Drug repurposing: identification of SARS-CoV-2 potential inhibitors by virtual screening and pharmacokinetics strategies.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. METHODOLOGY: We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. RESULTS: Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. CONCLUSIONS: Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.

Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Non-invasive prenatal screening: Testing motivations and decision making in the low-risk population.

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) and questions to assess patients' motivations for cfDNA screening was offered at four MFM clinics following genetic counseling. It was found that 44% of participants (n = 100) made an uninformed decision about testing. Participants with private insurers were 4.25 times more likely to make an informed decision (95% CI = 1.10-16.37). Informed decision makers scored avoiding invasive procedures higher (p = 0.007) and ranked doing what family/friends desire lower (p = 0.005) than uninformed decision makers. While most participants scored receiving information about genetic conditions highest, 12% of participants reported fetal sex disclosure as a priority. However, this was not found to be associated with uninformed decision making. This study ultimately established that following genetic counseling, a low-risk population shared motivations with high-risk populations which highlights the importance of complete pre-test counseling for all. Future research should investigate the effect of modifying variables, such as socioeconomic status, on the performance of informed choice measures and critically evaluate the parameters that determine informed choice.

Trastuzumab-Induced Cardiotoxicity: When and How Much Should We Worry?

This review critically analyzes the incidence of trastuzumab-induced left ventricular systolic dysfunction and congestive heart failure (CHF), distinguishing between cases with and without prior anthracycline exposure. It highlights the fact that the elevated risk of trastuzumab-induced cardiotoxicity is closely associated with prior anthracycline exposure. In the absence of prior anthracycline exposure, the incidence rates of trastuzumab-induced cardiotoxicity, particularly CHF (ranging from 0% to 0.5%), are largely comparable with those reported in the general population, especially when reversibility is taken into account. Current cardiac surveillance recommendations during trastuzumab treatment have not yet adapted to the increasing adoption of nonanthracycline treatment strategies and the associated low risk of cardiotoxicity. We propose a refined monitoring protocol to reduce the frequency of cardiac evaluations for low-risk to moderate-risk patients, especially those receiving nonanthracycline treatments. By focusing on patients at high risk or those with prior anthracycline exposure, this strategy seeks to optimize the cost-effectiveness of cardiac care in oncology.

Comparing the Performance of Popular Large Language Models on the National Board of Medical Examiners Sample Questions.

INTRODUCTION: Large language models (LLMs) have transformed various domains in medicine, aiding in complex tasks and clinical decision-making, with OpenAI's GPT-4, GPT-3.5, Google's Bard, and Anthropic's Claude among the most widely used. While GPT-4 has demonstrated superior performance in some studies, comprehensive comparisons among these models remain limited. Recognizing the significance of the National Board of Medical Examiners (NBME) exams in assessing the clinical knowledge of medical students, this study aims to compare the accuracy of popular LLMs on NBME clinical subject exam sample questions. METHODS: The questions used in this study were multiple-choice questions obtained from the official NBME website and are publicly available. Questions from the NBME subject exams in medicine, pediatrics, obstetrics and gynecology, clinical neurology, ambulatory care, family medicine, psychiatry, and surgery were used to query each LLM. The responses from GPT-4, GPT-3.5, Claude, and Bard were collected in October 2023. The response by each LLM was compared to the answer provided by the NBME and checked for accuracy. Statistical analysis was performed using one-way analysis of variance (ANOVA). RESULTS: A total of 163 questions were queried by each LLM. GPT-4 scored 163/163 (100%), GPT-3.5 scored 134/163 (82.2%), Bard scored 123/163 (75.5%), and Claude scored 138/163 (84.7%). The total performance of GPT-4 was statistically superior to that of GPT-3.5, Claude, and Bard by 17.8%, 15.3%, and 24.5%, respectively. The total performance of GPT-3.5, Claude, and Bard was not significantly different. GPT-4 significantly outperformed Bard in specific subjects, including medicine, pediatrics, family medicine, and ambulatory care, and GPT-3.5 in ambulatory care and family medicine. Across all LLMs, the surgery exam had the highest average score (18.25/20), while the family medicine exam had the lowest average score (3.75/5).  Conclusion: GPT-4's superior performance on NBME clinical subject exam sample questions underscores its potential in medical education and practice. While LLMs exhibit promise, discernment in their application is crucial, considering occasional inaccuracies. As technological advancements continue, regular reassessments and refinements are imperative to maintain their reliability and relevance in medicine.

