Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.

We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.

Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis.

Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. HPV-16 and -18 are mainly responsible for the progression of several cancers, including cervix, anus, vagina, penis, vulva, and oropharynx. The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment. Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. In addition, vaccination awareness programs and preventive strategies could help reduce the rate and incidence of HPV infection. In this review, we emphasize HPV infection and its role in cancer progression, molecular and immunopathogenesis, host immune response, immune evasion by HPV, vaccination, and preventive schemes battling HPV infection and HPV-related cancers.

Discovery of Selective Tertiary Amide Inhibitors of Cyclin-Dependent Kinase 2 (CDK2).

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

Expression of miR-145 and miR-18b in Peripheral Blood Samples of Head and Neck Cancer Patients.

Head and neck squamous cell carcinomas (HNSCC) is one of the most prevalent type of cancer known in Indian population. Studies are needed to identify the early biomarkers for HNSCC. MicroRNAs (miRNAs) are non-coding RNA molecules, expression of which can be used as biomarker for early diagnosis of HNSCC. For miRNA profiling total RNA, which also contained small RNAs were isolated from ten HNSCC tissue samples and adjacent control. Purity and concentration of eluted RNA was assessed using the NanoDrop1000® spectrophotometer, Reverse Transcription reaction was carried out with megaplex RT primers of pool A and pool B and the expression of selected miRNAs (miR-143/145 and miR-18a/b) was measured using TaqMan primers specific for mature miRNAs. Our study showed dramatic downregulation in expression of two miRNAs, miR-18b and miR-145 in blood samples of HNSCC patients, which are inhibitor of tumorigenesis and can be targeted as biomarker of HNSCC pathogenesis therefore developing avenues for miRNA role in prognosis and therapeutics. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-023-01119-2.

A prospective randomized comparative study to evaluate the effect of palliative hypo-fractionated radiotherapy with concurrent chemotherapy versus hypo-fractionated radiotherapy alone in advanced and unresectable head and neck cancer with no metastasis.

Introduction: A short duration, palliative radiotherapy schedule for locally advanced and unresectable head and neck cancer (LAUHNC) was evaluated in terms of palliation of cancer-related symptoms and acute toxicities. Aims and objectives: The aim of the study was to compare the role and feasibility of hypo-fractionated radiotherapy with concurrent chemotherapy and hypo-fractionated radiotherapy in LAUHNC. Materials and methods: All the patients included in this study of LAUHNC were not fit for curative treatment. These patients are assessed on the basis of quality of life (QOL), tumour response, toxicities, and relief in symptoms. QOL was assessed on the basis of University of Washington QOL questionnaire version 4 before and after treatment. Patients are divided into two arms, Arm A patients received 40 Gy in ten fractions concurrent cisplatin 50 mg/m2 with weekly and Arm B patients received 40 Gy in ten fractions. To assess the tumour response response evaluation criteria in solid tumours criteria were used. Results: A total of 40 patients were enrolled in this study, with 20 patents in both arms. Three patients defaulted during treatment and one patient died during treatment. A total of 36 patients completed treatment. Before treatment common complaints was distressing pain in primary site, and difficulty in chewing and swallowing. After treatment there was reduction of pain and improvement in swallowing in both arms. Overall QOL improvement in Arm A (28.89 ± 18.44 to 46.67 ± 15.34) and in Arm B (31.11 ± 15.68 to 43.33 ± 15.72). Neither of the arms experienced grade IV mucositis and skin reaction. Conclusion: Toxicity in the form of mucositis and dermatitis was higher in the concurrent hypo-fractioned arm compared to the only hypo-fractionated radiotherapy arm during the treatment and in follow up period. The QOL in both individual arms showed statistically significant results, however when the QOL of both the arms was compared, the results were not statistically significant.

Diabetes in Pregnancy Study Group India (DIPSI) and WHO (1999) diagnostic criteria for GDM: A meta-analysis.

