Improved production of class I phosphatidylinositol 4,5-bisphosphate 3-kinase.

Phosphatidylinositol 4,5-bisphosphate 3-kinases (PI3K) are a family of kinases whose activity affects pathways needed for basic cell functions. As a result, PI3K is one of the most mutated genes in all human cancers and serves as an ideal therapeutic target for cancer treatment. Expanding on work done by other groups we improved protein yield to produce stable and pure protein using a variety of modifications including improved solubility tag, novel expression modalities, and optimized purification protocol and buffer. By these means, we achieved a 40-fold increase in yield for p110α/p85α and a 3-fold increase in p110α. We also used these protocols to produce comparable constructs of the ß and δ isoforms of PI3K. Increased yield enhanced the efficiency of our downstream high throughput drug discovery efforts on the PIK3 family of kinases.

Successful cetuximab rechallenge in metastatic colorectal cancer: A case report.

BACKGROUND: Metastatic colorectal cancer (mCRC) treatment has been evolving and increasingly driven by tumor biology and gene expression analysis. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors (anti-EGFR) represents a promising strategy for patients with RAS wild-type (RAS-wt) mCRC and circulating tumor DNA has emerged as a potential selection strategy. Herein, we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge. CASE SUMMARY: Our patient was diagnosed with stage IV RAS-wt, microsatellite-stable rectosigmoid junction adenocarcinoma. He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response, allowing for a left hepatectomy (R0), followed by post-operative chemotherapy and an anterior resection; progression-free survival (PFS) of 16 months was obtained. Due to hepatic and nodal relapse, second-line treatment with FOLFOX and bevacizumab was started with partial response; metastasectomy was performed (R0), achieving a PFS of 11 months. After a 15 months anti-EGFR-free interval, FOLFIRI and cetuximab were reintroduced upon disease progression, again with partial response and a PFS of 16 months. Following extensive hepatic relapse, cetuximab was reintroduced and a marked clinical and analytical improvement was seen, after only one cycle. RAS-wt status was confirmed on circulating tumor DNA. The patient's overall survival exceeded 5 years. CONCLUSION: Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.

A review and perspective paper: Ras oncogene gets modest, from kingpin to mere henchman.

The concomitant activation of both the YAP1 co-transcription factor and RAS GTPases is a hallmark of several aggressive cancers, though the intricacies of their relationship and implications for oncogenesis are still poorly understood. This review has presented a cooperative model where YAP1 and RAS are not independently acting oncogenes but rather interdependently acting ones, with each fulfilling an essential role within the oncogenic process. YAP1 is responsible for initiating the expression of key proteins that contribute to various cancer traits. However, these proteins must often be transported into the cytoplasm to exert their effects. We suggest that oncogenic RAS actually facilitates this transport, enabling the phosphorylation and subsequent activation of the nuclear transporter XPO1 (aka Exportin1). This mechanism is particularly crucial for anti-apoptotic proteins. Instead of being sequestered within the nucleus in an ineffective state, these proteins are rather shuttled into the cytoplasm. Within the cytoplasm, they can effectively inhibit apoptosis, undermining by these means the efficacy of chemotherapeutic agents designed to induce cell death in cancer cells. Therefore, a clearer understanding of the oncogenic partnership between RAS and YAP1 will likely provide new insights into the molecular underpinnings of cancer and highlight as well potential targets for therapeutic interventions designed to disrupt this pernicious interaction.

A comprehensive evaluation and meta-analysis of the perioperative and oncological outcomes of robotic radical prostatectomy using the DaVinci vs the Hugo RAS surgical platforms.