Menopausal hormone therapy and risk of venous thromboembolism: The story so far.

Menopausal hormone therapy (MHT) is known to increase the risk of venous thromboembolism (VTE), which includes deep vein thrombosis, pulmonary embolism, and less frequently cerebral vein thrombosis, but the absolute risk for a given patient is very low. After starting MHT, the risk of VTE seems to be at its highest, declining to the non-HRT user baseline level of risk after stopping. Whether estrogen-only or estrogen-progestin HRT combination is linked to a similar risk of VTE is unclear from the available evidence. The aim of this study is to evaluate the risks of developing VTE in relation to different types as well as different modes of administration of MHT through a database search including PubMed, MEDLINE, Google Scholar, Cochrane Library, and others in order to provide the women carers with the up-to-date and evidence-based guidelines and recommendations while counseling the post-menopausal women enquiring on use of hormonal therapies either to alleviate the menopausal symptoms or to prevent the long-term sequelae of estrogen deficiency.

On sait que l'hormonothérapie ménopausique (MHT) augmente le risque de thromboembolie veineuse (TEV), qui comprend la thrombose veineuse profonde, l'embolie pulmonaire et, moins fréquemment, la thrombose veineuse cérébrale, mais le risque absolu pour un patient donné est très faible. Après le début du MHT, le risque de TEV semble être à son plus haut niveau, diminuant jusqu'au niveau de risque de base des non-utilisatrices de THS après l'arrêt. Les preuves disponibles ne permettent pas de savoir si un THS à base d'œstrogène seul ou d'association œstroprogestative est lié à un risque similaire de TEV. Le but de cette étude est d'évaluer les risques de développer une TEV par rapport à différents types ainsi qu'à différents modes d'administration du MHT grâce à une recherche dans des bases de données comprenant PubMed, MEDLINE, Google Scholar, Cochrane Library et autres afin de fournir aux femmes les soignants avec les lignes directrices et recommandations à jour et fondées sur des preuves tout en conseillant les femmes ménopausées qui se renseignent sur l'utilisation de thérapies hormonales, soit pour soulager les symptômes de la ménopause, soit pour prévenir les séquelles à long terme d'une carence en œstrogènes.

The behavior and welfare of neglected species: some examples from fish and mammals.

Animal welfare is the state of an animal's body and mind and the level to which its requirements are satisfied. Animal welfare is affected by human decisions and actions. Numerous decisions concerning animals are driven by human desires to enhance their own lives, and some of these decisions may be influenced by self-interest or a strong emphasis on economic factors. How to assess the welfare state of animals is a central issue in animal welfare science. Two critical questions can be used to address animal welfare: first, is the animal healthy, and second, does the animal have what it needs? Both of these questions can potentially be answered using the study of animal behavior. The development of behavioral methodologies is crucial for evaluating welfare in contexts where concern for animal welfare is often highest, such as on intensive modern farms and sites where working animals are used. Herein, we discuss animal welfare by focusing on some of its major concepts and explanations. Later, to illustrate key aspects of animal welfare, we chose to examine the information that is available for some 'neglected' livestock species, which are commercially important on a global basis and found in large numbers: buffaloes (Bubalus bubalis), camels (Camelus dromedarius), donkeys (Equus asinus), mules (Equus asinus × Equus caballus), and lumpfish (Cyclopterus lumpus). We chose these species because there are major ongoing concerns about their welfare, and more research is required to help solve the various problems. Overall, there are strong imbalances in terms of the species that are usually studied in terms of animal welfare research, and we call for greater attention to those that have traditionally been neglected.

Ovarian tumor cell-derived JAGGED2 promotes omental metastasis through stimulating the Notch signaling pathway in the mesothelial cells.