BACKGROUND AND AIMS: The diagnosis of Gestational diabetes mellitus (GDM) is challenging and controversial due to the heterogeneity or lack of consensus regarding the screening and diagnostic criteria for GDM. METHODS: A meta-analysis of studies comparing Diabetes in Pregnancy Study Group India (DIPSI) and WHO 1999 for diagnosing GDM was carried out. RESULTS: A total of 6 comparative studies were included. Pooled analysis showed sensitivity and specificity as 0.79 (95% CI: 0.53 to 0.92) and 0.97 (95% CI: 0.94 to 0.98) respectively. CONCLUSION: Based on the results of the meta-analysis, DIPSI showed higher specificity when compared to WHO 1999, hence may be used to rule in disease in probable GDM cases. However, the results should be interpreted more cautiously and carefully since only a few studies were included.

Managing brain tumors in pregnancy: The oncologist's struggle with maternal-fetal conflict.

The diagnosis of malignancy, particularly brain tumors, in pregnancy is uncommon but poses a complex dilemma for the management of both the patient and her fetus, as the interplay of disease with the physiological state of pregnancy affects both outcomes. The routine evaluations (symptomatology, imaging, and hormonal assessments) and treatments (surgery, radiation therapy, and chemotherapy) that are commonplace in brain tumor management may need to be omitted or modified keeping in mind the risk to offspring. Multidisciplinary care and extensive prenatal and perinatal counseling and monitoring are essential. In this review, we discuss the available data addressing these issues and factors which may affect considerations of therapeutic abortions, changes in surgical or medical practices, and outcomes thereof.

Trichoscopy of Pressure-Induced Alopecia and Alopecia Areata: A Comparative Study.

Background: Pressure-induced alopecia is an uncommon type of alopecia. It can occur in both scarring as well as non-scarring form and occurs due to ischemia resulting from prolonged head immobilisation during surgery or hospitalisation. The patchy hair loss generally involves convexities of scalp specially vertex and occiput. The hair loss is usually noticed 3 -28 days after the inciting event and regrowth of hair occurs between 1 - 4 months. Objective: To describe trichoscopic features of pressure alopecia and compare it with the closest differential, alopecia areata. Methodology: It is a retrospective observational study. Trichoscopic features of six cases of pressure alopecia seen during the study period were compared with alopecia areata and analyzed using appropriate statistical methods. Results: The study had 30 cases, six cases of pressure alopecia and 24 cases of alopecia areata. The mean age of patients with pressure alopecia and alopecia areata was 45.16 and 29.08 years respectively. Comedone- like black dots, black dots and area of scarring were statistically significant for pressure alopecia while exclamation mark hairs were significant for alopecia areata. Conclusion: Trichoscopy is a non-invasive test for diagnosis of alopecia and "Comedone-like black dots" are unique trichoscopic feature of pressure alopecia.

Mapping Dual-Base-Enabled Nickel-Catalyzed Aryl Amidations: Application in the Synthesis of 4-Quinolones.

The C-N cross-coupling of (hetero)aryl (pseudo)halides with NH substrates employing nickel catalysts and organic amine bases represents an emergent strategy for the sustainable synthesis of (hetero)anilines. However, unlike protocols that rely on photoredox/electrochemical/reductant methods within NiI/III cycles, the reaction steps that comprise a putative Ni0/II C-N cross-coupling cycle for a thermally promoted catalyst system using organic amine base have not been elucidated. Here we disclose an efficient new nickel-catalyzed protocol for the C-N cross-coupling of amides and 2'-(pseudo)halide-substituted acetophenones, for the first time where the (pseudo)halide is chloride or sulfonate, which makes use of the commercial bisphosphine ligand PAd2-DalPhos (L4) in combination with an organic amine base/halide scavenger, leading to 4-quinolones. Room-temperature stoichiometric experiments involving isolated Ni0, I, and II species support a Ni0/II pathway, where the combined action of DBU/NaTFA allows for room-temperature amide cross-couplings.

