Citations

Significance We describe a genomic disorder that causes obesity, intellectual disability, and seizures. Children with this syndrome carry an unbalanced chromosome translocation that results in the duplication of over 100 genes, including G protein β3 ( GNB3 ). Although GNB3 polymorphisms have been associated with obesity, hypertension, and diabetes, the mechanism of GNB3 pathogenesis is unknown. We created a transgenic mouse model that carries a duplication of GNB3 , weighs significantly more than wild-type mice, and has excess abdominal fat. GNB3 is highly expressed in the brain and may be important for signaling related to satiety and/or metabolism.

Abstract Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer-relevant synthetic lethal interactions whereby candidate interactions are prioritized on the basis of genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As a proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1 and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer. Cancer Res; 73(20); 6128–36. ©2013 AACR.

Introduction. Accessory breast tissue is a rare finding in the general population with an incidence of 1-2%. An even rarer occurrence is accessory breast tissue afflicted with breast carcinoma. We present a brief report discussing diagnosis and management of a patient who presented with primary breast adenocarcinoma in vulval supranumerary tissue.Brief Report. A 60-year-old Caucasian female presented with a lesion in her left vulva that she first identified during adolescence. The lesion began to grow and ulcerate prompting her to receive treatment. Biopsy was inconclusive, and metastatic workup was negative, so her lesion was treated as an isolated breast lump and removed via wide local excision.Conclusion. Primary breast adenocarcinoma of the vulva is exceedingly rare. A paucity of the literature on this topic unfortunately means that strong evidence does not exist detailing the best management of this patient cohort. However, given that histological data confirms these cancers are virtually the same as breast cancers, it logically follows that the best treatment practices for breast cancer may be applied to treat these patients presenting with primary vulva cancers of ectopic breast tissue.

BACKGROUNDThe cytological diagnosis of malignant mesothelioma (MM) on serous effusion is challenging due to significant morphologic overlap with reactive mesothelial cells and adenocarcinoma. One of the morphologic features of MM in effusion cytology, small orangiophilic squamous‐like cells (SOSLC), has received little attention. To the best of the authors' knowledge, the current study is the first to assess the sensitivity and specificity of SOSLC in serous effusion specimens from histology‐proven MM cases along with those of reactive mesothelial and adenocarcinoma cases.METHODSA total of 130 cases of pleural (86 cases) and peritoneal (44 cases) effusion cytology cases (30 with histology‐proven MM, 41 with adenocarcinoma, and 59 with reactive mesothelial cells) were studied. The presence or absence of SOSLC was recorded in each case.RESULTSThe cytological diagnoses of the 30 histology‐proven MM cases included 1) atypical mesothelial cells, favor reactive (4 cases); 2) atypical mesothelial cells, suspicious for or cannot exclude mesothelioma (18 cases); and 3) positive for MM (8 cases). SOSLC were found in 10 of the 30 MM effusion cases (33.3%), 1 of the 41 adenocarcinoma cases (2.4%), and 5 of the 59 reactive mesothelial cell cases (8.5%). SOSLC were more likely to be present in MM effusions compared with either adenocarcinoma (P < .0001) or reactive mesothelial cell (P < .02) effusions. All 10 cases of MM with SOSLC were from pleural fluids. One case of peritoneal serous adenocarcinoma had SOSLC and 5 cases of reactive mesothelial cells in peritoneal fluid were found to have SOSLC.CONCLUSIONSAlthough not sensitive, the presence of SOSLC is quite specific for MM in pleural fluid cytology specimens. Finding this morphological feature in pleural fluid should alert the pathologist to a possible diagnosis of MM.Cancer (Cancer Cytopathol) 2014;122:70–75. © 2013 American Cancer Society.

Medical professionalism is a multifaceted paradigm and is an essential component of medical education. Gross anatomy is a laboratory to teach professionalism, and promoting critical reflection in medical students is a prerequisite to furthering professionalism. The aim of this study was to determine if professionalism case discussions during a Gross Anatomy course improve students' reflections using a validated reflection instrument (12 items; five‐point Likert scale where 1 = Disagree, 2 = Disagree with reservation, 3 = Neutral, 4 = Agree with reservation, 5 = Agree). Four facilitated reflection sessions were aimed at fostering reflective capacity through reflection on elements of professionalism. Results did not show a significant change between pre‐and postintervention reflection scores (3.45 ± 0.61 vs. 3.48 ± 0.51; P = 0.82). Historical control students were found to have significantly higher reflection scores when compared with postintervention students (3.91 ± 0.53 vs. 3.48 ± 0.51; P < 0.001). However, the historical control students were found to have significantly higher professionalism scores (P = 0.001) as compared with the intervention students. Student satisfaction was high, with 25 of 28 (89.2%) students reporting that the sessions should be included as a component of future anatomy courses. While reflection scores were not significantly increased as a result of the intervention, students expressed appreciation for the opportunity to discuss professionalism issues related to the dissection of cadavers. Additionally, the intervention students had both lower professionalism scores and lower reflection scores, which supports the idea that highly professional students are more capable of reflecting on professionalism. Future studies should determine whether this case discussion intervention improves objective measures of professionalism. Anat Sci Educ 7: 191–198. © 2013 American Association of Anatomists.

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.

Abstract This spotlight review focuses on the second-generation immunomodulatory drug pomalidomide, which was recently approved by the US Food and Drug Administration. This drug was approved for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. This review focuses on the clinical trial data that led to approval and provides advice for treating physicians who are now prescribing this drug for patients.