Because of the increasing popularity of Hugo RAS as a surgical platform, a comparison examination of intraoperative and oncological outcomes across DaVinci and Hugo RAS robotic surgery platforms is urgently needed. We carried out a comprehensive review and meta-analysis of the literature of current research, comprehensively searching PubMed, Cochrane and Embase for eligible studies comparing the results between the DaVinci and Hugo RAS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were followed in the conduct of this study, with language restricted to English and a final search date of June 2024. We excluded articles composed solely of conference abstracts and irrelevant content. Composite outcomes were assessed using weighted mean differences (WMD) and odds ratios (ORs). The risk of bias in individual research was assessed using the Newcastle-Ottawa Scale (NOS), and heterogeneity and bias risk were controlled for using a sensitivity analysis. Six studies in all were considered, comprising 1025 patients, including 626 DaVinci patients and 399 Hugo RAS patients. Review Manager V5.4.1 software (Cochrane Collaboration, Oxford, UK) was utilized to conduct the meta-analysis, including 6 trials, which demonstrated that compared to Hugo RAS, DaVinci was associated with statistically significant differences in several outcomes: a reduction in operative time (OT) (WMD - 8.46, 95% CI - 13.56 to 3.36; p = 0.001), an increase in estimated blood loss (EBL) (WMD 41.68, 95% CI 23.59 to 59.77; p < 0.00001), and an increased pelvic lymphadenectomy ratio (OR 1.5, 95% CI 1.05-2.05; p = 0.01). On the contrary, there were no statistically noteworthy differences in the length of hospital stay (LOS) between the two teams (WMD - 0.05, 95% CI - 0.14 to 0.04; p = 0.25), nerve sparing (unilateral or bilateral) (OR 0.96, 95% CI 0.68-1.35; p = 0.8), postoperative complications (OR 1.15, 95% CI 0.50-2.64; p = 0.75), or positive surgical margins (PSM) (OR 1.08, 95% CI 0.76-1.54; p = 0.68). Although DaVinci offers shorter operating times (OT) and increased pelvic lymph node dissection rates, Hugo RAS demonstrates lower estimated blood loss (EBL). Overall, Hugo RAS Robot-Assisted Radical Prostatectomy (RARP) results seem to be similar to those obtained with the DaVinci system. Further research and long-term follow-up are necessary to ascertain durable oncological and functional outcomes, allowing doctors to switch between robotic systems and use their skills. These findings are crucial for patients, surgeons, and healthcare policymakers and warrant future studies with extended follow-up.

Computer-Simulated Virtual Image Datasets to Train Machine Learning Models for Non-Invasive Fish Detection in Recirculating Aquaculture.

Artificial Intelligence (AI) and Machine Learning (ML) can assist producers to better manage recirculating aquaculture systems (RASs). ML is a data-intensive process, and model performance primarily depends on the quality of training data. Relatively higher fish density and water turbidity in intensive RAS culture produce major challenges in acquiring high-quality underwater image data. Additionally, the manual image annotation involved in model training can be subjective, time-consuming, and labor-intensive. Therefore, the presented study aimed to simulate fish schooling behavior for RAS conditions and investigate the feasibility of using computer-simulated virtual images to train a robust fish detection model. Additionally, to expedite the model training and automate the virtual image annotation, a process flow was developed. The 'virtual model' performances were compared with models trained on real-world images and combinations of real and virtual images. The results of the study indicate that the virtual model trained solely with computer-simulated images could not perform satisfactorily (mAP = 62.8%, F1 score = 0.61) to detect fish in a real RAS environment; however, replacing a small number of the virtual images with real images in the training dataset significantly improved the model's performance. The M6 mixed model trained with 630 virtual and 70 real images (virtual-to-real image ratio: 90:10) achieved mAP and F1 scores of 91.8% and 0.87, respectively. Furthermore, the training time cost for the M6 model was seven times shorter than that for the 'real model'. Overall, the virtual simulation approach exhibited great promise in rapidly training a reliable fish detection model for RAS operations.

Liraglutide effects on epicardial adipose tissue micro-RNAs and intra-operative glucose control.

BACKGROUND AND AIM: Epicardial adipose tissue (EAT) plays a role in coronary artery disease (CAD). EAT has regional distribution throughout the heart and each location may have a different genetic profile and function. Glucagon like peptide-1 receptor analogs (GLP-1RAs) reduce cardiovascular risk. However, the short-term effects of GLP-1RA on microRNA (miRNA) profile of each EAT location is unknown. Objective was to evaluate if EAT miRNAs were different between coronary (CORO-EAT), left atrial EAT (LA-EAT) and subcutaneous fat (SAT), and liraglutide can modulate EAT miRNAs expression. METHODS AND RESULTS: This was a 12-week randomized, double-blind, placebo-controlled study in 38 patients with type 2 diabetes (T2DM) and coronary artery disease (CAD) who were started on either liraglutide or placebo for a minimum of 4 up to 12 weeks prior to coronary artery by-pass grafting (CABG). Fat samples were collected during CABG. miR16, miR155 and miR181a were significantly higher in CORO-EAT and in LA-EAT than SAT (p < 0.01 and p < 0.05) in overall patients. miR16 and miR181-a were significantly higher in CORO-EAT than SAT (p < 0.01), and miR155 and miR181a were higher in LA-EAT than SAT (p < 0.05) in the liraglutide group. Liraglutide-treated patients had better intra-op glucose control than placebo (146 ± 21 vs 160 ± 21 mg/dl, p < 0.01). CONCLUSIONS: Our study shows that CORO- and LA-miRNAs profiles were significantly different than SAT miRNAs in overall patients and miRNAs were significantly higher in CORO-EAT and LA-EAT than SAT in the liraglutide group. Pre-op liraglutide was also associated with better intra operative glucose control than placebo independently of weight loss.