A Feature Extraction Using Probabilistic Neural Network and BTFSC-Net Model with Deep Learning for Brain Tumor Classification.

BACKGROUND AND OBJECTIVES: Brain Tumor Fusion-based Segments and Classification-Non-enhancing tumor (BTFSC-Net) is a hybrid system for classifying brain tumors that combine medical image fusion, segmentation, feature extraction, and classification procedures. MATERIALS AND METHODS: to reduce noise from medical images, the hybrid probabilistic wiener filter (HPWF) is first applied as a preprocessing step. Then, to combine robust edge analysis (REA) properties in magnetic resonance imaging (MRI) and computed tomography (CT) medical images, a fusion network based on deep learning convolutional neural networks (DLCNN) is developed. Here, the brain images' slopes and borders are detected using REA. To separate the sick region from the color image, adaptive fuzzy c-means integrated k-means (HFCMIK) clustering is then implemented. To extract hybrid features from the fused image, low-level features based on the redundant discrete wavelet transform (RDWT), empirical color features, and texture characteristics based on the gray-level cooccurrence matrix (GLCM) are also used. Finally, to distinguish between benign and malignant tumors, a deep learning probabilistic neural network (DLPNN) is deployed. RESULTS: according to the findings, the suggested BTFSC-Net model performed better than more traditional preprocessing, fusion, segmentation, and classification techniques. Additionally, 99.21% segmentation accuracy and 99.46% classification accuracy were reached using the proposed BTFSC-Net model. CONCLUSIONS: earlier approaches have not performed as well as our presented method for image fusion, segmentation, feature extraction, classification operations, and brain tumor classification. These results illustrate that the designed approach performed more effectively in terms of enhanced quantitative evaluation with better accuracy as well as visual performance.

Comprehension of Prescriptions and Errors in Taking Prescribed Medicines by Veterans - Polypharmacy a Problem Underrated.

BACKGROUND: Polypharmacy is a significant problem in the elderly. The veteran population is unique in terms of better access to health-care services and higher educational qualifications. However, the studies to assess the burden and effects of polypharmacy in this cohort are rare. Hence, the research was done to find the prevalence of polypharmacy in the veteran population. METHODS: In this cross-sectional observational study, we included veterans with more than 35 years visiting the medical outpatient department. All participants were interviewed about polypharmacy after taking informed consent. RESULTS: Out of 394 patients included in the study, 110 were prescribed five or more medicines for their illnesses (27.91%: 95% confidence interval [CI] 21.1%-30%). More than 95% (377/394) of the study participants were unaware of the concept of polypharmacy. There was high compliance to treatment in veterans (97.46%, 95% CI 95.1%-98.6%). CONCLUSION: This study shows that the prevalence of polypharmacy is significant in veterans, including patients in their fourth and fifth decades of life, despite fewer morbidities.

Nickel-Catalyzed N-Arylation of Fluoroalkylamines.

The Ni-catalyzed N-arylation of ß-fluoroalkylamines with broad scope is reported for the first time. Use of the air-stable pre-catalyst (PAd2-DalPhos)Ni(o-tol)Cl allows for reactions to be conducted at room temperature (25 °C, NaOtBu), or by use of a commercially available dual-base system (100 °C, DBU/NaOTf), to circumvent decomposition of the N-(ß-fluoroalkyl)aniline product. The mild protocols disclosed herein feature broad (hetero)aryl (pseudo)halide scope (X=Cl, Br, I, and for the first time phenol-derived electrophiles), encompassing base-sensitive substrates and enantioretentive transformations, in a manner that is unmatched by any previously reported catalyst system.

Small cell glioblastoma multiforme: a case series and clinicopathological update.

Small cell glioblastoma (scGBM) is a rare histological variant of classical glioblastoma (GBM). Presence of necrosis and microvascular proliferation is not essential for the diagnosis. It is thought to have more aggressive behavior as compared with classical GBM; however, because of its rarity standard treatment guidelines are not available. Adjuvant treatment for these cancers consists of postoperative radiotherapy with concurrent and maintenance temozolomide similar to classical GBM. Here we present a case series of five small cell glioblastoma patients along with the clinical-pathological review.

