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Climate change has been noticed in the agricultural sector of Nepal which calls for strategies for adaptation and resilience building. We assessed the influence of demographic, institutional factors, and farm characteristics on the adoption of twenty climate change adaptation practices. We used climate change impact survey data of 800 households for Province 1 and analyzed the data using the Poisson regression and corrected the overdispersion using Negative Binomial regression. The results revealed that the operational size of landholding, years of experience in farming and formal education of the household head, the association of members in cooperatives and community-based organizations, the occurrence of disasters in the last five years, male-headed households, and receiving remittance influenced the adoption of a package of climate change adaptation practices in agriculture in Nepal. The results imply that policies should be geared towards enhancing the capacity of farmers through education and skill training, strengthening social networks, increasing investment for the generation and dissemination of climate-resilient agricultural technologies and practices, implementing additional off-farm and on-farm activities to increase income, and improving access to physical resources, education, and information to female-headed households.

Locally relapsed prostate cancer (PCa) after radiation therapy (RT) is associated with substantial morbidity and mortality. Morphological and molecular consequences that may contribute to RT resistance and local recurrence remain poorly understood. Locally recurrent PCa tissue from 53 patients with clinically localized PCa who failed with primary RT and subsequently underwent salvage radical prostatectomy (RP) was analyzed for tumor focality, clinicopathological, molecular, and genomic characteristics. Targeted next-generation sequencing with full exon coverage of 1,425 cancer-related genes was performed on 10 representative radiorecurrent PCas exhibiting no RT effect with matched adjacent benign prostate tissue. At RP, 37 (70%) of PCas had no RT effect with the following characteristics: grade group (GG) ≥ 3 (70%), unifocal tumor (75%), extraprostatic disease (78%), lymph node metastasis (8%), and "cribriform" morphologies (84%) [cribriform PCa (78%) or intraductal carcinoma (IDC-P) (61%)] at a median percentage of approximately 80% of tumor volume. In the setting of multifocal tumors (25%) at RP, the cribriform morphologies were restricted to index tumors. Of 32 patients with available pre-RT biopsy information, 16 had GG1 PCa, none had cribriform morphologies at baseline but 81% demonstrated cribriform morphologies at RP. Notable alterations detected in the sequenced tumors included: defects in DNA damage response and repair (DDR) genes (70%) (TP53, BRCA2, PALB2, ATR, POLQ), PTEN loss (50%), loss of 8p (80%), and gain of MYC (70%). The median tumor mutational burden was 4.18 mutations/Mb with a range of 2.16 to 31.86. Our findings suggest that most radiorecurrent PCas are enriched in cribriform morphologies with potentially targetable genomic alterations. Understanding this phenotypic and genotypic diversity of radiorecurrent PCa is critically important to facilitate optimal patient management.

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK–STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK–STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK–STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.

Testosterone is a steroid hormone that is responsible for the development of normal male sexual characteristics and function as well as the maintenance of homeostasis among multiple organ systems throughout life. Testosterone production is regulated by the hypothalamic-pituitary axis under the direction of gonadotropin-releasing hormone and luteinizing hormone. The testosterone-bound androgen receptor (AR) is a potent regulator of gene expression and may regulate a significant proportion of genes in prostate cells. Therapeutic modulation of testosterone levels and AR signaling activity can be achieved by several different approaches, with distinct consequences and side effects.

The contamination of trace elements (TEs) in freshwater sources has become an alarming issue globally. This study evaluates the contamination level of TEs, their spatial distributions, and the health risks in the Ghodaghodi Lake complex, Nepal. Altogether, ten water samples were collected, and As, Ba, Cd, Co, Cr, Cs, Cu, Li, Mn, Ni, Pb, Rb, Sc, Sr, Ti, Tl, V, Y, and Zn were determined by inductively coupled plasma mass spectrometry. The results revealed that Sr, Zn, Cu, As, Sc, and Rb were dominated TEs, contributing to the contamination. The principal component analysis and correlation matrices demonstrated both the geogenic and anthropic origin of the TEs in the lake. The water quality index (WQI=10.08) and hazard indices

