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Inactivation of cyclin‐dependent kinase 12 (CDK12) characterizes an aggressive sub‐group of castration‐resistant prostate cancer (CRPC). Hyper‐activation of MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss of CDK12 promotes MYC activity, which renders the cells dependent on the otherwise non‐essential splicing regulatory kinase SRSF protein kinase 1 (SRPK1). High MYC expression is associated with increased levels of SRPK1 in patient samples, and overexpression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO‐101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well‐characterized SRPK1 inhibitor SRPIN340 on nascent transcription. This is the first study to show that Endovion is an SRPK1 inhibitor. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, and transcriptionally activates the unfolded protein response. In brief, here we discover that CDK12 inactivation promotes MYC signaling in an SRPK1‐dependent manner, and show that the clinical grade compound Endovion selectively targets the cells with CDK12 inactivation.

Parth J Rana,1 Himanshu Deshmukh,2 Urmil Shah,3 Vinod Kumar,4 Sanghamitra Kanungo,5 Deepika Singhal,6 Santosh Kumar Mahapatra,7 Ira Vakharia,8 Mukesh Jaiswal,9 Ajitkumar Gondane,10 Pooja Vaidya,10 Vinayaka Shahavi,9 Harish Shandilya,11 Dattatray Pawar,10 Akhilesh Sharma12 1Department of Retina and Trauma Surgery, Netralaya Superspeciallity Hospital, Ahmedabad, Gujarat, India; 2Department of Retina; ‘Daulat’ Deshmukh Eye Hospital, Khaparde Gardens, Amravati, Maharashtra, India; 3Department of Retina, P.N. Desai Eye Hospital, Ahmedabad, Gujarat, 380052, India; 4Department of Ophthalmology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India; 5Department of Retina, Kar Vision Eye Hospital, Bhubaneswar, Odisha, 751007, India; 6Department of Ophthalmology, GMERS Medical College and Civil Hospital, Ahmedabad, Gujarat, India; 7Department of Retina, JPM Rotary Club of Cuttack Eye Hospital and Research Institute, Cuttak, Odisha, 753014, India; 8Department of Retina, Nirmal Hospital Pvt Ltd, Surat, Gujarat, 395002, India; 9Clinical Research Department, Alkem Laboratories Ltd., Lower Parel, Mumbai, India; 10Medical Affairs Department, Alkem Laboratories Ltd., Lower parel, Mumbai, India; 11Global Product Development, IPM & Regulatory Affairs, Enzene Biosciences Ltd., Pune, India; 12Medical Affairs and Clinical Research Department, Alkem Laboratories Ltd., Lower Parel, Mumbai, IndiaCorrespondence: Ajitkumar Gondane, Medical Affairs, ALKEM Laboratories Ltd., ALKEM HOUSE, “Devashish”, Adjacent to Matulya Centre, Senapati Bapat Marg, Lower Parel, Mumbai, 400 013, India, Tel +8983375722, Email ajitkumar.gondane@alkem.comObjective: This study aimed to compare efficacy, safety, and immunogenicity of the biosimilar ranibizumab in comparison with the Innovator Ranibizumab in treatment-naive patients with neovascular (wet) age-related macular degeneration (nAMD or wAMD).Materials and Methods: This comparative, double blind, multicentre, Phase III clinical study randomized eligible patients in a 3:1 ratio to receive either OPTIMAB® (Alkem Laboratories Ltd./ Enzene Biosciences Ltd.) or Innovator Ranibizumab. Intravitreal injections of Innovator Ranibizumab (0.5 mg in 0.05 mL) and OPTIMAB® (0.5 mg in 0.05 mL) were administered every four weeks for 12 weeks (three doses). Primary efficacy endpoints included loss of < 15 letters from baseline, gain of ≥ 15 letters from baseline in visual acuity, mean change in best corrected visual acuity (BCVA) from baseline, and change in central subfoveal thickness (CSFT) from baseline at week 12. Safety was assessed through monitoring of adverse events (AEs) and serious adverse events (SAEs) throughout the study.Results: Overall, of the 152 patients randomized, 141 (92.8%) patients (mean age, 66.6 ± 9.37 years) completed the study. Percentage of patients who lost < 15 letters in BCVA at week 12 from baseline was comparable in both the groups (100.0%, each). On secondary end point analysis, the two groups had comparable mean changes in BCVA (OPTIMAB®, 11.8 ± 9.18; innovator ranibizumab, 12.9 ± 10.29; P = 0.5509); proportion of patients who gained ≥ 15 letters in visual acuity (OPTIMAB®, 32.18%; innovator ranibizumab, 25.74%; P = 0.4785) and mean change in CSFT (OPTIMAB®, − 76.6 ± 89.03; Innovator ranibizumab, − 73.1 ± 92.23 μm; P = 0.8422) at week 12 as compared to baseline. OPTIMAB® and innovator ranibizumab demonstrated comparable safety over the 12-week treatment period and no patient expressed anti-ranibizumab antibody in either group patient.Conclusion: Biosimilar ranibizumab (OPTIMAB®) was non-inferior to innovator ranibizumab in terms of efficacy, safety, and immunogenicity in the patients of nAMD.Keywords: biosimilar ranibizumab, best corrected visual acuity, central subfoveal thickness, nAMD

