Alkoxy-functionalised dihydropyrimido[4,5-b]quinolinones enabling anti-proliferative and anti-invasive agents.

In this communication, we explored the synthesis of novel alkoxy-functionalised dihydropyrimido[4,5-b]quinolinones using a microwave-assisted multicomponent reaction. All the synthesized molecules were screened for anti-proliferative and anti-invasive activity against glioblastoma cells. 5c shows the most potent anti-proliferative activity with a half maximal effective concentration of less than 3 µM against primary patient-derived glioblastoma cells. 5c effectively inhibited invasion and tumor growth of 3D primary glioma cultures in a basement membrane matrix. This suggests that the novel compounds could inhibit both the proliferation and invasive spread of glioma and they were selected for further study.

Overall Polyp Detection Rate as a Surrogate Measure for Screening Efficacy Independent of Histopathology: Evidence from National Endoscopy Database.

Adenoma detection rate (ADR) is challenging to measure, given its dependency on pathology reporting. Polyp detection rate (PDR) (percentage of screening colonoscopies detecting a polyp) is a proposed alternative to overcome this issue. Overall PDR from all colonoscopies is a relatively novel concept, with no large-scale studies comparing overall PDR with screening-only PDR. The aim of the study was to compare PDR from screening, surveillance, and diagnostic indications with overall PDR and evaluate any correlation between individual endoscopist PDR by indication to determine if overall PDR can be a valuable surrogate for screening PDR. Our study analyzed a prospectively collected national endoscopy database maintained by the National Institute of Health from 2009 to 2014. Out of 354,505 colonoscopies performed between 2009-2014, 298,920 (n = 110,794 average-risk screening, n = 83,556 average-risk surveillance, n = 104,770 diagnostic) met inclusion criteria. The median screening PDR was 25.45 (IQR 13.15-39.60), comparable with the median overall PDR of 24.01 (IQR 11.46-35.86, p = 0.21). Median surveillance PDR was higher at 33.73 (IQR 16.92-47.01), and median diagnostic PDR was lower at 19.35 (IQR 9.66-29.17), compared with median overall PDR 24.01 (IQR 11.46-35.86; p < 0.01). The overall PDR showed excellent concordance with screening, surveillance, and diagnostic PDR (r > 0.85, p < 0.01, 2-tailed). The overall PDR is a reliable and pragmatic surrogate for screening PDR and can be measured in real time, irrespective of colonoscopy indication.

MicroRNA biogenesis is broadly disrupted by inhibition of the splicing factor SF3B1.

In animals, microRNA (miRNA) biogenesis begins with cotranscriptional cleavage of the primary (pri-)miRNA by the Microprocessor complex. Cotranscriptional splicing has been shown to influence Microprocessor cleavage when miRNAs are hosted in introns of protein-coding pri-miRNAs, but the impact of splicing on production of miRNAs hosted in long non-coding (lnc)RNAs is largely unknown. Here, we investigated the role of splicing in the biogenesis of miR-122, an lncRNA-hosted, highly expressed, medically important, liver-specific miRNA. We found that splicing inhibition by the SF3B1 inhibitor pladienolide B (PlaB) led to strong and rapid reduction in transcription of endogenous, but not plasmid-encoded, pri-miR-122, resulting in reduced production of mature miR-122. To allow detection of rapid changes in miRNA biogenesis despite the high stability of mature miRNAs, we used SLAMseq to globally quantify the effects of short-term splicing inhibition on miRNA synthesis. We observed an overall decrease in biogenesis of mature miRNAs following PlaB treatment. Surprisingly, miRNAs hosted in exons and introns were similarly affected. Together, this study provides new insights into the emerging role of splicing in transcription, demonstrating novel biological importance in promotion of miR-122 biogenesis from an lncRNA, and shows that SF3B1 is important for global miRNA biogenesis.

National Trends in the Incidence of Sporadic Malignant Colorectal Polyps in Young Patients (20-49 Years): An 18-Year SEER Database Analysis.