The primary site of metastasis for epithelial ovarian cancer (EOC) is the peritoneum, and it occurs through a multistep process that begins with adhesive contacts between cancer cells and mesothelial cells. Despite evidence that Notch signaling has a role in ovarian cancer, it is unclear how exactly it contributes to ovarian cancer omental metastasis, as well as the cellular dynamics and intrinsic pathways that drive this tropism. Here we show that tumor cells produced the Notch ligand Jagged2 is a clinically and functionally critical mediator of ovarian cancer omental metastasis by activating the Notch signaling in single-layered omental mesothelial cells. In turn, Jagged2 promotes tumor growth and therapeutic resistance by stimulating IL-6 release from mesothelial cells. Additionally, Jagged2 is a potent downstream mediator of the omental metastasis cytokine TGF-ß that is released during omental destruction. Importantly, therapeutic inhibition of Jagged2-mediated omental metastasis was significantly improved by directly disrupting the Notch pathway in omental mesothelial cells. These findings highlight the key role of Jagged2 to the functional interplay between the TGF-ß and the Notch signaling pathways during the metastatic process of ovarian cancer cells to the omentum and identify the Notch signaling molecule as a precision therapeutic target for ovarian cancer metastasis.

Assessment of Knowledge and Attitudes Related to HIV/AIDS Among the Population With Increasing Incidence Rate.

Introduction Lack of awareness and negative attitudes toward people living with HIV/AIDS (PLWHA) are key barriers to minimizing the transmission of HIV. Therefore, the present survey-based study aimed to assess the knowledge regarding HIV/AIDS and attitudes toward PLWHA. Methods In the present study, we collected data from 612 Kyrgyz national participants using a self-administered questionnaire. Results Among the participants, 59% (361) were females, and 41% (251) were males. The mean age of the participants was 26.23 (SD = 7.7) years. All participants were aware of HIV/AIDS, and 59.1% (362) agreed to have sufficient information about HIV/AIDS. Overall, the participants displayed a high level of knowledge about HIV/AIDS transmission, and 89.2% (546) of them were aware of sexual transmission of HIV/AIDS. Among the participants, 54% (330) believed that using condoms during sexual intercourse could prevent the transmission of HIV/AIDS. Concerning social attitudes, 17% (104) of the participants agreed that HIV-infected individuals should be isolated from society. Moreover, 39% (238) of them disagreed to work with PLWHA. The results of the study suggest that female participants were more aware of the modes of HIV/AIDS transmission than males. However, misconceptions regarding transmission routes were present in both genders. Conclusion The present study revealed that study participants had correct knowledge about HIV/AIDS transmission modes such as unsafe blood transfusion and injectable drug abuse. However, knowledge about unsafe tattooing and mother-to-baby mode of HIV/AIDS transmission was observed to be lower. Female participants were found to be more aware of HIV/AIDS transmission. There is a need to address the knowledge and awareness gap in the general population of Kyrgyzstan, especially among the male population.

Bridging drug discovery through hierarchical subtractive genomics against asd, trpG, and secY of pneumonia causing MDR Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is an opportunistic gram-positive, non-motile, and non-sporulating bacteria that induces pneumonia, a provocative lung infection affecting mainly the terminal bronchioles and the small air sacs known as alveoli. Recently, it has developed antibiotic resistance to the available consortium as per the WHO reports; thereby, novel remedial targets and resilient medications to forestall and cure this illness are desperately needed. Here, using pan-genomics, a total of 1,387 core proteins were identified. Subtractive proteome analyses further identified 12 proteins that are vital for bacteria. One membrane protein (secY) and two cytoplasmic proteins (asd and trpG) were chosen as possible therapeutic targets concerning minimum % host identity, essentiality, and other cutoff values, such as high resistance in the MDR S. aureus. The UniProt AA sequences of the selected targets were modelled and docked against 3 drug-like chemical libraries. The top-ranked compounds i.e., ZINC82049692, ZINC85492658 and 3a of Isosteviol derivative for Aspartate-semialdehyde dehydrogenase (asd); ZINC38222743, ZINC70455378, and 5 m Isosteviol derivative for Anthranilate synthase component II (trpG); and finally, ZINC72292296, ZINC85632684, and 7 m Isosteviol derivative for Protein translocase subunit secY (secY), were further subjected to molecular dynamics studies for thermodynamic stability and energy calculation. Our study proposes new therapeutic targets in S. aureus, some of which have previously been reported in other pathogenic microorganisms. Owing to further experimental validation, we anticipate that the adapted methodology and the predicted results in this work could make major contributions towards novel drug discovery and their targets in S. aureus caused pneumonia.

