Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging

Background

Multiparametric magnetic resonance imaging (mpMRI) undoubtedly affects the diagnosis and treatment of localized prostate cancer (CaP). However, clinicians need a better understanding of its accuracy and limitations in detecting individual CaP foci to optimize management.

Multiplexing Seven miRNA-Based shRNAs to Suppress HIV Replication

Multiplexed miRNA-based shRNAs (shRNA-miRs) could have wide potential to simultaneously suppress multiple genes. Here, we describe a simple strategy to express a large number of shRNA-miRs using minimal flanking sequences from multiple endogenous miRNAs. We found that a sequence of 30 nucleotides flanking the miRNA duplex was sufficient for efficient processing of shRNA-miRs. We inserted multiple shRNAs in tandem, each containing minimal flanking sequence from a different miRNA. Deep sequencing of transfected cells showed accurate processing of individual shRNA-miRs and that their expression did not decrease with the distance from the promoter. Moreover, each shRNA was as functionally competent as its singly expressed counterpart. We used this system to express one shRNA-miR targeting CCR5 and six shRNA-miRs targeting the HIV-1 genome. The lentiviral construct was pseudotyped with HIV-1 envelope to allow transduction of both resting and activated primary CD4 T cells. Unlike one shRNA-miR, the seven shRNA-miR transduced T cells nearly abrogated HIV-1 infection in vitro. Additionally, when PBMCs from HIV-1 seropositive individuals were transduced and transplanted into NOD/SCID/IL-2R γc^−/− mice (Hu-PBL model) efficient suppression of endogenous HIV-1 replication with restoration of CD4 T cell counts was observed. Thus, our multiplexed shRNA appears to provide a promising gene therapeutic approach for HIV-1 infection.     

Specialty training in child and adolescent psychiatry in India

European Child & Adolescent Psychiatry - India has a considerable skilled manpower deficit in the area of child and adolescent mental health, given its population and their needs. To address...     

Ocular myasthenia gravis: A review

Myasthenia gravis (MG) is a disease that affects the neuro-muscular junction resulting in classical symptoms of variable muscle weakness and fatigability. It is called the great masquerader owing to its varied clinical presentations. Very often, a patient of MG may present to the ophthalmologist given that a large proportion of patients with systemic myasthenia have ocular involvement either at presentation or during the later course of the disease. The treatment of ocular MG involves both the neurologist and ophthalmologist. Thus, the aim of this review was to highlight the current diagnosis, investigations, and treatment of ocular MG.     

A BAFfling liver aspirate: Metastatic high grade SMARCA4 deficient undifferentiated gastroesophageal junction carcinoma masquerading as a hematolymphoid malignancy

Undifferentiated malignant SMARCA4‐deficient neoplasms are rare, recently characterized, high grade, potentially lethal malignancies. Such tumors are characterized by the loss of BRG1 encoded by SMARCA4, a key component of the Switch/Sucrose Non‐Fermenting (SWI/SNF) chromatin remodeling complex. As this complex, also referred as BAF (BRG1/BRM associated factors) complex, is involved in the epigenetic control of hundreds of genes, including those involved in lineage‐specific differentiation, BAF‐deficient tumors, show minimal or no differentiation and are difficult to classify. Their fine needle aspiration (FNA) cytologic features are still poorly defined. Here, we describe a 70‐year‐old man who presented with thickening of the wall of the distal esophagus and stomach and multiple liver and lung lesions. Liver FNA showed relatively uniform dispersed malignant cells with high nucleus: cytoplasm ratio, scant microvacuolated cytoplasm, eccentric nuclei and prominent nucleoli. Mitoses, necrotic debris, nuclear streak artifact, “ghost cells” and focal rhabdoid cytoplasmic inclusions were also present. The liver core biopsy and GI biopsies demonstrated sinusoidal and respectively submucosal involvement by a high grade undifferentiated malignant neoplasm. The tumor cells were negative for all applied markers on immunohistochemistry and flow cytometry, and only showed CD138 and weak PAX5 staining. After an initial diagnosis of hematolymphoid neoplasm, additional stains showed intact INI1 protein and loss of BRG1 protein immunoexpression, establishing the accurate diagnosis. This case highlights the difficulties and potential pitfalls encountered in the FNA diagnosis of BAF‐deficient tumors, the accurate diagnosis of which is important due to their lack of response to conventional therapy and potential response to targeted therapy.     

Hazard Ratio Estimation in Small Samples

When comparing survival times between groups in the setting of proportional hazards, the Cox model is typically used for estimation and inference, the latter based on large sample considerations. Mehrotra and Roth introduced a generalized log-rank (GLR) method for better statistical efficiency in estimating relative risk in small samples. In this article, we propose a refined GLR (RGLR) statistic by eliminating an unnecessary approximation in the development of the original GLR approach, and provide further insights into the performance of GLR and RGLR statistics. We also extend RGLR to allow for tied event times. We show across a variety of simulated scenarios that RGLR provides a smaller bias than commonly used Cox model, parametric models and GLR in small samples (up to 40 subjects per group), and has notably better efficiency relative to Cox and parametric models in terms of mean squared error. The RGLR method also consistently delivers adequate confidence interval coverage and Type I error control, while parametric methods and the Cox model tend to under-perform on that front in small samples. We further show that while the performance of the parametric model can be significantly influenced by misspecification of the true underlying survival distribution, the RGLR approach provides a consistently low bias and high relative efficiency. We apply all competing methods to data from two clinical trials. Supplementary materials for this article are available online.