Erectile dysfunction and cancer: current perspective.

Erectile dysfunction (ED) is one of the major but underreported concerns in cancer patients and survivors. It can lead to depression, lack of intimacy between the couple, and impaired quality of life. The causes of erectile dysfunction are psychological distress and endocrinal dysfunction caused by cancer itself or side effect of anticancer treatment like surgery, radiotherapy, chemotherapy and hormonal therapy. The degree of ED depends on age, pre-cancer or pre-treatment potency level, comorbidities, type of cancer and its treatment. Treatment options available for ED are various pharmacotherapies, mechanical devices, penile implants, or reconstructive surgeries. A complete evaluation of sexual functioning should be done prior to starting anticancer therapy. Management should be individualized and couple counseling should be an integral part of the anticancer treatment.

Endothelial corneal transplants: indications, clinical profile and surgical outcomes in a tertiary care hospital.

BACKGROUND: Endothelial keratoplasties have become the surgical procedure of choice over full thickness penetrating keratoplasty for corneal decompensation because of endothelial dysfunction. METHODS: A retrospective data review was performed from February 2016 to April 2017 for all the patients who underwent endothelial keratoplasty in a tertiary care center for Indian Armed Forces. RESULTS: A total of 161 corneal transplants were performed; endothelial keratoplasties accounted for 34 (21.1%) transplants. Most common indication was pseudophakic/aphakic bullous keratopathy followed by Ahmed glaucoma valve-related corneal decompensation and Fuchs' corneal dystrophy, respectively. Mean preoperative corneal thickness was 845.96 ± 106.9 microns. Mean lenticule thickness was 131.55 ± 42.47 microns with microkeratome for descemet stripping automated endothelial keratoplasty (DSAEK) and 174 ± 70.4 microns manually for descemet stripping endothelial keratoplasty (DSEK). Mean preoperative best-corrected visual acuity (BCVA) was 1.65 LogMAR (Snellen equivalent in meters 2/60 approx) which significantly improved to 0.82 LogMAR (Snellen equivalent in meters 6/36 approx) after surgery. In the DSAEK group, BCVA improved from 1.61 to 0.7 LogMAR, whereas in the DSEK group, the visual acuity improved from 1.7 to 0.94 LogMAR at one-month postoperative period. Postoperatively, two patients had graft detachment and had to undergo repeat DSAEK. CONCLUSION: Study results suggest the similar trends in our tertiary care hospital as in other most advanced ophthalmic centers around the world for adoption of newer techniques of lamellar corneal transplants and their outcomes.

Nickel-Catalyzed Cross-Coupling of Sulfonamides With (Hetero)aryl Chlorides.

The development of Ni-catalyzed C-N cross-couplings of sulfonamides with (hetero)aryl chlorides is reported. These transformations, which were previously achievable only with Pd catalysis, are enabled by use of air-stable (L)NiCl(o-tol) pre-catalysts (L=PhPAd-DalPhos and PAd2-DalPhos), without photocatalysis. The collective scope of (pseudo)halide electrophiles (X=Cl, Br, I, OTs, and OC(O)NEt2 ) demonstrated herein is unprecedented for any reported catalyst system for sulfonamide C-N cross-coupling (Pd, Cu, Ni, or other). Preliminary competition experiments and relevant coordination chemistry studies are also presented.

Real world clinical outcomes of adjuvant sequential chemoradiation in patients with gallbladder carcinomas with poor performance status.