Mandibular Osteoblastoma: A Case Report of a Rare Entity.

Osteoblastoma, an uncommon bone neoplasm characterized by the formation of osteoid tissue, constitutes a rare subset of bone tumors, representing only a negligible percentage of cases. While extensive research on the condition has identified a predilection for long bones and vertebrae, occurrences in facial bones are infrequent. This case report discusses a unique presentation in a nine-year-old female diagnosed with a tumor located in the mandibular parasymphysis region. Radiological examination revealed distinctive irregular contours surrounding the lesion, prompting a comprehensive investigation involving biopsy and subsequent histological analysis. The ensuing evaluation definitively confirmed the diagnosis of a typical benign osteoblastoma. This report highlights the novelty of an unresected benign osteoblastoma situated in the mandible, currently undergoing periodic review, with the option of surgery also on the table.

Arterial Spin-Labeling and DSC Perfusion Metrics Improve Agreement in Neuroradiologists' Clinical Interpretations of Posttreatment High-Grade Glioma Surveillance MR Imaging-An Institutional Experience.

BACKGROUND AND PURPOSE: MR perfusion has shown value in the evaluation of posttreatment high-grade gliomas, but few studies have shown its impact on the consistency and confidence of neuroradiologists' interpretation in routine clinical practice. We evaluated the impact of adding MR perfusion metrics to conventional contrast-enhanced MR imaging in posttreatment high-grade glioma surveillance imaging. MATERIALS AND METHODS: This retrospective study included 45 adults with high-grade gliomas who had posttreatment perfusion MR imaging. Four neuroradiologists assigned Brain Tumor Reporting and Data System scores for each examination on the basis of the interpretation of contrast-enhanced MR imaging and then after the addition of arterial spin-labeling-CBF, DSC-relative CBV, and DSC-fractional tumor burden. Interrater agreement and rater agreement with a multidisciplinary consensus group were assessed with κ statistics. Raters used a 5-point Likert scale to report confidence scores. The frequency of clinically meaningful score changes resulting from the addition of each perfusion metric was determined. RESULTS: Interrater agreement was moderate for contrast-enhanced MR imaging alone (κ = 0.63) and higher with perfusion metrics (arterial spin-labeling-CBF, κ = 0.67; DSC-relative CBV, κ = 0.66; DSC-fractional tumor burden, κ = 0.70). Agreement between raters and consensus was highest with DSC-fractional tumor burden (κ = 0.66-0.80). Confidence scores were highest with DSC-fractional tumor burden. Across all raters, the addition of perfusion resulted in clinically meaningful interpretation changes in 2%-20% of patients compared with contrast-enhanced MR imaging alone. CONCLUSIONS: Adding perfusion to contrast-enhanced MR imaging improved interrater agreement, rater agreement with consensus, and rater confidence in the interpretation of posttreatment high-grade glioma MR imaging, with the highest agreement and confidence scores seen with DSC-fractional tumor burden. Perfusion MR imaging also resulted in interpretation changes that could change therapeutic management in up to 20% of patients.

Can preoperative Carbohydrate Antigen 19-9 predict metastatic pancreatic cancer? Results of a systematic review and meta-analysis.