Introduction: Estrogen receptor gene (ESR1) drives approximately 70-80% of breast cancer cases, which are primarily treated with endocrine therapies. Mutations in the ESR1 exclusively occur in the ligand binding domain (LBD) and are significantly enriched following endocrine therapy. These mutations retain the estrogen receptor (ER) expression thus conferring ligand-independent growth, which is a paramount contributor to endocrine therapy resistant disease. Worse progression-free survival is consistently associated with ESR1 mutation status; therefore, there is an unmet need for therapies against these mutations. To this end, we recently developed TX-245, a bis-benzamide molecule that hampers the function of the two most common ESR1 mutations - Y537S and D538G. Methods: TX-245 was evaluated in vitro using MTT cell proliferation assay and colony formation assay carried out in multiple ER+ breast cancer cells harboring wild type (WT) ESR1 or mutant (MT) ESR1. Approaches such as tumor spheroid cultures were also implemented to study the effect of TX-245 compared to selected SERDs/SERMs via CellTiter-Glo 3D viability assay. Mechanistic insights were obtained performing TR-FRET assay, fluorescence polarization assay, RNA-seq, ChIP-seq, western blot, and qRT-PCR. The therapeutic efficacy in vivo was evaluated using cell xenografts, patient derived xenografts (PDX), patient derived explants (PDE), and metastatic mouse models of MT-ER breast cancer. Results: TX-245 demonstrated greater anti-proliferative dose-dependent activity in models harboring WT and MT ESR1, including those resistant to fulvestrant and tamoxifen, when compared to other SERDs/SERMs. RNAseq data suggests that TX-245 dramatically alters the transcription of ERα-regulated genes, with repression of canonical estradiol-upregulated and induction of estradiol-repressed genes. TX-245 was able to antagonize ER-chromatin interaction and ER-transcriptional signaling in breast cancer cells driven by ESR1 mutation. TX-245 treatment downregulated ER protein expression and decreased expression of ER targeted genes (i.e., GREB and PGR) in multiple ER+ cell lines. TX-245 treatment as a single agent or in combination with palbociclib resulted in tumor regression in xenografts expressing WT, Y537S or D538G ESR1 mutation. PDX and PDE models consistently exhibited substantial tumor growth inhibition as well as decreased proliferation (Ki67 staining). Metastases studies using intracardiac and intratibial injection demonstrated that TX-245 inhibited the progression of established metastatic niches in mice injected with Y537S or D538G ER+ breast cancer cells. Conclusion: Our results indicate that TX-245 inhibits cell proliferation in cell lines that express WT or mutant ESR1, induce ER degradation, suppress ER-mediated signaling and reduce tumor burden in mouse models. These studies highlight the utility of TX-245 in targeting mutations in the ER-LBD. Citation Format: Karla Parra, Suryavathi Viswanadhapalli, Tanner Reese, Xihui Liu, JunHao Liu, Zexuan Liu, Tae-Kyung Lee, Chia Yuan Chen, Kara Kassees, Jung-Mo Ahn, Ratna Vadlamudi, Ganesh Raj, Carlos Roggero. Targeting the mutant estrogen receptor in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3440.

Climate change has severely impacted the rain-fed agricultural production system which is dominant in Nepal. This situation demands implementable strategies like supplemental irrigation for mitigating adverse impacts. In spite of the importance of supplemental irrigation, it is not adopted on a wider scale. Hence, this paper aims to assess perceptions of climate change and identify factors that influence the adoption of supplemental irrigation practices. Climate change impact survey data for Province No. 1 (one of the seven provinces in Nepal) with a sample of 800 households were analyzed by using the probit regression model. The results showed that the majority of the farmers perceived increasing temperature and decreasing precipitation, resulting in climate-induced disasters such as drought. Similarly, only about 27% of the households have adopted supplemental irrigation practices. The significant factors influencing the adoption of supplemental irrigation practices were the household head’s number of years of farming experience and education level, distance to motorable roads, operational size of landholding, membership in community-based organizations, and the perception of changes in summer temperature. Considering the empirical results, it is necessary to undertake research on sustainable practices and develop support measures for scaling up this practice as the adoption of this practice is very low in Province No. 1. The policy and strategy should also emphasize enhancing the capacity of farmers in technical and managerial aspects of supplemental irrigation practices, raising awareness about climate change and its impact, and strengthening community-based organizations for sharing and exchanging knowledge and skills. In addition, creating additional employment opportunities to enhance the income of the farmers for mitigating the capital constraint and increasing investment in infrastructures like roads for improving physical access thereby promoting adoption.