PURPOSE: The purpose of the study is to analyze the overall survival, relapse-free survival, and relapse patterns of adjuvant sequential chemoradiation for gallbladder cancers after curative resection in patients with poor performance status. MATERIALS AND METHODS: We retrospectively reviewed clinical records of gallbladder patients with pathologic stage T2-4 or node positivity treated with sequential chemoradiation at our institute between January 2015 and January 2019. Sequential chemoradiotherapy protocol consisted of six cycles of gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2 administered every 2 weekly and postoperative radiation therapy (45 Gy in 25 fractions over 5 weeks) by three-dimensional conformal technique. RESULTS: A total of 36 patients were included. The median overall survival and relapse-free survival was 26 months (95% confidence interval [CI], 21.4-30.5) and 21 months (95% CI, 11.8-30.1), respectively. The 2-year overall and relapse-free survival rates were 55.1% (95% CI, 37.9%-72.3%) and 44.7% (95% CI, 27.5%-61.9%), respectively. Locoregional, systemic, and combined recurrence were noted in 2 (5.5%), 14 (38.8%), and 3 (8.3%) patients, respectively. On univariate analysis, tumour grading significantly influenced relapse free survival; nodal stage and overall stage demonstrated a statistically significant influence on overall survival (p < 0.05) with a trend towards significance for lymphovascular invasion. On multivariate analysis, no significant factors were found. Grade 3 and 4 haematological adverse events were observed only in 2 (5.5%) with chemotherapy. No grade 3 and 4 adverse events were observed due to radiation therapy. CONCLUSION: Sequential chemoradiation is feasible and tolerable with acceptable efficacy in the adjuvant setting in patients unfit for concurrent chemoradiotherapy.

Is occupation the "driving force" for tobacco consumption? A cross-sectional study to assess prevalence, patterns, and attitude towards tobacco use among long-distance bus drivers and conductors in Western Maharashtra.

BACKGROUND: Tobacco use remains a major cause of preventable deaths worldwide. The recent Global Adult Tobacco Survey 2016-2017 has shown the prevalence of tobacco use among Indian population to be 28.6%. In Maharashtra, 35.5% of all adult males either smoke tobacco or use some form of smokeless tobacco. Not much data are available on tobacco use with respect to different occupations in India, though risk of tobacco use is known to be higher among individuals in certain occupations. METHODS: This cross-sectional descriptive study was conducted among 190 long-distance bus drivers and conductors of long route buses departing from one of the main bus stations of the State Transport Corporation in Pune city. Data were collected using a pretested, structured questionnaire by interview method. RESULTS: Prevalence of tobacco consumption (TC) among the respondents was 55.8% (95% confidence interval; 48.4-63). Among the tobacco users, 54% reported initiation at age <18 years "peer pressure" and "curiosity" were the main reasons for initiation while "feeling alert" and "feeling mature" were reasons for continued use. A large proportion (74.5%) of the respondents expressed their intention to quit tobacco in the near future. CONCLUSION: Long-distance bus drivers and conductors showed a high prevalence of TC which may be linked to certain occupation-related factors. Targeted tobacco cessation activities at workplaces may be considered as a strategy for better impact of tobacco control activities in India.

Role of anti-oxidant (vitamin-C) in post-operative pain relief in foot and ankle trauma surgery: A prospective randomized trial.

BACKGROUND: Post-operative pain may adversely affect a patient's quality of life. Studies have shown that vitamin C, being an anti-oxidant and neuro-modulating agent, can help to reduce pain in a variety of clinical settings. The objective of this randomized controlled trial was to assess the effectiveness of vitamin C in reducing post-operative pain, analgesia requirements and improving functional outcome. METHODS: Patients with isolated foot and ankle trauma, who had undergone surgery, were randomly assigned to receive either vitamin C 500mg or a placebo tablet twice a day. VAS score, analgesia requirement and functional outcome were assessed during their regular follow up. Results were compared and analyzed at the end of 3 months. RESULTS: The group which received vitamin C, showed improvement in VAS score at the end of second and sixth week of follow up, reduced analgesia requirements and improved functional outcome as compared to the placebo group. CONCLUSIONS: This study shows that the supplementation of vitamin C in patients undergoing surgery for foot and ankle trauma helps to reduce analgesic requirements, improve VAS scores and achieve better functional outcome.