BACKGROUND: To investigate the relationship between preoperative Carbohydrate Antigen19-9(CA19-9)and pancreatic cancer occult metastasis. METHODS: Systematic search of MEDLINE, CENTRAL, Web of Science and bibliographic reference lists were conducted. All comparative observational studies investigating the predictive ability of preoperative CA 19-9 in patients with pancreatic cancer were considered. Mean CA-19-9 value in the pancreatic cancer patients with and without metastasis were evaluated. Best cut-off value of CA 19-9 for metastasis was determined using ROC analysis. RESULTS: Ten comparative observational studies reporting a total of 1431 pancreatic cancer patients with (n = 496) and without (n = 935) metastasis were included. Subsequent meta-analysis demonstrated that mean preoperative CA 19-9 level was significantly higher in patients with metastases compared to those without (MD: 904.4; 95 % CI, 642.08-1166.74, P < 0.0001). The between-study heterogeneity was significant (I2: 99 %, P < 0.00001). ROC analysis yielded a cut-off CA 19-9 level of 336 with a sensitivity and specificity for predicting metastasis of 90 % and 80 %, respectively (AUC = 0.90). CONCLUSIONS: CA 19-9 level is significantly higher in patients with metastatic pancreatic cancer. A preoperative CA 19-9 value of 336 should be considered as an acceptable cut-off value to design prospective studies.

Investigating the Cognitive Style of Patients With Substance Use Disorder: A Cross-Sectional Study.

Background The causal attributions we make to the events in our lives reflect our Cognitive Style. The use of substances can be precipitated by stressful life events, and substance use can be a result of maladaptive coping to alleviate negative effects in stressful situations. So, individuals with substance dependence may infer situations differently. The inferences made about the cause of these stressful events can give an understanding of their cognition and can further help in therapeutic interventions. Purpose The present study aims to assess the cognitive style of young patients with substance use disorder. Methods A cross-sectional research design was used and a total of 50 participants were chosen through purposive sampling from the in-patient departments of Psychiatric Hospitals and De-addiction centers. The Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) was used to assess the specific substances used by the patients and the Cognitive Style Questionnaire-Short form (CSQ-SF) was used to assess the negative cognitive style of the patients. Results Results revealed a more negative cognitive style among young patients with Dual Substance Use than patients with Multiple Substance Use, indicating that patients with Substance Use Disorder tend to attribute stressful events to causes like internal (because of self), global (applicable to all domains of life) and stable (consistent), as well as the negative consequences (leading to other bad things) and self-worth implications (something wrong in self).

Risk factors for failure to rescue after hepatectomy in a high-volume UK tertiary referral center.

BACKGROUND: Mortality after severe complications after hepatectomy (failure to rescue) is strongly linked to center volume. The aim of this study was to evaluate the risk factors for failure to rescue after hepatectomy in a high-volume center. METHODS: Retrospective study of 1,826 consecutive patients who underwent hepatectomy from 2011 to 2018. The primary outcome was a 90-day failure to rescue, defined as death within 90 days posthepatectomy after a severe (Clavien-Dindo grade 3+) complication. Risk factors for 90-day failure to rescue were evaluated using a multivariable binary logistic regression model. RESULTS: The cohort had a median age of 65.3 years, and 56.6% of patients were male. The commonest indication for hepatectomy was colorectal metastasis (58.9%), and 46.9% of patients underwent major or extra-major hepatectomy. Severe complications developed in 209 patients (11.4%), for whom the 30- and 90-day failure to rescue rates were 17.0% and 35.4%, respectively. On multivariable analysis, increasing age (P = .006) and modified Frailty Index (P = .044), complication type (medical or combined medical/surgical versus surgical; P < .001), and body mass index (P = .018) were found to be significant independent predictors of 90-day failure to rescue. CONCLUSION: Older and frail patients who experience medical complications are particularly at risk of failure to rescue after hepatectomy. These results may inform preoperative counseling and may help to identify candidates for prehabilitation. Further study is needed to assess whether failure to rescue rates could be reduced by perioperative interventions.

Correction: Novel and pragmatic exploration of variation in glottic parameters in non-parallel versus parallel vocal cord CT planes with potential reporting pitfalls.

[This corrects the article DOI: 10.1371/journal.pone.0293659.].

Long noncoding RNA DLEU2 and ROR1 pathway induces epithelial-to-mesenchymal transition and cancer stem cells in breast cancer.