Background and Objectives: Conflicting guidelines exist for initiating average-risk colorectal cancer screening at the age of 45 years. The United States Preventive Services Task Force (USPSTF) changed its guidelines in 2021 to recommend initiating screening at 45 years due to an increasing incidence of young-onset colorectal cancer. However, the American College of Physicians (ACP) recently recommended not screening average-risk individuals between 45 and 49 years old. We aim to study the national trends in the incidence of sporadic malignant polyps (SMP) in patients from 20 to 49 years old. Materials and Methods: We analyzed the Surveillance, Epidemiology, and End Results database (2000-2017) on patients aged 20-49 years who underwent diagnostic colonoscopy with at least a single malignant sporadic colorectal polyp. Results: Of the 10,742 patients diagnosed with SMP, 42.9% were female. The mean age of incidence was 43.07 years (42.91-43.23, 95% CI). Approximately 50% of malignant polyps were diagnosed between 45 and 49 years of age, followed by 25-30% between 40 and 45. There was an upward trend in malignant polyps, with a decreased incidence of malignant villous adenomas and a rise in malignant adenomas and tubulovillous adenomas. Conclusions: Our findings suggest that almost half of the SMPs under 50 years occurred in individuals under age 45, younger than the current screening threshold recommended by the ACP. There has been an upward trend in malignant polyps in the last two decades. This reflects changes in tumor biology, and necessitates further research and support in the USPSTF guidelines to start screening at the age of 45 years.

A genomic toolkit for winged bean Psophocarpus tetragonolobus.

A sustainable supply of plant protein is critical for future generations and needs to be achieved while reducing green house gas emissions from agriculture and increasing agricultural resilience in the face of climate volatility. Agricultural diversification with more nutrient-rich and stress tolerant crops could provide the solution. However, this is often hampered by the limited availability of genomic resources and the lack of understanding of the genetic structure of breeding germplasm and the inheritance of important traits. One such crop with potential is winged bean (Psophocarpus tetragonolobus), a high seed protein tropical legume which has been termed 'the soybean for the tropics'. Here, we present a chromosome level winged bean genome assembly, an investigation of the genetic diversity of 130 worldwide accessions, together with two linked genetic maps and a trait QTL analysis (and expression studies) for regions of the genome with desirable ideotype traits for breeding, namely architecture, protein content and phytonutrients.

A Retrospective Comparison of Electrocardiographic Parameters in Ketamine and Tiletamine-Zolazepam Anesthetized Indian Rhesus Monkeys (Macaca mulatta).

Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.

Endoscopic retrograde cholangiopancreatography-related early perforations: A study of effects of procedure duration, complexity, and endoscopist experience.

BACKGROUND: Perforations (Perf) during endoscopic retrograde cholangiopancreatography (ERCP) are rare (< 1%) but potentially fatal events (up to 20% mortality). Given its rarity, most data is through case series studies from centers or analysis of large databases. Although a meta-analysis has shown fewer adverse events as a composite (bleeding, pancreatitis, Perf) during ERCP performed at high-volume centers, there is very little real-world data on endoscopist and center procedural volumes, ERCP duration and complexity on the occurrence of Perf. AIM: To study the profile of Perf related to ERCP by center and endoscopist procedure volume, ERCP time, and complexity from a national endoscopic repository. METHODS: Patients from clinical outcomes research initiative-national endoscopic database (2000-2012) who underwent ERCP were stratified based on the endoscopist and center volume (quartiles), and total procedure duration and complexity grade of the ERCP based on procedure details. The effects of these variables on the Perf that occurred were studied. Continuous variables were compared between Perf and no perforations (NoPerf) using the Mann-Whitney U test as the data demonstrated significant skewness and kurtosis. RESULTS: A total of 14153 ERCPs were performed by 258 endoscopists, with 20 reported Perf (0.14%) among 16 endoscopists. Mean patient age in years 61.6 ± 14.8 vs 58.1 ± 18.8 (Perf vs. NoPerf, P = NS). The cannulation rate was 100% and 91.5% for Perf and NoPerf groups, respectively. 13/20 (65%) of endoscopists were high-volume performers in the 4th quartile, and 11/20 (55%) of Perf occurred in centers with the highest volumes (4th quartile). Total procedure duration in minutes was 60.1 ± 29.9 vs 40.33 ± 23.5 (Perf vs NoPerf, P < 0.001). Fluoroscopy duration in minutes was 3.3 ± 2.3 vs 3.3 ± 2.6 (Perf vs NoPerf P = NS). 50% of the procedures were complex and greater than grade 1 difficulty. 3/20 (15%) patients had prior biliary surgery. 13/20 (65%) had sphincterotomies performed with stent insertion. Peritonitis occurred in only 1/20 (0.5%). CONCLUSION: Overall adverse events as a composite during ERCP are known to occur at a lower rate with higher volume endoscopists and centers. However, Perf studied from the national database show prolonged and more complex procedures performed by high-volume endoscopists at high-volume centers contribute to Perf.

