Diagnostic accuracy of ultrasonography in differentiating benign and malignant thyroid nodules using fine needle aspiration cytology as the reference standard

Background: In Pakistan thyroid cancer is responsible for 1.2% cases of all malignant tumors. Ultrasonography (US) is helpful in detecting cancerous thyroid nodules on basis of different features like echogenicity, margins, microcalcifications, size, shape and abnormal neck lymph nodes. We therefore aimed to calculate diagnostic accuracy of ultrasound in detection of carcinoma in thyroid nodules taking fine needle aspiration cytology as the reference standard.MATERIALS AND Methods: A cross-sectional analytical study was designed to prospectively collect data from December 2010 till December 2012 from the Department of Radiology in Aga Khan University Hospital, Karachi, Pakistan. A total of 100 patients of both genders were enrolled after informed consent via applying non-probability consecutive sampling technique. Patients referred to Radiology department of Aga Khan University to perform thyroid ultrasound followed by fine-needle aspiration cytology of thyroid nodules were included. They were excluded if proven for thyroid malignancy or if their US or FNAC was conducted outside our institution.Results: The subjects comprised 76 (76%) females and 24 males. Mean age was 41.8±SD 12.3 years. Sensitivity and specificity with 95%CI of ultrasound in differentiating malignant thyroid nodule from benign thyroid nodule calculated to be 91.7% (95%CI, 0.72-0.98) and 78.94% (0.68-0.87) respectively. Reported positive predictive value and negative PV were 57.9% (0.41-0.73) and 96.8% (0.88-0.99) and overall accuracy was 82%. Likelihood ratio (LR) positive was computed to be 4.3 and LR negative was 0.1.CONCLUSIONS: Ultrasonography has a high diagnostic accuracy in detecting malignancy in thyroid nodules on the basis of features like echogenicity, margins, micro calcifications and shape

Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as standalone or in combination with targeted drugs.Peer reviewe

Advances in covalent kinase inhibitors.

Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords a unique set of advantages as well as challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, covalent inhibitors irreversibly modify a proximal nucleophilic residue on the protein via reaction with an electrophile. To date, the acrylamide group remains the predominantly employed electrophile in CKI development, with its incorporation in the majority of clinical candidates and FDA approved covalent therapies. Nonetheless, in recent years considerable efforts have ensued to characterize alternative electrophiles that exhibit irreversible or reversibly covalent binding mechanisms towards cysteine thiols and other amino acids. This review article provides a comprehensive overview of CKIs reported in the literature over a decade period, 2007-2018. Emphasis is placed on the rationale behind warhead choice, optimization approach, and inhibitor design. Current FDA approved CKIs are also highlighted, in addition to a detailed analysis of the common trends and themes observed within the listed data set

Soil Microbiome: A Treasure Trove for Soil Health Sustainability under Changing Climate

Climate change imprints on soil are projected primarily through the changes in soil moisture and surge in soil temperature and CO2 levels in response to climate change and is anticipated to have varying impacts on soil characteristics and processes that are instrumental in the restoration of soil fertility as well as productivity. Climate change encompasses a major concern of sharing its impact on the stability and functionality of soil microbiome and is characterized by one or more chief stability metrics encircling resistance, resilience, and functional redundancy. Nevertheless, the explorations over the past years have unveiled the potential of microbial interventions in the regeneration of soils or assurance of perked-up resilience to crops. The strategies involved therein encompass harnessing the native capability of soil microbes for carbon sequestration, phyto-stimulation, bio fertilization, rhizo-mediation, biocontrol of plant pathogens, enzyme-mediated breakdown, antibiosis, prompting of anti-oxidative defense mechanism, exudation of volatile organic compounds (VOCs) and induced systemic resistance (ISR) response in the host plant. However, the short storage and shelf-life of microbe-based formulations stay a significant constraint and rigorous efforts are necessary to appraise their additive impact on crop growth under changing climate scenarios