Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.

Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.

Quack-induced dermatitis: A case report of two dermatitis artefacta induced by quacks advise.

This report delineates two instances of dermatitis artefacta (DA), a psychodermatological condition marked by self-induced or exacerbated skin lesions. These cases, triggered by treatments from non-qualified practitioners, highlight the critical need for healthcare professionals to discern the potential repercussions of unsound medical guidance.

Dermatoscopy of primary localised cutaneous amyloidosis - A cross-sectional study in a setting of South Asian public dermatology department.

Background: Amyloidosis, deposition of misfolded protein in body, is a fairly common condition. The deposition of misfolded proteins in skin which occurs in absence of systemic comorbidities, namely Primary Cutaneous Amyloidosis (PCA) is also a well-known entity in skin of colour patients of Asian subcontinent. Primary Cutaneous Amyloidosis is usually diagnosed with good clinical acumen and typical clinical phenotype and involved site. Dermoscope has been used as an adjunct non-invasive tool to confirm cases with diagnostic uncertainty and in those in whom biopsy is deferred. Typical dermoscopic features of PCA helps differentiate it from other pigmentary dermatoses and avoids unwanted invasive biopsies and investigations especially in resource poor settings with financial constraints. Objectives: This study aims to identify and corroborate clinically, typical dermoscopic features in PCA in 42 patients which includes Macular Amyloidosis (MA) and Papular Amyloidosis (PA) predominantly in skin of colour patients from government based hospital of a south east Asian country. Materials and methods: Patients with classic clinical features of PCA were selected. Primary Cutaneous Amyloidosis was subclassified into MA or PA and their corresponding clinically corroborative dermoscopic features were enlisted respectively. All patients (treatment naïve and previously treated), who consented to participate in the study were included. Patients were diagnosed based on the prototypical clinical features. Dermoscopy was done using DermLite III DL3N Polarised and Fluid Dermoscope w/PigmentBoost Brand (3Gen, DermLite LLC, San Juan Capistrano, CA, USA) and images were obtained to create digital dermoscopy system by attaching camera-equipped mobile device via an optional connection kit (Redmi Note 11, MIUI version 13.0.5, CHINA) and the findings were enlisted concurrently. Results: In this study of dermoscopic findings of PCA, 42 patients were evaluated for their clinical lesions along with its corroboration with the dermoscopic features. Macular Amyloidosis was seen in 30 patients and 12 patients had typical cutaneous phenotypic and dermoscopic feature of PA. The most common dermoscopic finding seen in patients with MA was shiny to dull white, circular or oval central hub surrounded with halo of light brown dots. Most common configuration of brownish pigmentation around central hub was fine streak type. Also eccrine clues were seen in some cases of MA, which was a unique finding. Similarly in the PA subtype, the central hub was replaced by scar like structureless translucent white area surrounded by brownish black dot like structures, especially in those with large and thick plaques. Conclusion: Dermoscopic findings of PCA and their clinical corroboration is a much-needed aspect in treating patients with pigmentary disorders and in those with skin of colour, especially in developing countries. Utilization of dermoscope in clinical settings of low income countries and in government based hospitals will decrease the add on economic burden of invasive diagnostic modalities like biopsy and other inadvertent tests done to rule out pigmentary conditions.

Extensive acute cutaneous graft versus host disease: A rare case report of survival.

Graft versus host disease (GVHD) is an immunologically mediated condition seen in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Because of the rarity of the disease, nonspecific presentation, and lack of clinicopathological correlation, its diagnosis is often delayed and prompt treatment is deferred, with increased mortality.

DermatoFibroSarcoma Protuberans: A case report of a complete cure.

DermatoFibroSarcoma Protuberans (DFSP) is a rare recurrent fibrohistiocytic tumor. Given the limitation of available diagnostic modalities in a resource poor setting, diagnosis can be confusing. As most of the tumors recur with time, our case of complete cure was interesting phenomenon observed in our case.