Introduction: The oral cavity, the beginning of the digestive system, has diverse lesions affecting it other than Oral Squamous Cell Carcinoma (OSCC). Soft-tissue Tumours (STT) are uncommon lesions. Overlapping of the signs and symptoms in diverse conditions creates significant problems for reaching their definitive diagnosis. Histopathological Examination (HPE) plays a central role in giving their final diagnosis. Assessment of the clinical features, histopathology, along with Immunohistochemistry (IHC), helps in reaching an accurate diagnosis in these cases, which further aids in the proper management of the patient. Aim: To study the spectrum of oral cavity lesions and tumours with emphasis on STT. Materials and Methods: A retrospective cross-sectional study was conducted at the Department of Pathology and Otolaryngology, Dr. Ulhas Patil Medical College, Jalgaon, Maharashtra, India included the oral cavity lesion samples received over two years (from January 2021 to December 2022) in the histopathology section of a Medical College in Maharashtra, India. A total of 170 cases were included in the study. Complete clinical information including age, sex, anatomical location, clinical diagnosis, and histological subtypes were compiled. The HPE diagnosis were classified into four categories-Non neoplastic, Benign, Epithelial Proliferative lesions {including viral/Human Papillomavirus (HPV) related}/Intraepithelial neoplastic lesions/Precursor or Pre-malignant, and malignant with special emphasis on STTs found. The data was statistically analysed and the results were presented as percentages. Full details of the soft-tissue lesions were recorded, entered into an Excel sheet, and studied for the percentage-wise distribution of various recorded parameters. Results: A total of 170 cases were found. Male:female distribution was 2.78:1, and most patients were in the seventh decade, n=38 (22.35%). The most common lesions other than SCC, n=110 (64.71%) found were mucocele, chronic inflammatory lesion and wart. The Buccal Mucosa/Gingivo-buccal Sulcus (GBS) were the most commonly involved site, n=82 (48.24%). Malignant lesions were more common in the sixth and seventh decades, with a male preponderance of 2.71:1. The uncommon STTs found were-Benign: Haemangioma/pyogenic granuloma (n=2), a Schwanomma, and a Proliferative Fasciitis (PF); Malignant: two fibrosarcomas and a high-grade sarcoma. All three malignant STTs were found in males of the sixth decade involving the buccal mucosa. Conclusion: Among the variety of lesions found in the oral cavity, HPE facilitates the recognition of the STT, especially the malignant ones, aiding in proper management. Being an extremely uncommon entity at this site, the documentation of these findings is of utmost importance.

Author(s): Vaishali B. Nagose (corresponding author) [1,2]; Sachin S. Ingle [3]; Nilesh O. Chandak [4]; Shirish R. Gondane [2] Introduction Primary cutaneous carcinosarcoma (PCCS) is a rare cutaneous biphasic tumour [...], Primary cutaneous carcinosarcoma (PCCS) is a rare cutaneous biphasic tumour with just 120 cases being reported till date. The epithelial component trichoblastic carcinoma/ malignant trichoblastoma (trichoblastic carcinosarcoma) is even rarer, so is the present case. An eighty years old male patient presented with a rapidly progressing ulceroproliferative nodular growth on the left temporal region. The incisional biopsy showed primary cutaneous carcinomasarcoma (PCCS). IHC showed epithelial and stromal component marked exclusively for pancytokeratin (AE1/AE3) CK56/ p40 and vimentin respectively. Both components were immunopositive for D2-40 and immunonegative for BerEP4/ S100/ Melan A/ MITF, thus final diagnosis given was Trichoblastic carcinosarcoma. Wide excision of the lesion with local rotation flap and skin grafting (thigh skin) was done. Patient remains disease free after four years also. Present case thus highlights the importance of HPE, IHC and early surgery for excellent prognosis of PCCS. Keywords: Adnexal and skin appendage, carcinoma, carcinosarcoma, metaplastic carcinoma, neoplasms, skin appendage, skin cancer

