio was low, with small to intermediate sized vesicular nuclei and only rare discernable small nucleoli. Cellular cytoplasm was characteristically granular pink with sharply defined cell membranes. Positive AMACR (P504S) epithelial immunohistochemical staining and absence of staining for prostatic basal cells confirmed the tumor to be primary prostatic adenocarcinoma. AMACR immunohistochemical staining was also helpful with accurate grading of the tumor due to the difficulty of differentiating tumor cells from residual prostate myocytes at routine hematoxylin and eosin (HE) staining. This new case adds to the exceptionally small number of previously reported cases of the oncocytic variant of primary prostatic adenocarcinoma. It also highlights the difficulty associated with Gleason scoring of the oncocytic variant by routine HE evaluation and the usefulness of AMACR (P504S) immunostaining for accurate grading of prostatic adenocarcinoma in the oncocytic variant.

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic ß-catenin Signaling and EMT Progression.

Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), ß-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3ß. In molecular docking analysis, ormeloxifene showed proficient docking with ß-catenin and GSK3ß. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G0-G1 phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 µg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving ß-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267-80. ©2017 AACR.

Disparity in rates of HPV infection and cervical cancer in underserved US populations.

There is a higher rate of HPV infection and cervical cancer incidence and mortality in underserved US population who reside in Appalachian mountain region compared to Northern Plains. Social and behavioral factors such as smoking and alcohol consumption are for such a high incidence. However, by and large, the reasons for these discrepancies lie in the reluctance of the underserved population to adopt preventive measures such as prophylactic Human papilloma virus (HPV) vaccines and Pap smear screening that have significantly reduced the incidence and mortality rate of cervical cancer in Caucasian women. Thus, it is clear that drastic change in social behavior and implementation of preventive measures is required to effectively reduce the incidence and mortality from cervical cancer in this underserved population.

Androgen receptor agonists increase lean mass, improve cardiopulmonary functions and extend survival in preclinical models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that predominantly affects boys as a result of mutation(s) in the dystrophin gene. DMD is characterized by musculoskeletal and cardiopulmonary complications, resulting in shorter life-span. Boys afflicted by DMD typically exhibit symptoms within 3-5 years of age and declining physical functions before attaining puberty. We hypothesized that rapidly deteriorating health of pre-pubertal boys with DMD could be due to diminished anabolic actions of androgens in muscle, and that intervention with an androgen receptor (AR) agonist will reverse musculoskeletal complications and extend survival. While castration of dystrophin and utrophin double mutant (mdx-dm) mice to mimic pre-pubertal nadir androgen condition resulted in premature death, maintenance of androgen levels extended the survival. Non-steroidal selective-AR modulator, GTx-026, which selectively builds muscle and bone was tested in X-linked muscular dystrophy mice (mdx). GTx-026 significantly increased body weight, lean mass and grip strength by 60-80% over vehicle-treated mdx mice. While vehicle-treated castrated mdx mice exhibited cardiopulmonary impairment and fibrosis of heart and lungs, GTx-026 returned cardiopulmonary function and intensity of fibrosis to healthy control levels. GTx-026 elicits its musculoskeletal effects through pathways that are distinct from dystrophin-regulated pathways, making AR agonists ideal candidates for combination approaches. While castration of mdx-dm mice resulted in weaker muscle and shorter survival, GTx-026 treatment increased the muscle mass, function and survival, indicating that androgens are important for extended survival. These preclinical results support the importance of androgens and the need for intervention with AR agonists to treat DMD-affected boys.

NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016.

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.