Climate change has severely impacted the rain-fed agricultural production system which is dominant in Nepal. This situation demands implementable strategies like supplemental irrigation for mitigating adverse impacts. In spite of the importance of supplemental irrigation, it is not adopted on a wider scale. Hence, this paper aims to assess perceptions of climate change and identify factors that influence the adoption of supplemental irrigation practices. Climate change impact survey data for Province No. 1 (one of the seven provinces in Nepal) with a sample of 800 households were analyzed by using the probit regression model. The results showed that the majority of the farmers perceived increasing temperature and decreasing precipitation, resulting in climate-induced disasters such as drought. Similarly, only about 27% of the households have adopted supplemental irrigation practices. The significant factors influencing the adoption of supplemental irrigation practices were the household head’s number of years of farming experience and education level, distance to motorable roads, operational size of landholding, membership in community-based organizations, and the perception of changes in summer temperature. Considering the empirical results, it is necessary to undertake research on sustainable practices and develop support measures for scaling up this practice as the adoption of this practice is very low in Province No. 1. The policy and strategy should also emphasize enhancing the capacity of farmers in technical and managerial aspects of supplemental irrigation practices, raising awareness about climate change and its impact, and strengthening community-based organizations for sharing and exchanging knowledge and skills. In addition, creating additional employment opportunities to enhance the income of the farmers for mitigating the capital constraint and increasing investment in infrastructures like roads for improving physical access thereby promoting adoption.

Nepal has been persistently encountering food insecurity and under-nutrition. It is therefore utmost important to determine the factors responsible for influencing food insecurity in Nepal. This study examines the factors determining food insecurity in Nepal applying binary logistic models for food poverty, household with inadequate food consumption and poor dietary diversity using data from Nepal Living Standard Survey 2010/11. Food security was determined to be strongly associated with education level and age of household head, household with higher female education level, larger farm size with higher ratio of irrigated land, better access to markets, roads and cooperatives, better household assets and remittance recipient households. Food insecure is relatively more prevalent in rural areas with higher dependent on rain-fed agriculture, higher dependency ratio and larger family size. Improving both physical and economic access to foods, together with investment in education and agriculture could help to reduce food insecurity and hunger from Nepal.

Approximately 75% of breast cancers are classified as hormone receptor-positive, most of which are estrogen receptor alpha-positive (ER+), which is the primary driver of growth in these tumors. Consequently, endocrine or anti-estrogen therapy is used for treatment. However, despite the benefits of endocrine therapeutics, treatment-resistant relapse is a significant problem that affects 30-50% of patients who initially respond to endocrine therapy. Therefore, studying resistance to endocrine therapy is critical for breast cancer research.We have shown that invasive lobular breast cancer (ILC) cells resistant to the anti-estrogen tamoxifen increase their expression of metabotropic glutamate receptors (GRMs/mGluRs). GRMs are well-known to play important roles in learning and memory in the brain and protect neurons from excitotoxicity (cell death caused by prolonged exposure to neurotransmitters). It is now appreciated that this pro-survival function of GRMs can be highjacked by cancer cells, including breast cancer. Thus, targeting GRM signaling could prove a valuable therapeutic strategy. We chose to target the GRM signaling pathway with the FDA-approved drug Riluzole currently being used to treat amyotrophic lateral sclerosis.In this study, we test the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated, ILC-derived patient-derived xenograft model HCI-013EI. In addition to measuring tumor growth rate and size, primary tumors and organs were collected for immunohistochemistry analysis.Riluzole as a single agent suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing differential histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In tamoxifen-resistant ILC cells, Riluzole induced apoptotic and ferroptotic cell death, and inhibited phosphorylation of focal adhesion kinase. Riluzole combined with either fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro. Using proliferating cell nuclear antigen (PCNA) staining as a proxy for cell proliferation, the combination of Riluzole plus Fulvestrant significantly reduced PCNA in a patient-derived explant model (t-test p = 0.013). The in vivo experiment showed reduced tumor size and growth between the control and combination treatments. However, unlike in the in vitro experiment, there was little difference between the single-agent fulvestrant and the combination groups. The observed difference between the in vitro and in vivo study may be attributed to the bioavailability of Riluzole in mice.In conclusion, our results show that Riluzole enhances response to endocrine therapy in ER+ breast cancer. Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.