Comparison of Structural and Short Variants Detected by Linked-Read and Whole-Exome Sequencing in Multiple Myeloma.

Linked-read sequencing was developed to aid the detection of large structural variants (SVs) from short-read sequencing efforts. We performed a systematic evaluation to determine if linked-read exome sequencing provides more comprehensive and clinically relevant information than whole-exome sequencing (WES) when applied to the same set of multiple myeloma patient samples. We report that linked-read sequencing detected a higher number of SVs (n = 18,455) than WES (n = 4065). However, linked-read predictions were dominated by inversions (92.4%), leading to poor detection of other types of SVs. In contrast, WES detected 56.3% deletions, 32.6% insertions, 6.7% translocations, 3.3% duplications and 1.2% inversions. Surprisingly, the quantitative performance assessment suggested a higher performance for WES (AUC = 0.791) compared to linked-read sequencing (AUC = 0.766) for detecting clinically validated cytogenetic alterations. We also found that linked-read sequencing detected more short variants (n = 704) compared to WES (n = 109). WES detected somatic mutations in all MM-related genes while linked-read sequencing failed to detect certain mutations. The comparison of somatic mutations detected using linked-read, WES and RNA-seq revealed that WES and RNA-seq detected more mutations than linked-read sequencing. These data indicate that WES outperforms and is more efficient than linked-read sequencing for detecting clinically relevant SVs and MM-specific short variants.

Opportunistic Respiratory Infections in HIV Patients Attending Sukraraj Tropical and Infectious Diseases Hospital in Kathmandu, Nepal.

INTRODUCTION: Opportunistic bacterial and fungal infections are the major cause of morbidity and mortality among immune suppressed HIV-positive patients. The main objective of this study was to determine bacterial and fungal organisms causing respiratory infections and their susceptibility to commonly prescribed antimicrobials among HIV patients attending a tertiary infectious disease hospital in Kathmandu. METHODS: Sputum samples were collected from the HIV-positive patients attending Sukraraj Tropical and Infectious Disease Hospital (STIDH) from August 2017 to March 2018. A total of 100 sputum samples were cultured on conventional bacterial and fungal culture media. Bacterial and fungal isolates were identified based on their colony characteristics, microscopic morphology and various biochemical tests. Antibiotic susceptibility test (AST) of bacterial isolates was performed by modified Kirby Bauer disc diffusion method. RESULTS: Out of 100 sputum samples cultured, 24% (n=24) showed bacterial growth, 42% (n=42) showed fungal growth and 10% (n=10) had both bacterial and fungal growth. Among bacteria, 91.6% (n=22) were monomicrobial and 8.4% (n=2) were polymicrobial in growth, of which, Klebsiella pneumoniae (37.5%) were predominant isolates, followed by Pseudomonas aeruginosa (29.2%), and Escherichia coli (16.7%). The antibiotic susceptibility test (AST) showed 68% (17/25) of bacterial isolates were multi-drug resistant (MDR) and among them 41.2% (7/17) were found to be extended spectrum ß lactamase (ESBL) producers. Fungal growth was observed in 42% of samples (42/100). A total of six different species of Candida and four different genera of molds were identified. On species differentiation, Candida albicans (20%) were followed by Candida parapsilosis (4%), and Candida dubliniensis (3%); and various molds were Aspergillus fumigatus (4%), Aspergillus flavus (2%), and Penicillium species (5%). CD4 count was inversely associated with bacterial and fungal infections. Fifty percent of the patients with the fungal infections had a CD4 count below 200. No fungal organisms were isolated from HIV-positive patients under antifungal drug treatment. CONCLUSION: HIV-positive patients with a CD4 count less than 200 cells/µL are more vulnerable to opportunistic infections of bacterial and fungal origin. Early isolation, identification and appropriate treatment can reduce mortality due to co-infections. Routine screening of opportunistic pathogens is critical to contain the disease progression.