Tag: nevin manimala

Ther Innov Regul Sci. 2024 Mar 30. doi: 10.1007/s43441-024-00634-5. Online ahead of print.

ABSTRACT

In June 2021, FDA released a Draft Guidance on Sponsor Responsibilities for IND Safety Reporting and cited components of a recommended Safety Surveillance Plan (SSP). To meet the expectations of the 2021 FDA guidance, sponsors should document their plan for aggregate safety assessment. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group has proposed an Aggregate Safety Assessment Plan (ASAP) that addresses this recommendation. The 2021 FDA guidance also discusses potential strategies for unblinded review of safety data from ongoing studies by an independent Assessment Entity, which could occur via planned periodic evaluations or “triggered” reviews based on blinded data assessments. The Assessment Entity reviewing unblinded data makes recommendations as to whether the threshold has been met for submission of an aggregate IND safety report. In this paper, we discuss how the ASAP supports IND aggregate safety reporting decisions, including elements to be included in a proposed SSP appendix to the ASAP. In addition, the authors advocate for the benefits of developing a charter (or specific section of the Data Monitoring Committee charter, if applicable) that describes the responsibilities and conduct of the Assessment Entity. With these components in place, study sponsors will meet the objective of having clearly defined processes for the monitoring of clinical trial safety data in aggregate and making IND safety reporting decisions.

PMID:38555342 | DOI:10.1007/s43441-024-00634-5

Bull Math Biol. 2024 Mar 30;86(5):48. doi: 10.1007/s11538-024-01277-1.

ABSTRACT

Carcinomas often utilize epithelial-mesenchymal transition (EMT) programs for cancer progression and metastasis. Numerous studies report SNAIL-induced miR200/Zeb feedback circuit as crucial in regulating EMT by placing cancer cells in at least three phenotypic states, viz. epithelial (E), hybrid (h-E/M), mesenchymal (M), along the E-M phenotypic spectrum. However, a coherent molecular-level understanding of how such a tiny circuit controls carcinoma cell entrance into and residence in various states is lacking. Here, we use molecular binding data and mathematical modeling to report that the miR200/Zeb circuit can essentially utilize combinatorial cooperativity to control E-M phenotypic plasticity. We identify minimal combinatorial cooperativities that give rise to E, h-E/M, and M phenotypes. We show that disrupting a specific number of miR200 binding sites on Zeb as well as Zeb binding sites on miR200 can have phenotypic consequences-the circuit can dynamically switch between two (E, M) and three (E, h-E/M, M) phenotypes. Further, we report that in both SNAIL-induced and SNAIL knock-out miR200/Zeb circuits, cooperative transcriptional feedback on Zeb as well as Zeb translation inhibition due to miR200 are essential for the occurrence of intermediate h-E/M phenotype. Finally, we demonstrate that SNAIL can be dispensable for EMT, and in the absence of SNAIL, the transcriptional feedback can control cell state transition from E to h-E/M, to M state. Our results thus highlight molecular-level regulation of EMT in miR200/Zeb circuit and we expect these findings to be crucial to future efforts aiming to prevent EMT-facilitated dissemination of carcinomas.

PMID:38555331 | DOI:10.1007/s11538-024-01277-1

Br J Cancer. 2024 Mar 30. doi: 10.1038/s41416-024-02663-1. Online ahead of print.

ABSTRACT

BACKGROUND: Modifying public awareness of oesophageal cancer symptoms might help to decrease late-stage diagnosis and, in turn, improve cancer outcomes. This study aimed to explore oesophageal cancer symptom awareness and determinants of lower awareness and anticipated time to help-seeking.

METHODS: We invited 18,156 individuals aged 18 to 75 years using random sampling of the nationwide Dutch population registry. A cross-sectional web-based survey containing items adapted from the Awareness and Beliefs about Cancer measure (i.e., cancer symptom awareness, anticipated time to presentation with dysphagia, health beliefs, and sociodemographic variables) was filled out by 3106 participants (response rate: 17%). Descriptive statistics were calculated and logistic regression analyses were performed to explore determinants of awareness and anticipated presentation (dichotomised as <1 month or ≥1 month).

