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Background Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. Methods To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. Results We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1 . To further investigate the role of BAP1 , we used our recently developed cancer driver gene prioritization algorithm, HIT’nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. Conclusions Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

Development of neuroendocrine prostate cancer (NEPC) is emerging as a major problem in clinical management of advanced prostate cancer (PCa). As increasingly potent androgen receptor (AR)‐targeting antiandrogens are more widely used, PCa transdifferentiation into AR‐independent NEPC as a mechanism of treatment resistance becomes more common and precarious, since NEPC is a lethal PCa subtype urgently requiring effective therapy. Reprogrammed glucose metabolism of cancers, that is elevated aerobic glycolysis involving increased lactic acid production/secretion, plays a key role in multiple cancer‐promoting processes and has been implicated in therapeutics development. Here, we examined NEPC glucose metabolism using our unique panel of patient‐derived xenograft PCa models and patient tumors. By calculating metabolic pathway scores using gene expression data, we found that elevated glycolysis coupled to increased lactic acid production/secretion is an important metabolic feature of NEPC. Specific inhibition of expression of MCT4 (a plasma membrane lactic acid transporter) by antisense oligonucleotides led to reduced lactic acid secretion as well as reduced glucose metabolism and NEPC cell proliferation. Taken together, our results indicate that elevated glycolysis coupled to excessive MCT4‐mediated lactic acid secretion is clinically relevant and functionally important to NEPC. Inhibition of MCT4 expression appears to be a promising therapeutic strategy for NEPC. Neuroendocrine prostate cancer (NEPC) is considered a next‐generation clinical problem in prostate cancer management in urgent need of effective therapeutic strategies. This is the first description of NEPC metabolism in a clinically relevant and biologically functional manner, filling in a crucial knowledge gap regarding the metabolic phenotype of NEPC and its therapeutic possibilities.

We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF) by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB) and the upper hair sheaths (HS) including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER) family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation.

Traumatic rotator cuff tears in patients younger than 25 years are rare events, with few reports in the literature. When compared with the more mature shoulder, the young, healthy supraspinatus tendon is a robust tendon that is able to absorb a significant amount of energy before tendon failure. Therefore, the diagnosis of a rotator cuff tear can be often overlooked in this population due to the patient’s age. This is a report of traumatic supraspinatus repairs in patients younger than 25 years. Nine patients younger than 25 years were identified with a posttraumatic supraspinatus tear as visualized during routine diagnostic shoulder arthroscopy. These 9 patients represented 0.33% of all rotator cuff repairs during a 9-year period. Average patient age was 19.1 years (±3.7 years; range, 13 to 25 years). Magnetic resonance imaging failed to diagnose a rotator cuff tear in 50% of the patients. Mean delay from injury to surgery was 6.6 months. All tears were arthroscopically repaired. Concomitant anterior instability pathology was demonstrated among 66.7% of the patients. No complications were reported. At latest follow-up, all patients reported minimal to no shoulder pain and were tolerating strenuous work, activities, and sports without significant complaints. Even with advanced imaging, the diagnosis of a rotator cuff tear can often be missed in this patient population. Although clinical outcomes can be good, care must be taken to broaden the diagnostic differential in young patients with posttraumatic shoulder pain. [Traumatic rotator cuff tears in patients younger than 25 years are rare events, with few reports in the literature. When compared with the more mature shoulder, the young, healthy supraspinatus tendon is a robust tendon that is able to absorb a significant amount of energy before tendon failure. Therefore, the diagnosis of a rotator cuff tear can be often overlooked in this population due to the patient’s age. This is a report of traumatic supraspinatus repairs in patients younger than 25 years. Nine patients younger than 25 years were identified with a posttraumatic supraspinatus tear as visualized during routine diagnostic shoulder arthroscopy. These 9 patients represented 0.33% of all rotator cuff repairs during a 9-year period. Average patient age was 19.1 years (±3.7 years; range, 13 to 25 years). Magnetic resonance imaging failed to diagnose a rotator cuff tear in 50% of the patients. Mean delay from injury to surgery was 6.6 months. All tears were arthroscopically repaired. Concomitant anterior instability pathology was demonstrated among 66.7% of the patients. No complications were reported. At latest follow-up, all patients reported minimal to no shoulder pain and were tolerating strenuous work, activities, and sports without significant complaints. Even with advanced imaging, the diagnosis of a rotator cuff tear can often be missed in this patient population. Although clinical outcomes can be good, care must be taken to broaden the diagnostic differential in young patients with posttraumatic shoulder pain. [ Orthopedics. 2015; 38(7):e631–e634.]

Clear-cell renal cell carcinoma (ccRCC) is a common therapy resistant disease with aberrant angiogenic and immunosuppressive features. Patients with metastatic disease are treated with targeted therapies based on clinical features: low-risk patients are usually treated with anti-angiogenic drugs and intermediate/high-risk patients with immune therapy. However, there are no biomarkers available to guide treatment choice for these patients. A recently published phase II clinical trial observed a correlation between ccRCC patients’ clustering and their response to targeted therapy. However, the clustering of these groups was not distinct. Here, we analyzed the gene expression profile of 469 ccRCC patients, using featured selection technique, and have developed a refined 66-gene signature for improved sub-classification of patients. Moreover, we have identified a novel comprehensive expression profile to distinguish between migratory stromal and immune cells. Furthermore, the proposed 66-gene signature was validated using a different cohort of 64 ccRCC patients. These findings are foundational for the development of reliable biomarkers that may guide treatment decision-making and improve therapy response in ccRCC patients.