Hip-Spine Discordance in Bone Mineral Densities in Patients Undergoing Dual Energy X-Ray Absorptiometry Scan in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: The discordance in the diagnosis of osteoporosis is characterized by the variation in bone mineral density measurements at different skeletal sites. The presence of discordance significantly alters the treatment plan as different treatment is required for different skeletal sites. The aim of this study was to find out the prevalence of hip-spine discordance in bone mineral densities in patients undergoing dual-energy x-ray absorptiometry scans for suspected osteoporosis. Methods: A descriptive cross-sectional study was conducted among patients undergoing dual-energy x-ray absorptiometry scans from 1 December 2020 to 30 October 2022. Ethical approval was taken from the Institutional Review Committee (Reference number: IRC-2020-11-18-08). Patients undergoing dual-energy x-ray absorptiometry scans for suspected osteoporosis were included. Patients aged less than 50 years, already diagnosed and under treatment for osteoporosis, and incomplete information about T-scores of hips and spine were excluded. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. Results: Among 1028 patients, 602 (58.56%) (55.55-61.57, 95% Confidence Interval) had discordance in hip and spine bone mineral densities. The majority of them, 570 (94.68%) were female and 32 (5.71%) were male. Major discordance was observed in 101 (16.77%) patients and minor discordance was observed in 501 (83.22%) patients. Conclusions: The prevalence of discordance in hip and spine bone mineral densities in patients undergoing dual-energy x-ray absorptiometry scans was higher than that reported in other similar studies done in similar settings. Keywords: bone density; osteoporosis; prevalence.

Cancer-specific survival in non-mucinous appendiceal adenocarcinomas after local resection versus right hemicolectomy: A Surveillance, Epidemiology, and End Results database study.

BACKGROUND: Adenocarcinomas of the appendix are rare cancers for which no National Comprehensive Cancer Network guidelines exist, and for patients who undergo resection with curative intent, there is a paucity of data on prognostic factors affecting long-term cancer-specific survival. We aimed to compare the cancer-specific survival outcomes in adult patients with appendiceal non-mucinous adenocarcinoma undergoing either local resection versus right hemicolectomy. METHODS: This was a retrospective study from the National Cancer Institute Surveillance, Epidemiology, and End Results of patients who underwent curative resection over a 15-year period (2004-2019) for primary appendiceal adenocarcinoma. Out of 16,699 patients, 14,945 were excluded (exclusion criteria were non-adenocarcinoma histological types and patients with regional or distant metastasis as per National Cancer Institute Surveillance, Epidemiology, and End Results stage). Effects of factors (age, race, tumor biology [mucinous versus non-mucinous tumors], the extent of resection of the primary lesion, and lymph nodes) on cancer-specific long-term survival were studied. Survival analysis was performed using the Kaplan-Meier method. Survival outcomes were reported as mean survival (months). RESULTS: Of 1,754 patients, 827 (47.1%) were women, and 927 (52.1%) were men. The mean age in years (± standard deviation) was 62.43 ± 14.3. The racial distribution was as follows: Black 237 (13.5%), White 1,398 (79.7%), and Other 119 (6.8%). A total of 771 (44.6%) underwent local resection (appendectomy or segmental resection of colon without lymph node resection), and 983 (55.4%) underwent hemicolectomy with lymph node resection. Favorable survival prognosticators were age <50 years, White race, and well-differentiated histology. Patients with mucinous tumors experienced better survival. Patients who underwent right hemicolectomy with lymph node resection experienced better survival compared with those who had an appendectomy or segmental colonic resection for non-mucinous tumors rather than mucinous tumors. CONCLUSION: We report novel demographic, tumor-related, and operative prognostic factors impacting long-term cancer-specific survival in patients who undergo resection for appendiceal adenocarcinoma. The extent of resection of the primary lesion with draining lymph nodes determines long-term cancer-specific survival in non-mucinous appendiceal adenocarcinomas.