RESULTS: The number of participants that recognised dysphagia as a potential symptom of cancer was low (47%) compared with symptoms of other cancer types (change in bowel habits: 77%; change of a mole: 93%; breast lump: 93%). In multivariable analyses, non-recognition of dysphagia was associated with male gender (OR 0.50, 95% CI 0.43-0.58), lower education (OR 0.44, 0.35-0.54), and non-western migration background (OR 0.43, 0.28-0.67). Anticipated delayed help-seeking for dysphagia was associated with not recognising it as possible cancer symptom (OR 1.58, 1.27-1.97), perceived high risk of oesophageal cancer (OR 2.20, 1.39-3.47), and negative beliefs about oesophageal cancer (OR 1.86, 1.20-2.87).

CONCLUSION: Our findings demonstrate a disconcertingly low public awareness of oesophageal cancer symptoms. Educational interventions targeting groups with decreased awareness and addressing negative cancer beliefs may lead to faster help-seeking behaviour, although additional studies are needed to determine the effect on clinical cancer outcomes.

PMID:38555316 | DOI:10.1038/s41416-024-02663-1

Sci Rep. 2024 Mar 30;14(1):7568. doi: 10.1038/s41598-024-57814-4.

ABSTRACT

The aim of this study was to investigate and analyse the predictive value of systemic inflammatory markers based on peripheral blood biomarkers for the prognosis of non-small cell lung cancer (NSCLC) patients. Based on a retrospective monitoring cohort of 973 NSCLC patients from an Affiliated Tumor Hospital from 2012 to 2023. The log-rank test and Cox proportional risk regression model were used to identify independent prognostic inflammatory markers. Subsequently, a nomogram prediction model was constructed and evaluated. The results of multivariate Cox regression analysis showed that patients with high NLR group (HR = 1.238, 95% CI 1.015-1.510, P = 0.035), and high CAR group (HR = 1.729, 95% CI 1.408-2.124, P < 0.001) were risk factors affecting the prognosis of NSCLC patients. The nomogram that includes age, tumor stage, smoking history, BMI, NLR, and CAR can effectively predict the prognosis of NSCLC patients.The inflammatory markers NLR and CAR, which combine inflammatory and nutritional status, are effective predictors of the prognosis of NSCLC patients. The combination of clinical information and these easily accessible inflammatory markers has significant research value for prognostic assessment, clinical treatment, and follow-up monitoring of NSCLC patients.

PMID:38555313 | DOI:10.1038/s41598-024-57814-4

Sci Rep. 2024 Mar 30;14(1):7581. doi: 10.1038/s41598-024-57989-w.

ABSTRACT

There are 16 species in the genus Satureja L. (Lamiaceae), of which 10 are native. This research aimed to investigate the effect of gamma rays and storage conditions and duration on the percentage and components of the essential oil and some biochemical characteristics of Satureja mutica Fisch & C.A. Mey at the Research Institute of Forests and Rangelands. Plants were collected at the full flowering stage and exposed to different doses of gamma rays (0, 2.5, 5, 7.5, and 10 kGy) at the Atomic Energy Organization, Iran. The samples were kept in a refrigerator (4 °C) and in the shade (25 ± 2 °C) for 0, 120, and 240 h. This experiment was performed in a completely randomized design. Essential oil extraction was done by water distillation for 2 h. The composition of their essential oil components was identified using GC and GC/MS. Some biochemical traits, including phenol content, antioxidant capacity, and carbohydrate content, were measured. The results indicated that irradiation on the percentage of essential oil showed a statistically significant difference. In addition, the interaction effect of irradiation × storage conditions, irradiation × duration of storage, on the percentage of essential oil was significant. According to a comparison of the means, 2.5 kGy irradiation produced the highest percentage of essential oil (0.4%); in contrast, a significant decrease was detected in components with 7.5 and 10 kGy irradiation. It was observed that the percentage of some essential oil compounds decreased with the gamma-ray intensity increase. 2.5 kGy of gamma rays and shade storage conditions for 240 h led to the highest content of p-cymene and carvacrol. Nevertheless, the highest thymol content was obtained under refrigeration conditions without irradiation. The maximum phenol content and antioxidant capacity were obtained when the plants were irradiated with 2.5 and 7.5 kGy gamma rays. However, the maximum carbohydrate rate was observed in non-irradiated plants. It was concluded that low-intensity gamma rays could improve the percentage of essential oil and main components like p-cymene and carvacrol in S. mutica Fisch & C.A. Mey.