Advances in RNA-sequencing technologies have led to the development of intriguing experimental setups, a massive accumulation of data, and high demand for tools to analyze it. To answer this demand, computational scientists have developed a myriad of data analysis pipelines, but it is less often considered what the most appropriate one is. The RNA-sequencing data analysis pipeline can be divided into three major parts: data pre-processing, followed by the main and downstream analyses. Here, we present an overview of the tools used in both the bulk RNA-seq and at the single-cell level, with a particular focus on alternative splicing and active RNA synthesis analysis. A crucial part of data pre-processing is quality control, which defines the necessity of the next steps; adapter removal, trimming, and filtering. After pre-processing, the data are finally analyzed using a variety of tools: differential gene expression, alternative splicing, and assessment of active synthesis, the latter requiring dedicated sample preparation. In brief, we describe the commonly used tools in the sample preparation and analysis of RNA-seq data.

O-GlcNAc transferase (OGT) coordinates with regulators of transcription, including cyclin-dependent kinase 12 (CDK12), the major transcription elongation kinase. Here, we use inhibitor- and knockdown-based strategies to show that co-targeting of OGT and CDK12 is toxic to prostate cancer cells. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation and due to its essentiality in higher eukaryotes, it is not an ideal drug target. Our glycoproteomics-data revealed that short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in different models of prostate cancer. By integrating our glycoproteomics-, gene essentiality- and clinical-data from CDK12 mutant prostate cancer patients, we identify the non-essential serine-arginine protein kinase 1 (SRPK1) as a synthetic lethal partner with CDK12 -inactivation. Both normal and cancer cells become highly sensitive against inhibitors of OGT and SRPK1 if they have lowered activity of CDK12. Inactivating mutations in CDK12 are enriched in aggressive prostate cancer, and we propose that these patients would benefit from therapy targeting the spliceosome. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB) is the primary cause of neonatal mortality and long-term disabilities. The unknown mechanism behind PTB makes diagnosis difficult, yet early detection is necessary for controlling and averting related consequences. The primary focus of this work is to provide an overview of the known risk factors associated with preterm labor and the conventional and advanced procedures for early detection of PTB, including multi-omics and artificial intelligence/machine learning (AI/ML)- based approaches. It also discusses the principles of detecting various proteomic biomarkers based on lateral flow immunoassay and microfluidic chips, along with the commercially available point-of-care testing (POCT) devices and associated challenges. After briefing the therapeutic and preventive measures of PTB, this review summarizes with an outlook.

The healing of osteochondral defects (OCDs) that result from injury, osteochondritis, or osteoarthritis and bear lesions in the cartilage and bone, pain, and loss of joint function in middle- and old-age individuals presents challenges to clinical practitioners because of non-regenerative cartilage and the limitations of current therapies. Bioactive peptide-based osteochondral (OC) tissue regeneration is becoming more popular because it does not have the immunogenicity, misfolding, or denaturation problems associated with original proteins. Periodically, reviews are published on the regeneration of bone and cartilage separately; however, none of them addressed the simultaneous healing of these tissues in the complicated heterogeneous environment of the osteochondral (OC) interface. As regulators of cell adhesion, proliferation, differentiation, angiogenesis, immunomodulation, and antibacterial activity, potential therapeutic strategies for OCDs utilizing bone and cartilage-specific peptides should be examined and investigated. The main goal of this review was to study how they contribute to the healing of OCDs, either alone or in conjunction with other peptides and biomaterials.

Inactivation of cyclin‐dependent kinase 12 (CDK12) characterizes an aggressive sub‐group of castration‐resistant prostate cancer (CRPC). Hyper‐activation of MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss of CDK12 promotes MYC activity, which renders the cells dependent on the otherwise non‐essential splicing regulatory kinase SRSF protein kinase 1 (SRPK1). High MYC expression is associated with increased levels of SRPK1 in patient samples, and overexpression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO‐101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well‐characterized SRPK1 inhibitor SRPIN340 on nascent transcription. This is the first study to show that Endovion is an SRPK1 inhibitor. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, and transcriptionally activates the unfolded protein response. In brief, here we discover that CDK12 inactivation promotes MYC signaling in an SRPK1‐dependent manner, and show that the clinical grade compound Endovion selectively targets the cells with CDK12 inactivation. [ABSTRACT FROM AUTHOR]