Fibrolamellar hepatocellular carcinoma: An epidemiologic and 5-year cancer survival assessment based off SEER data.

The fibrolamellar variant of hepatocellular carcinoma makes up a small percentage of liver tumors. Despite being a subset, it has been noted in the literature to have variations in terms of its epidemiology and intervention recommendations. Using the Surveillance, Epidemiology, and End Results database, 339 cases from 1988 to 2016 were studied. Favorable prognostic epidemiological factors included male sex, younger ages, and white race. Those who underwent any lymph node resection (combined with liver resection) did better than those without lymph node resection; chemotherapy proved beneficial for those where surgery was contraindicated. To our knowledge, this report is the largest conglomerate dataset analyzing prognostic profiles and treatment strategies for fibrolamellar hepatocellular carcinoma.

Comparison of different QT correction methods for nonclinical safety assessment in ketamine-anesthetized Indian rhesus monkeys (Macaca mulatta).

Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs. As heart rate and QT interval have an inverse relationship, any change in heart rate causes a subsequent change in QT interval. This warrants for calculation of a corrected QT interval. This study aimed to identify an appropriate formula that best corrected QT for change in heart rate. We employed seven formulas based on source-species type, clinical relevance, and requirements of various international regulatory guidelines. Data showed that corrected QT interval values varied drastically for different correction formulas. Equations were compared on their slope values based on QTc versus RR plots. The rank order of the slope for different formulas was (closest to farthest from zero) QTcNAK, QTcHAS, QTcBZT, QTcFRD, QTcVDW, QTcHDG, and QTcFRM. QTcNAK emerged to be the best correcting formula in this study. It showed the least correlation with the RR interval (r = -0.01) and displayed no significant difference amongst the sexes. As there is no universally recognized formula for preclinical use, the authors recommend developing a best-case scenario model for specific study designs and individual organizations. The data from this research will be helpful in deciding an appropriate QT correction formula for the safety assessment of new pharmaceuticals and biologics.

Needle-free injection system delivery of ZyCoV-D DNA vaccine demonstrated improved immunogenicity and protective efficacy in rhesus macaques against SARS-CoV-2.

The apprehension of needles related to injection site pain, risk of transmitting bloodborne pathogens, and effective mass immunization have led to the development of a needle-free injection system (NFIS). Here, we evaluated the efficacy of the NFIS and needle injection system (NIS) for the delivery and immunogenicity of DNA vaccine candidate ZyCoV-D in rhesus macaques against SARS-CoV-2 infection. Briefly, 20 rhesus macaques were divided into 5 groups (4 animals each), that is, I (1 mg dose by NIS), II (2 mg dose by NIS), III (1 mg dose by NFIS), IV (2 mg dose by NFIS) and V (phosphate-buffer saline [PBS]). The macaques were immunized with the vaccine candidates/PBS intradermally on Days 0, 28, and 56. Subsequently, the animals were challenged with live SARS-CoV-2 after 15 weeks of the first immunization. Blood, nasal swab, throat swab, and bronchoalveolar lavage fluid specimens were collected on 0, 1, 3, 5, and 7 days post infection from each animal to determine immune response and viral clearance. Among all the five groups, 2 mg dose by NFIS elicited significant titers of IgG and neutralizing antibody after immunization with enhancement in their titers postvirus challenge. Besides this, it also induced increased lymphocyte proliferation and cytokine response. The minimal viral load post-SARS-CoV-2 challenge and significant immune response in the immunized animals demonstrated the efficiency of NFIS in delivering 2 mg ZyCoV-D vaccine candidate.