A product design and development process has been adopted to study and improve the performance of unit cleaner system. A hair trimmer with liquid detergent in cartridge is fixed as a cleaner system to design and analyse. The 3D model of the system is designed with NX CAD software. The modification is cartridge unit is made on counter face to increase the turbulence of the fluid in the wash zone. The file has been extracted and imported in LS Dyna for meshing the model for detergent liquid flow analysis. The velocity vector and pressure magnitude of the fluid flow is analysed through a StarCCM+ higher fluid analysis software. The input process condition of the pump in cartridge assemble unit has a speed 2000 rpm and velocity of the liquid as 1 m/s. From the analysis, the suction pressure noticed at the pump zone is 950 Pa and the discharge of fluid in the pump is 850 – 900 Pa at wash zone. Difference in fluid velocity found decreased and it is in the range of 0.8 to 0.95 m/s. The predominant factor in the design is alternate openings in case baffle has increased the turbulence in pressure and the velocity of the fluid found same.

Fraudulent activities in financial fields are continuously rising. The fraud patterns tend to vary with time, and no consistency can be observed in this regard. The incorporation of new technology by fraudsters is the reason for the execution of online fraud transactions. Given the volatility of the fraud patterns, a good fraud detection model must be able to evolve and update itself to the changing patterns. Thus we aim in this paper to analyze the fraud cases that are unable to be detected based on supervised learning or previous history, create an Auto-encoder model based on deep learning and Compare and assess the performance of the model based on data from different parts of the world and check for the demographic diversity of fraud patterns thereby inferring that the data from which part of the world the model fits the best. The proposed algorithm, deep learning based on the auto-encoder (AE) network is an unsupervised learning algorithm that utilizes backpropagation by setting the inputs and outputs identical. In this research, the Tensorflow package from Google has been employed to implement AE by using deep learning. The accuracy, precision, recall, F1 score and area under the curve(AUC) are all executed to assess the performance of the model.

Purpose The purpose of this paper is to find out the optimum machining parameters using Taguchi technique with principal component analysis (PCA) during end milling of GFRP composites. Design/methodology/approach In multi-objective optimization, weight criteria of each objective are important for producing better and accurate solutions. This method has been employed for simultaneous minimization of surface roughness, cutting force and delamination factor. Experiments were planned using Taguchi’s orthogonal array with the machining parameters, namely, helix angle of the end mill cutter, spindle speed, feed rate and depth of cut were optimized with considerations of multiple response characteristics, including machining force, surface roughness and delamination as the responses. PCA is adopted to find the weight factors involved for all objectives. Finally analysis of variance concept is employed on multi-SN ratio to find out the relative significance of machining parameter in terms of their percentage contribution. Findings The multi-SN ratio is achieved by the product of weight factor and SN ratio to the performance characteristics in the utility concept. The results show that a combination of machining parameters for the optimized results has helix angle of 35°, machining speed of 4,000 m/min, feed rate of 750 mm/rev and depth of cut of 2.0 mm. Originality/value Effect of milling of GFRP composites on delamination factor, surface roughness and machining force with various helix angle solid carbide end mill has not been analysed yet using PCA techniques.

Diabetes Mellitus (DM) is the group of diseases where the patient suffers from higher levels of sugar in blood over a prolonged time. Machine learning classifier helps to predict the disease based on the condition of the symptom suffered by the patient. The aim of this paper is to compare the performance of the machine learning tree classifiers in predicting Diabetes Mellitus (DM). Machine learning tree classifiers such as Random Forest, C4.5, Random Tree, REPTree, and Logistic Model Tree (LMT) were analyzed based on their accuracy and True Positive Rate (TPR). In this analysis of predicting diabetes mellitus Logistic Model Tree (LMT) machine learning tree classifier achieved higher accuracy of 79.31%, True Positive Rate (TPR) of 0.739 and an execution time of 1.09 sec than other classifiers under study.