This study aimed to compare efficacy, safety, and immunogenicity of the biosimilar ranibizumab in comparison with the Innovator Ranibizumab in treatment-naive patients with neovascular (wet) age-related macular degeneration (nAMD or wAMD). Materials and Methods: This comparative, double blind, multicentre, Phase III clinical study randomized eligible patients in a 3:1 ratio to receive either OPTIMAB® (Alkem Laboratories Ltd./ Enzene Biosciences Ltd.) or Innovator Ranibizumab. Intravitreal injections of Innovator Ranibizumab (0.5 mg in 0.05 mL) and OPTIMAB® (0.5 mg in 0.05 mL) were administered every four weeks for 12 weeks (three doses). Primary efficacy endpoints included loss of < 15 letters from baseline, gain of ≥ 15 letters from baseline in visual acuity, mean change in best corrected visual acuity (BCVA) from baseline, and change in central subfoveal thickness (CSFT) from baseline at week 12. Safety was assessed through monitoring of adverse events (AEs) and serious adverse events (SAEs) throughout the study. Results: Overall, of the 152 patients randomized, 141 (92.8%) patients (mean age, 66.6 ± 9.37 years) completed the study. Percentage of patients who lost < 15 letters in BCVA at week 12 from baseline was comparable in both the groups (100.0%, each). On secondary end point analysis, the two groups had comparable mean changes in BCVA (OPTIMAB®, 11.8 ± 9.18; innovator ranibizumab, 12.9 ± 10.29; P =  0.5509); proportion of patients who gained ≥ 15 letters in visual acuity (OPTIMAB®, 32.18%; innovator ranibizumab, 25.74%; P = 0.4785) and mean change in CSFT (OPTIMAB®, − 76.6 ± 89.03; Innovator ranibizumab, − 73.1 ± 92.23 μm; P = 0.8422) at week 12 as compared to baseline. OPTIMAB® and innovator ranibizumab demonstrated comparable safety over the 12-week treatment period and no patient expressed anti-ranibizumab antibody in either group patient. Conclusion: Biosimilar ranibizumab (OPTIMAB®) was non-inferior to innovator ranibizumab in terms of efficacy, safety, and immunogenicity in the patients of nAMD. [ABSTRACT FROM AUTHOR]

Background: The evaluation of histopathological outcomes post-elective surgical procedures is crucial in understanding the prevalence of various pathologies and the efficacy of surgical interventions. Objective: To assess and analyze the histopathological outcomes of elective surgical procedures performed in a tertiary care hospital. Methods: A cross-sectional study was conducted involving 200 patients who underwent elective surgical procedures. Histopathological examinations of surgical specimens were performed, and data were analyzed using statistical methods to determine the prevalence and types of histopathological findings. Results: The study revealed a diverse range of histopathological outcomes with the most common findings being benign neoplasms, chronic inflammatory conditions, and malignant tumors. Statistical analysis indicated significant correlations between certain preoperative clinical diagnoses and histopathological results. Conclusion: Histopathological evaluation of elective surgical specimens provides critical insights into the underlying pathologies and helps in guiding postoperative management. Regular audits of histopathological outcomes can enhance the quality of surgical care. [ABSTRACT FROM AUTHOR]

Background: Clinical trials aim to improve health care by reducing treatment costs, enhancing quality, and advancing the discovery of safe treatments. Notably, limited knowledge among resident doctors may impact research quality. Aims and Objectives: The study seeks to evaluate awareness and knowledge of clinical trials among undergraduate, intern, and postgraduate medical students. Materials and Methods: It was an observational, cross-sectional study conducted on 300 medical students over 3 months after approval from the Institutional Ethics Committee (IEC). The pre-validated questionnaire containing 24 items was administered through email, WhatsApp, or in person. Data were analyzed using descriptive statistics. Results: In the study, 96.7% of participants believe the necessity of clinical trials. Notably, 72% of undergraduates and 76% of postgraduates express willingness to participate in a clinical trial. Furthermore, 93% of participants view trials as vital for innovative therapies, and 74.3% believe that they enhance health-care services. Knowledge gaps in clinical trials were evident: 56.3% of participants knew good clinical practice guidelines, 46.7% of participants were aware of them, and only 12.3% of participants knew the IEC role. However, 66.7% of participants recognized the Drug Controller General of India (DCGI) and IEC approvals as crucial for trials, and 53.7% of participants identified DCGI as the regulatory authority. 68.3% of participants could not define a placebo-controlled trial. However, 75% of participants were aware of the consequences of informed consent form non-compliance. Most knew about post-marketing surveillance (80.33%), but awareness of healthy volunteer involvement in Phase 1 was lower (48%). In addition, 62.33% of participants knew about marketing access after Phase 3, and 60% of participants were aware of adverse effects reporting procedures. Conclusion: The study reveals a concerning lack of awareness regarding clinical trials among undergraduate, intern, and postgraduate medical students, emphasizing the need for targeted educational interventions in medical curricula. [ABSTRACT FROM AUTHOR]