Hematological and biochemical reference intervals of wild-caught and inhouse adult Indian rhesus macaques (Macaca mulatta).

BACKGROUND: Nonhuman primates are used for research purposes such as studying diseases and drug discovery and development programs. Various clinical pathology parameters are used as biomarkers of disease conditions in biomedical research. Detailed reports of these parameters are not available for Indian-origin rhesus macaques. To meet the increasing need for information, we conducted this study on 121 adult Indian rhesus macaques (57 wild-sourced and 64 inhouse animals, aged 3-7 years). A total of 18 hematology and 18 biochemistry parameters were evaluated and reported in this study. Data from these parameters were statistically evaluated for significance amongst inhouse and wild-born animals and for differences amongst sexes. The reference range was calculated according to C28-A3 guidelines for reporting reference intervals of clinical laboratory parameters. RESULTS: Source of the animals and sex appeared to have statistically significant effects on reference values and range. Wild-born animals reported higher WBC, platelets, neutrophils, RBC, hemoglobin, HCT, MCV, and total protein values in comparison to inhouse monkeys. Sex-based differences were observed for parameters such as RBCs, hemoglobin, HCT, creatinine, calcium, phosphorus, albumin, and total protein amongst others. CONCLUSIONS: Through this study, we have established a comprehensive data set of reference values and intervals for certain hematological and biochemical parameters which will help researchers in planning, conducting, and interpreting various aspects of biomedical research employing Indian-origin rhesus monkeys.

Demographic profile, management, and survival of primary Gastrointestinal Kaposi Sarcoma: A USA Nationwide SEER-based study.

Kaposi Sarcoma (KS) is a Human Herpes Virus-8 (HHV-8) associated angio-proliferative disorder commonly seen in patients with HIV. It most commonly involves the skin as classic purple lesions but occasionally involves the gastrointestinal (GI) tract. To date, published data is scarce on primary GI KS. Using a national database, this study analyzes the incidence, demographics, and survival of primary GI KS. We conducted a retrospective analysis (1975-2019) on biopsy-proven primary GI KS cases from 17 registries from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. A total of 685 patients with GI KS were identified. Female gender, Non-Hispanic Asian or Pacific Islander (NHAPI), married marital status, and large bowel site-specific primary KS to have better overall survival. Luminal gastrointestinal KS was more frequent (84.96%) than solid organ involvement (3.07% of all cases). This study is the most extensive population-based study about the epidemiological and survival data of patients with primary GI KS, revealing GI KS to be a young male disease with best outcomes in the large bowel and anal canal KS while inferior outcomes in extraintestinal GI KS.

Widespread and transgenerational retrotransposon activation in inter- and intraspecies recombinant inbred populations of Lotus japonicus.

Transposable elements (TEs) constitute a large proportion of genomes of multicellular eukaryotes, including flowering plants. TEs are normally maintained in a silenced state and their transpositions rarely occur. Hybridization between distant species has been regarded as a 'shock' that stimulates genome reorganization, including TE mobilization. However, whether crosses between genetically close parents that result in viable and fertile offspring can induce TE transpositions has remained unclear. Here, we investigated the activation of long terminal repeat (LTR) retrotransposons in three Lotus japonicus recombinant inbred line (RIL) populations. We found that at least six LTR retrotransposon families were activated and transposed in 78% of the RILs investigated. LORE1a, one of the transposed LTR retrotransposons, showed transgenerational epigenetic activation, indicating the long-term effects of epigenetic instability induced by hybridization. Our study highlights TE activation as an unexpectedly common event in plant reproduction.