PMID:38555296 | DOI:10.1038/s41598-024-57989-w

Sci Rep. 2024 Mar 30;14(1):7588. doi: 10.1038/s41598-024-57470-8.

ABSTRACT

Establishing sustainable communities requires bridging the gap between academic knowledge and societal requirements; this is where entrepreneurial education comes in. The first phase involved a comprehensive review of the literature and extensive consultation with experts to identify and shortlist the components of entrepreneurship education that support sustainable communities. The second phase involved Total Interpretative Structural Modelling to explore or ascertain how the elements interacted between sustainable communities and entrepreneurial education. The factors are ranked and categorized using the Matrice d’impacts croises multiplication appliquee an un classement (MICMAC) approach. The MICMAC analysis classifies partnerships and incubators as critical drivers, identifying Student Entrepreneurship Clubs and Sustainability Research Centers as dependent elements. The study emphasizes alumni networks and curriculum designs as key motivators. The results highlight the critical role that well-designed entrepreneurial education plays in developing socially conscious entrepreneurs, strengthening communities, and generating long-term job prospects. The study provides a valuable road map for stakeholders dedicated to long-term community development agendas by informing the creation of strategic initiatives, curriculum updates, and policies incorporating entrepreneurial education.

PMID:38555294 | DOI:10.1038/s41598-024-57470-8

Nat Commun. 2024 Mar 30;15(1):2805. doi: 10.1038/s41467-024-47215-6.

ABSTRACT

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

PMID:38555285 | DOI:10.1038/s41467-024-47215-6

J Prosthet Dent. 2024 Mar 29:S0022-3913(24)00198-7. doi: 10.1016/j.prosdent.2024.02.035. Online ahead of print.

ABSTRACT

STATEMENT OF PROBLEM: The use of a scannable healing abutment is a convenient option for fabricating implant-supported restorations (ISRs) with a digital workflow; however, clinical studies evaluating prosthetic efficacy are lacking.

PURPOSE: The purpose of this randomized controlled trial was to investigate the prosthetic efficacy of definitive posterior single ISRs fabricated after scanning using a scannable healing abutment-scan peg (SHA-SP) in comparison with a conventional scan body (CSB). The time for data acquisition, quality of proximal and occlusal contacts, and relative occlusal force of ISRs were measured.

MATERIAL AND METHODS: Twenty-four participants eligible for single ISRs to replace the mandibular first molar with adjacent and antagonist teeth present were randomly allocated to either a study group (n=12) receiving ISRs after intraoral scanning using an SHA-SP or a control group (n=12) receiving ISRs after intraoral scanning using CSB. During the surgical procedure, a prefabricated contoured scannable healing abutment was screwed to the implant in the SHA-SP group, while a custom-made healing abutment was used in the CSB group. After a healing period of 3 months, an intraoral scan was made, and the duration of data acquisition was recorded. The ISRs were milled from zirconia and evaluated for the quality of proximal and occlusal contacts using dental floss and shim stock, respectively. The relative occlusal forces of the ISRs and their contralateral natural teeth were measured using a digital occlusal analyzer. Statistical analysis was done using an independent sample t test for quantitative variables and a Pearson chi-squared test for qualitative variables between the tested groups (α=.05).

RESULTS: The direct digital workflow using SHA-SP was statistically less time consuming than the CSB (P<.001). The 2 groups were statistically similar regarding the quality of the proximal contacts (P=.281) or occlusal contacts (P=.307) and the relative occlusal forces of ISRs (P=.315). The relative occlusal forces of the ISRs in both groups were significantly lower than those of their contralateral natural teeth (P<.001).

CONCLUSIONS: Direct digital workflow using SHA-SP was more rapid, saving clinical chairside time, and produced proximal and occlusal contacts of comparable quality with those obtained with CSB. The relative occlusal forces of ISRs in both workflows were lower than their contralateral natural teeth.