One of the deadliest and riskiest natural disasters is an earthquake. They often occur without a warning or any further alert. Therefore there was a need for its prognosis as it is extremely important for mankind as well as the environment. In this project, the successful application of machine learning techniques have been used for different elements of research which would be possible to use to make a more accurate short-term prognosis of upcoming earthquakes. Random Forest Classifier is the algorithm used for the research.

Maximum family members in India are using traditional stoves to prepare their three meals per day. Generally, raw wood, cow dung and rice husk are the main fuels for running traditional stoves. Due to improper design of conventional stoves, incomplete combustion of fuel occurs which creates air pollution. The World Health Organization (WHO) estimates that about 4 million people die prematurely each year from diseases caused by indoor air pollution caused by inefficient eating practices. The survey also found that 60% to 70% of rural women are suffering from throat cancer and most of them are respiratory system problem. Accordingly, the AYUSH Department of the Government of India found that most of the deaths during the Corona period were due to failure of the respiratory system. To solve the problem of air pollution from traditional home stoves. We have developed a smokeless stove that uses wood as primary fuel and superheated steam as secondary fuel. Due to supply of hot steam, the built-in stove is used for household and community purposes. The main objective of this work is to establish complete combustion of fuel, provide a smoke free environment and thereby reduce health hazards in rural households, especially among women.

Introduction: The oral cavity, the beginning of the digestive system, has diverse lesions affecting it other than Oral Squamous Cell Carcinoma (OSCC). Soft-tissue Tumours (STT) are uncommon lesions. Overlapping of the signs and symptoms in diverse conditions creates significant problems for reaching their definitive diagnosis. Histopathological Examination (HPE) plays a central role in giving their final diagnosis. Assessment of the clinical features, histopathology, along with Immunohistochemistry (IHC), helps in reaching an accurate diagnosis in these cases, which further aids in the proper management of the patient. Aim: To study the spectrum of oral cavity lesions and tumours with emphasis on STT. Materials and Methods: A retrospective cross-sectional study was conducted at the Department of Pathology and Otolaryngology, Dr. Ulhas Patil Medical College, Jalgaon, Maharashtra, India included the oral cavity lesion samples received over two years (from January 2021 to December 2022) in the histopathology section of a Medical College in Maharashtra, India. A total of 170 cases were included in the study. Complete clinical information including age, sex, anatomical location, clinical diagnosis, and histological subtypes were compiled. The HPE diagnosis were classified into four categories-Non neoplastic, Benign, Epithelial Proliferative lesions {including viral/Human Papillomavirus (HPV) related}/Intraepithelial neoplastic lesions/Precursor or Pre-malignant, and malignant with special emphasis on STTs found. The data was statistically analysed and the results were presented as percentages. Full details of the soft-tissue lesions were recorded, entered into an Excel sheet, and studied for the percentage-wise distribution of various recorded parameters. Results: A total of 170 cases were found. Male:female distribution was 2.78:1, and most patients were in the seventh decade, n=38 (22.35%). The most common lesions other than SCC, n=110 (64.71%) found were mucocele, chronic inflammatory lesion and wart. The Buccal Mucosa/Gingivo-buccal Sulcus (GBS) were the most commonly involved site, n=82 (48.24%). Malignant lesions were more common in the sixth and seventh decades, with a male preponderance of 2.71:1. The uncommon STTs found were-Benign: Haemangioma/pyogenic granuloma (n=2), a Schwanomma, and a Proliferative Fasciitis (PF); Malignant: two fibrosarcomas and a high-grade sarcoma. All three malignant STTs were found in males of the sixth decade involving the buccal mucosa. Conclusion: Among the variety of lesions found in the oral cavity, HPE facilitates the recognition of the STT, especially the malignant ones, aiding in proper management. Being an extremely uncommon entity at this site, the documentation of these findings is of utmost importance. [ABSTRACT FROM AUTHOR]