Background: Women with triple-negative breast cancer (TNBC) have a more aggressive clinical course, with a higher propensity to metastasize and a worse outcome due to a lack of effective therapies and significant intratumoral and intertumoral heterogeneity. Development of novel therapeutic strategies represents a clear unmet need. We have developed a first-in-class compound, an oligobenzamide, ERX-41, that has anti-proliferative activity against all six molecular subtypes of TNBC. Methods: In vitro activity of ERX-41 on TNBC cell lines was tested using CellTiter glo, MTT, and apoptosis assays. Efficacy of ERX-41 was tested using TNBC patient derived explants (PDEs) ex vivo, cell line-derived xenografts (CDXs), and patient derived xenografts (PDX) in vivo. To examine the mechanism, we conducted mass spec analyses using total lysates of TNBC cells treated with vehicle or ERX-41. Results: ERX-41 demonstrated potent activity in both blocking proliferation and inducing apoptosis in 30 distinct cell line models of TNBC, (representing all six molecular subtypes of TNBC), with an IC50 that ranges from 50-250nM. Incubation of ERX-41 with PDEs from primary TNBC patient tumors ex vivo caused a significant reduction in proliferation indices, as measured by Ki67 staining. ERX-41 also decreased proliferation and increased apoptosis in explants from TNBC CDX and PDX tumors cultured ex vivo. Oral administration of ERX-41 (10 mg/kg/daily) was shown to be non-toxic and dramatically limited the growth of CDX tumors derived from MDA-MB-231, SUM-159 or D2A1 syngeneic tumors. Importantly, ERX-41 treatment also significantly reduced tumor progression in four TNBC PDX (PDX-1, PDX-89, PDX-96 and PDX-98) models compared to the vehicle treated control group. Our ultrastructural and molecular studies indicate that ERX-41 induces significant endoplasmic reticulum (ER) stress within TNBC cells but not in primary epithelial cells. Global mass spectrometry studies indicated that ERX-41 treatment resulted in the alteration [down regulation (265 proteins) or upregulation (218 proteins)] of 483 proteins out of ~4000 proteins quantified with two or more peptides. Reactome pathway analysis indicated that the top pathways modulated by ERX-41 included Intra-Golgi and retrograde Golgi-to-ER traffic, membrane trafficking and TP53 mediated apoptosis. ER stress induced by ERX-41 blocks de novo protein synthesis, and triggers ER-assisted degradation (ERAD) pathways, causing TNBC apoptotic cell death. Conclusions: ERX-41 is orally bioavailable, non-toxic, and demonstrated activity in primary PDEs, CDXs and PDXs. The ability of ERX-41 to induce ER stress and apoptotic cell death in multiple types of TNBC suggests that this drug targets a fundamental weakness in TNBC cells (the high basal level of ER stress) and can effectively overcome the heterogeneity of TNBC. These studies strongly support the further clinical translation of ERX-41. Citation Format: Suryavathi Viswanadhapalli, Xihui Liu, Shi-Hong Ma, Tae-Kyung Lee, Mengxing Li, Weiwei Tang, Junhao Liu, Xiaonan Li, Gangadhara R. Sareddy, Rajeshwar Rao Tekmal, Jung-Mo Ahn, Ratna K. Vadlamudi, Ganesh V. Raj. Preclinical evaluation of ERX-41 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1237.

Climate change has become unequivocal with its implications in every aspects of life and livelhood options, including agriculture. The present paper analyzes the agrarian households’ perception on climate change, identify the major agricultural practices adopted to minimize the effects of climate change and their determinants in Rasuwa district of Nepal. Nepal's agricultural production system being rain-fed in nature, the impact of climate change on productivity and production has already been experienced. During the study, the purposive sampling technique was adopted while selecting the VDCs located within the buffer zone of Langtang National Park. Four VDCs namely Laharepauwa, Dhaibung, Dhunche and Syaphru were purposively selected representing paddy, wheat, maize, and potato production area of the district. Thirty households from each VDC were interviewed by using the structured questionnaire totaling a sample size of 120 households. In addition, the present study also used Focus Group Discussions with local government officials, buffer zone communities and other stakeholders about the climate change knowledge and adaptation, and to assess perception on different climate change related threats and strategies adapted to cope the impact. Information with regard to the experience of the respondent in cultivating the crop in question, changes in rainfall amount and time, seasonal change in temperature and their effect on the time of planting and yield, and the adaptation strategy were collected. The factors influencing whether to adopt climate adaptation practices in agriculture was analyzed using binary logit model. The education level of household head, household size, food self-sufficiency from their own production and inadequacy of current knowledge on agricultural adaptation influenced the adoption. In the Nepalese context, where agricultural occupation is the dominant means of living, climate adaptation seems to be the most efficient and friendly way for farmers to neutralize the potential adverse effects. The farmer’s knowledge and skills on techniques of adaptation need to be enhanced and support in availing such practices and technologies which may result for better adoption. The awareness raising campaigns need to be organized and indigenous knowledge and practices should be documented and verified for further replication.

The chapter assesses the impact of climate change on agricultural production, food security, livelihoods, and economy. It reviews the ongoing and planned policies, plans, programs and projects to respond to the impacts of climate change. It also identifies policy responses and technology needs to help smallholders adapt to climate change impacts. The mainstreaming of climate resilience at the policies, plans and programs, developing and strengthening institutions for better service delivery, and ensuring and increasing the finance for research and development activities should be prioritized.