Breast cancer (BC) patient who receives chemotherapy for an extended length of time may experience profound repercussions in terms of metastases and clinical outcomes due to the involvement of the epithelial-to-mesenchymal transition (EMT) mechanism and enriched cancer stem cells (CSCs). BC cells that express high levels of lncRNA deleted in lymphocytic leukemia-2 (lncRNA DLEU2) and type I tyrosine kinase-like orphan receptor ROR1 (ROR1) may play roles in the enhanced ability of the activation EMT and CSC induction. Here we find that lncRNA DLEU2 and ROR1 are specifically upregulated in tumor tissues compared to their normal counterparts in TCGA, PubMed GEO datasets, and samples from archived breast cancer tumor tissues. Following chemotherapy, lncRNA DLEU2 and ROR1 were enhanced in BC tumor cells, coupled with the expression of CSCs, EMT-related genes, and BMI1. Mechanistically, ROR1 and lncRNA DLEU2 overexpression led to enhanced tumor cell proliferation, inhibition of apoptosis, cell-cycle dysregulation, chemoresistance, as well as BC cell's abilities to invade, migrate, develop spheroids. These findings imply that the role of lncRNA DLEU2 and ROR1 in BC therapeutic failure is largely attributed to EMT, which is intricately linked to enriched CSCs. In conclusion, our findings indicate that a lncRNA DLEU2 and ROR1-based regulatory loop governs EMT and CSC self-renewal, implying that targeting this regulatory pathway may improve patients' responses to chemotherapy and survival.

Staging Computed Tomography Parameters Predict the Need for Vein Resection during Pancreaticoduodenectomy in Resectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgery-first approach is the current standard of care for resectable pancreatic ductal adenocarcinoma (PDAC), and a proportion of these cases will require venous resection. This study aimed to identify parameters on staging computed tomography (CT) that predict the need for venous resection during pancreaticoduodenectomy (PD) for resectable PDAC. METHODS: We conducted a retrospective analysis of prospectively collected data on patients who underwent PD for resectable staged PDAC (as per NCCN criteria) between 2011 and 2020. Staging CTs were independently reviewed by two specialist radiologists blinded to the clinical outcomes. Univariate and multivariate risk analyses were performed. RESULTS: In total, 296 PDs were included. Venous resection was performed in 62 (21%) cases. There was a higher rate of resection margin positivity in the vein resection group (72.6% vs. 48.7%, p = 0.001). Tumour at the neck of the pancreas, superior mesenteric vein involvement of ≥10 mm and pancreatic duct dilatation were identified as independent predictors for venous resection. DISCUSSION: Staging CT parameters can predict the need for venous resection during PD for resectable cases of PDAC. This may assist in surgical planning, patient selection and counselling. Future efforts should concentrate on validating these results or identifying additional predictors in a multicentre and prospective setting.

Impact of lung cancer screening on surgical stage distribution and surgical practice: a regional analysis of patients operated in and out of a screening program.

OBJECTIVES: The aim of this study was to assess variations in surgical stage distribution in 2 centres within the same UK region. One centre was covered by an active screening program started in November 2018 and the other was not covered by screening. METHODS: Retrospective analysis of 1895 patients undergoing lung resections (2018-2022) in 2 centres. Temporal distribution was tested using Chi-squared for trends. A lowess curve was used to plot the proportion of stage 1A patients amongst those operated over the years. RESULTS: The surgical populations in the 2 centres were similar. In the screening unit (SU), we observed a 18% increase in the proportion of patients with clinical stage IA in the recent phase compared to the early phase (59% vs 50%, P = 0.004), whilst this increase was not seen in the unit without screening. This difference was attributable to an increase of cT1aN0 patients in the SU (16% vs 11%, P = 0.035) which was not observed in the other unit (10% vs 8.2%, P = 0.41). In the SU, there was also a three-fold increase in the proportion of sublobar resections performed in the recent phase compared to the early one (35% vs 12%, P < 0.001). This finding was not evident in the unit without screening. CONCLUSIONS: Lung cancer screening is associated with a higher proportion of lung cancers being detected at an earlier stage with a consequent increased practice of sublobar resections.