Prevalence and Risk Factors of Child Marriage Among Madhesi Women in Nepal's Terai Region.

Objective: Child marriage is a detrimental practice with negative consequences for girls' health and well-being. This study aims to identify the prevalence of child marriage and associated risk factors within the Madhesi community. Materials and methods: A cross-sectional study was conducted in a sub-metropolitan city of Lumbini Province, Nepal, in 2023. A total of 352 married women were randomly selected using simple random sampling and interviewed using a structured questionnaire between March 28th and April 17th. Descriptive categorical variables were expressed as proportions. Risk factors associated with child marriage were measured using the Chi-square test and multivariate logistic regression analysis. All statistical analyses were performed using SPSS version 26. Results: The majority of respondents (36.1%) were in the age group 21-25, with a mean age of 25.90 years ± 4.6 years. Most respondents (48.9%) received only basic-level education, with the majority (72.4%) reporting their parents as having no formal education. The primary family occupation was farming (40.1%). The prevalence of child marriage was high (77.0%), with a median marriage age of 18 years. Logistic regression analysis revealed significant risk factors including lower education levels of respondents and their parents, husband's occupation, lack of awareness about the legal marriage age, limited decision-making power regarding marriage, belief in the dowry system, discussions with friends about child marriage, and occurrence of child marriage among friends. Conclusion: Despite legal prohibition, child marriage remains prevalent in the Madhesi community. Educational interventions targeting women and parents, empowering women with decision-making authority, and addressing the dowry system are crucial for reducing this harmful practice.

Depression and anxiety among cancer patients visiting a tertiary care cancer hospital.

BACKGROUND: Cancer patients frequently experience psychological problems related to reactions to cancer diagnosis, cancer type and stage, treatment effects, recurrence, fear of end-of-life, survivorship, and financial burden. Depression and anxiety are both psychological and physiological disturbances among cancer patients. AIM: To assess the prevalence of depression and anxiety among cancer patients attending a tertiary care cancer hospital. METHODS: A cross-sectional study was conducted at Bhaktapur Cancer Hospital in Kathmandu Valley among 220 cancer patients aged from 18 years to 70 years. Ethical approval was taken from the Institutional Review Committee of CiST College. Convenient sampling was used to interview patients with the standardized Patient-Health Questionnaire (PHQ-9) for Depression and Hospital Anxiety and Depression sub-scale (HADS-A) for anxiety. Epi-Data was used for data entry and transferred to SPSS Version 25 for analysis. RESULTS: The study revealed that of 220 patients, most of the respondents belonged to the age group 51-60 years. More than half 131 (59.6%) of the respondents were female, most of them had depression, and one-third had anxiety. Among the respondents, 124 (56.4%) had mild depression, 70 (31.8%) had moderate depression, and 3 (1.3%) had severe depression; 79 (35.9%) had mild anxiety, 64 (29.1%) had moderate anxiety, and 4 (1.8%) had severe anxiety. CONCLUSION: Most respondents were depressed and one-third had anxiety. More than half and nearly one-third had mild and moderate depression, respectively, and nearly one-third had mild and moderate anxiety, which is higher than other studies.

Pesticide Use and Health Effects among Nepalese Farmers: A Cross-Sectional Study in Tokha Municipality.

Background: Pesticides are essential for agricultural development, but their increased use in developing countries like Nepal poses health risks to farmers. Methods: A cross-sectional study was conducted in wards 1, 2, and 3 of the Tokha Municipality in Kathmandu District to identify the health effects of pesticides and associated factors among farmers. The study included 333 respondents who were interviewed between April 26 and June 04, 2022. Results: The majority of farmers (36.6%) were aged between 40 and 49 years, with a median (IQR) age of 45.0 (38.0 to 51.0) years. All farmers reported using pesticides, with 100% usage in vegetables. Most respondents (73%) reported experiencing health effects: headache (69.5%), skin irritation (42.8%), and burning eyes (31.3%) were the most common symptoms. Only 8% sought medical care. Additionally, 94.6% of respondents had not received training on integrated pest management, and none of them reported using a complete set of personal protective equipment. The study found that older age groups, females, those who were unable to read and write, and those of the Hindu religion, as well as respondents with longer pesticide use, more frequent spraying, and not detecting wind direction, had significantly higher odds of self-reported health problems (P < 0.05). Conclusion: Our findings show that all farmers in the study were using pesticides, and the majority had reported health effects. Therefore, we recommend that farmers receive training on integrated pest management, use a complete set of personal protective equipment, and promptly seek medical care if they experience health issues.

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

Synthesis, metabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents.

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.

1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.

Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.