Epidemiology and outcomes of gastrointestinal mucosal melanomas: a national database analysis.

AIM: Gastrointestinal malignant melanoma is a rare mucosal melanoma (MM). Other MM include the respiratory and the genitourinary tract. All mucosal melanomas have a poor prognosis when compared to cutaneous melanomas. Ano-rectal melanomas are by far the most common and most studied gastrointestinal MM. Large-scale clinical data is lacking due to the rarity of the disease. We aim to analyze epidemiology and survival of the Gastrointestinal (G.I.) MM over 45 years using a national database. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was queried to identify patients with biopsy-proven G.I. Melanomas. We selected tumor site, intervention, and survival information for oncology codes as per the international classification of diseases. Survival analysis was performed using the SPSS v 27 ® IBM software. RESULTS: Of the 1105 biopsy-proven confirmed cases of primary G.I. melanoma's, 191 (17.3%) received chemotherapy (C.T.), 202 (18.3%) received radiotherapy (R.T.), 63 (5.7%) received both C.T and R.T., while 684 (61.9%) of the population received surgery alone or combined with C.T. and/or R.T. Statistically significant improvement in survival was noted in all treatment strategies that utilized surgery and also when site-specific MM cohorts underwent a surgical approach with or without C.T and/or R.T. CONCLUSION: This is the most extensive study reporting epidemiological and survival data of treatment strategy outcomes of primary G.I. mucosal melanoma elucidating best overall survival with a management strategy involving surgical intervention.

Characterization of gene expression patterns in mild cognitive impairment using a transcriptomics approach and neuroimaging endophenotypes.

INTRODUCTION: Identification of novel therapeutics and risk assessment in early stages of Alzheimer's disease (AD) is a crucial aspect of addressing this complex disease. We characterized gene-expression patterns at the mild cognitive impairment (MCI) stage to identify critical mRNA measures and gene clusters associated with AD pathogenesis. METHODS: We used a transcriptomics approach, integrating magnetic resonance imaging (MRI) and peripheral blood-based gene expression data using persistent homology (PH) followed by kernel-based clustering. RESULTS: We identified three clusters of genes significantly associated with diagnosis of amnestic MCI. The biological processes associated with each cluster were mitochondrial function, NF-kB signaling, and apoptosis. Cluster-level associations with cortical thickness displayed canonical AD-like patterns. Driver genes from clusters were also validated in an external dataset for prediction of amyloidosis and clinical diagnosis. DISCUSSION: We found a disease-relevant transcriptomic signature sensitive to prodromal AD and identified a subset of potential therapeutic targets associated with AD pathogenesis.

Tackling the challenges of providing surgical services in low resource LMICs: Shortcomings in surgical healthcare in Nepal.

Province-2 is small but densely populated area in the plains of Nepal with 20% of the population on 3% of the land. It is one of the two poorest provinces, with the lowest human and logistic resources. Therefore, there is an enormous and urgent need for improvement of appropriate health care facilities, accessible for all the people. The rural population remains desperately impoverished and to date the provincial and federal governments have lacked the funds to support these needy people. Our work aimed to create a small working model to address the existing problems by establishing the Janakpur Trauma and Orthopaedic Hospital, and ultimately in collaboration with Future Faces, the Craniofacial Centre Nepal, to provide appropriate care at an affordable price to the people in Province-2. This model has been successful, but one of the main challenge remains payments to the health care providers. It is difficult to balance the income and expenditure of hospital services in order to sustain these works and so regular external financial input is required for maintaining continuity of care. It is expected that government agencies and universities such as Madhesh Institute of Health Sciences (MIHS) should be able to educate and assist in the provision of standard care for common illnesses and create suitable human resources to face these challenges.