A subset of basal cell carcinomas (BCCs) are directly derived from hair follicles (HFs). In some respects, HFs can be defined as 'ordered' skin appendage growths, while BCCs can be regarded as 'disordered' skin appendage growths. The aim of the present study was to examine HFs and BCCs to define the expression of common and unique signaling pathways in each skin appendage. Human nodular BCCs, along with HFs and non-follicular skin epithelium from normal individuals, were examined using microarrays, qPCR, and immunohistochemistry. Subsequently, BCC cells and root sheath keratinocyte cells from HFs were cultured and treated with Notch signaling peptide Jagged1 (JAG1). Gene expression, protein levels, and cell apoptosis susceptibility were assessed using qPCR, immunoblotting, and flow cytometry, respectively. Specific molecular mechanisms were found to be involved in the process of cell self-renewal in the HFs and BCCs, including Notch and Hedgehog signaling pathways. However, several key Notch signaling factors showed significant differential expression in BCCs compared with HFs. Stimulating Notch signaling with JAG1 induced apoptosis of BCC cells by increasing Fas ligand expression and downstream caspase-8 activation. The present study showed that Notch signaling pathway activity is suppressed in BCCs, and is highly expressed in HFs. Elements of the Notch pathway could, therefore, represent targets for the treatment of BCCs and potentially in hair follicle engineering.

Tender Is the Night demonstrates the imbrication of life and art, the contingency of Fitzgerald's imagination, and the treachery of both the writer's prerogative and the reader's literal-mindedness. Partly because of its intimacy, the novel long gestated; ironically, because of its personal nature, the book was vastly undervalued when it finally appeared in 1934, and it never achieved the critical stature its author expected. Perhaps Fitzgerald was just too close to his work -- or his fiction was too close to the bone. To this day the legend of Zelda and Scott is far better known than the heartbreaking narrative of Dick and Nicole Diver. Here, Bell examines historical accounts of the Fitzgeralds in the novel that would help its reader see both the vexing relationship between autobiography and fiction and also the remarkable imaginative achievement of the novel.

Basal-cell carcinoma (BCC), the most common neoplasm in humans, occurs in a variety of morphological presentations. The mechanisms of BCC development downstream of the initial genetic mutations are not well understood, and different BCC morphological presentations might exhibit distinct gene expression patterns. We investigated superficial (n=8), nodular (n=8), and morpheiform (n=7) BCCs using 21K cDNA microarrays. Global gene expression profiles between respective BCC subtypes, and as compared with normal skin (n=8), were statistically defined by significance analysis of microarrays (SAM). Thirty-seven genes were subsequently validated by quantitative reverse transcriptase-PCR analysis using an expanded set of 31 BCCs. Gene ontology analysis indicated that gene expression patterns of BCC subtypes in multiple biological processes showed significant variation, particularly in genes associated with the mitogen-activated protein kinase (MAPK) pathway. Notably, genes involved in response to DNA-damage stimulus were uniquely upregulated in morpheiform BCCs. Our results indicate a relative similarity in gene expression between nodular and superficial BCC subtypes. In contrast, morpheiform BCCs are more diverse, with gene expression patterns consistent with their more “invasive” phenotype. These data may help us understand the complex behavior of BCC subtypes and may eventually lead to new therapeutic strategies.

Although postarthroscopic glenohumeral chondrolysis has become a well-known disastrous complication of arthroscopic shoulder surgery, little is known about postarthroscopic humeral head osteonecrosis. This article describes 3 patients who were referred to the authors’ practice with end-stage osteonecrosis after an arthroscopic rotator cuff repair or debridement. Three patients (average age, 63.3 years) presented to the authors’ practice reporting severe shoulder pain after a rotator cuff debridement or repair was performed at an outside facility. After an interval period of mild improvement, all patients experienced progressive pain and loss of shoulder range of motion at a mean of 4.8 months postoperatively. Plain radiographs and magnetic resonance imaging obtained prior to the index operation showed no evidence of osteonecrosis. Postoperatively, progressive clinical and radiographic evidence showed humeral head osteonecrosis and subsequent glenohumeral destruction with cuff tear arthropathy. The authors managed all patients with a reverse total shoulder arthroplasty due to severe glenohumeral arthrosis and massive rotator cuff tears not amendable to repair. Satisfactory results were achieved in all cases. Although many complications of arthroscopic shoulder surgery are documented, little is known about postarthroscopic humeral head osteonecrosis. Shoulder surgeons should be aware of this potential complication when performing arthroscopic rotator cuff surgery and when evaluating painful and stiff postarthroscopic shoulders.

The play Comedy of Errors was adapted from Plautus's Roman farce about long-separated identical twins, Shakespeare doubled the trouble and multiplied the fun with two sets of twins: clowns both named Dromio serve masters each called Antipholus. Comedy of Errors demonstrates the playwright's inchoate sense of fools and fooling as ways to enrich and complicate his material. Among other things Bell comments that Shakespeare's anatomy of folly draws on traditional representations of the fool, complicates conventions--and invest extraordinary energy in fools, mixing critical interrogation and imaginative empathy.