PMID:38555270 | DOI:10.1016/j.prosdent.2024.02.035

Prim Care Diabetes. 2024 Mar 29:S1751-9918(24)00069-X. doi: 10.1016/j.pcd.2024.03.005. Online ahead of print.

ABSTRACT

BACKGROUND: Based on the rapidly growing global burden of non-alcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), in order to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of NAFLD or NASH this paper presents a systematic review and meta-analysis of randomized controlled trials(RCTs).

METHODS: In this systematic review and meta-analysis, We searched PubMed, Medline, Web of Science and The Cochrane Library databases. All randomized controlled trials involving GLP-1RAs and NAFLD or NASH were collected since the database was established. A meta-analysis of proportions was done with the generalised linear mixed model. Continuous variables were represented by Mean and Standard Deviation (SD), and binary variable were represented by Relative Risk (RR) and 95% Confidence Interval (CI) as effect indicators. The research results were presented by Revman 5.4. This study is registered with PROSPERO (CRD42023390735).

FINDING: We included 16 placebo-controlled or active drug-controlled randomized controlled trials (involving 2178 patients) that used liraglutide, exenatide, dulaglutide, or semaglutie in the treatment of NAFLD or NASH, as measured by liver biopsy or imaging techniques. This study found that the effect of GLP-1RAs on histologic resolution of NASH with no worsening of liver fibrosis (n=2 RCTs; WMD:4.08, 95%CI 2.54-6.56, p < 0.00001) has statistically significant. At the same time, GLP-1RAs affected CRP (n = 7 RCTs; WMD:-0.41, 95% CI-0.78 to -0.04, p =0.002) and other serological indicators were significantly improved.

CONCLUSION: This study evaluated the efficacy of GLP-1RAs in patients with NAFLD and NASH. These results suggest that GLP-1RAs may be a potential and viable therapeutic approach as a targeted agent to intervene in disease progression of NAFLD and NASH.

PMID:38555202 | DOI:10.1016/j.pcd.2024.03.005

Injury. 2024 Mar 24:111514. doi: 10.1016/j.injury.2024.111514. Online ahead of print.

ABSTRACT

BACKGROUND: Finger nerve injuries have a significant impact on hand function and can result in reduced sensation, pain and impaired coordination. The socioeconomic implications of these injuries include decreased workplace productivity, reduced earning potential, and financial burdens associated with long-term medical treatment and rehabilitation. However, there is a lack of comprehensive literature regarding the incidence, mechanisms, and associated injuries of finger nerve lesions.

METHODS: A retrospective analysis was conducted on patients treated at our institution from January 2012 to July 2020. Cases of peripheral finger nerve lesions were identified using the digital hospital information system and ICD-10 Classification. Exclusion criteria included injuries to the median nerve at the carpal tunnel level or superficial branch of the radial nerve. Data were collected using a pseudonymized approach, and statistical analyses were performed using SPSS Statistics (Version 27).

RESULTS: A total of 2089 finger nerve lesions were analyzed, with a majority of cases occurring in men. Most injuries97.4 % were caused by trauma, predominantly cut/tear injuries. Isolated finger nerve injuries were more common than multiple nerve injuries, with the index finger being the most frequently affected. Concomitant tendon and vascular injuries were observed in a significant proportion51.7 % of cases. Surgical management included direct nerve coaptation, interposition grafting and neurolysis.

DISCUSSION: Finger nerve injuries are the most prevalent type of nerve injury, often resulting from small lacerations. These injuries have substantial societal costs and can lead to prolonged sick leave. Understanding the epidemiology and etiology of finger nerve injuries is crucial for implementing effective preventive measures. Accompanying tendon injuries and the anatomical location of the nerve lesions can impact sensory recovery and treatment outcomes. Proper management of peripheral finger nerve lesions is essential for optimizing functional outcomes and minimizing the impact on daily activities. Treatment options should be tailored to the severity and underlying cause of the nerve injury.

PMID:38555200 | DOI:10.1016/j.injury.2024.111514