Utility guideline and considerations for the novel Hugo™ RAS (robotic-assisted surgery) system in colorectal surgery: surgical outcomes and initial experience in a tertiary center.

PURPOSE: A novel robotic platform-Hugo™ RAS (robotic-assisted surgery) system-has been introduced with several innovations that may prove advantageous for surgeons, such as an open console and four interchangeable modular arms. Our study aims to evaluate this platform's safety, efficacy, and potential impact on the surgical treatment of colorectal pathology. METHODS: Patients underwent robotic-assisted colorectal procedures with the Hugo™ RAS system at the General University Hospital of Elche from October 2023 to July 2024. Patient characteristics, intraoperative and postoperative variables, and robotic technical issues were recorded. RESULTS: Forty consecutive patients were included (14 right, 13 left, and 8 rectum neoplasms; 4 left diverticulitis; and 1 ileocecal Crohn's disease). The patients' characteristics were as follows: median age, 69.5 years; 24 males and 16 females; 45% ASA III-IV; and Charlson Comorbidity Index > 5:42.5%. We recorded four medical (2 anemia, 1 phlebitis, and 1 admission to the intensive care unit) and three surgical (1 hematoma of the incision, 1 intestinal occlusion, and 1 dehiscence of the anastomosis) postoperative complications. We had no conversions neither open nor laparoscopic surgery. The average hospital stay was 3 days, with no mortality or readmission. CONCLUSIONS: The Hugo™ RAS system is safe and feasible for colorectal procedures. The modularity of the arms provides the versatility of configurations adjusted depending on the patient's body features and the surgeon's preferences and greater adaptability to operating rooms. The open console is highly comfortable and ergonomic for the surgeon, allowing communication with the operating room environment. TRIAL REGISTRATION: NCT06512480.

Severe hypertension in tuberous sclerosis complex caused by renal artery stenosis: A case report.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurocutaneous disease. Arterial hypertension is one of its uncommon complications, which is supposed to be caused by renal cysts or angiomyolipomas. Few studies have been reported in the literature on renal artery stenosis (RAS) as the cause of hypertension in TSC. Hence, we reported a boy who presented with uncontrolled hypertension under five anti-hypertension drugs and was diagnosed with TSC complicated with left RAS. His high blood pressure was relieved by percutaneous transluminal renal angioplasty (PTRA). In one and a half years follow-up, his blood pressure was normal whilst he took four anti-hypertensive drugs. In conclusion, children with TCS complicated with hypertension should be carefully screened for RAS, which might be relieved by percutaneous balloon dilatation.

Parthenolide Inhibits Synthesis and Promotes Degradation of Programmed Cell Death Ligand 1 and Enhances T Cell Tumor-Killing Activity.

Parthenolide is a germacrane sesquiterpene lactone separated from the traditional medicinal plant feverfew. Previous studies have shown that parthenolide possesses many pharmacological activities, involving anti-inflammatory and anticancer activities. However, the antitumor mechanism of parthenolide has not been fully elucidated. Thus, we investigate the potential antitumor mechanisms of parthenolactone. We predicted through network pharmacology that parthenolide may target HIF-1α to interfere with the occurrence and development of cancer. We found that parthenolide inhibited PD-L1 protein synthesis through mTOR/p70S6K/4EBP1/eIF4E and RAS/RAF/MEK/MAPK signaling pathways and promoted PD-L1 protein degradation through the lysosomal pathway, thereby inhibiting PD-L1 expression. Immunoprecipitation and Western blotting results demonstrated that parthenolide inhibited PD-L1 expression by suppressing HIF-1α and RAS cooperatively. We further proved that parthenolide inhibited cell proliferation, migration, invasion, and tube formation via down-regulating PD-L1. Moreover, parthenolide increased the effect of T cells to kill tumor cells. In vivo xenograft assays further demonstrated that parthenolide suppressed the growth of tumor xenografts. Collectively, we report for the first time that parthenolide enhanced T cell tumor-killing activity and suppressed cell proliferation, migration, invasion, and tube formation by PD-L1. The current study provides new insight for the development of parthenolide as a novel anticancer drug targeting PD-L1.

A near-zero-discharge recirculating aquaculture system with 3D-printed poly (lactic acid) honeycomb as solid carbon.

A novel near-zero-discharge recirculating aquaculture system was successfully set up and ran for six months or above. A uniquely designed and 3D printed poly (lactic acid) (PLA) structure was applied as carbon source. The system achieved over 50 % daily nitrogen removal capability and maintained a low NO3-N level of <0.5 mg/L. Steady water quality was observed throughout the experiment period. Microbial distribution was studied and top abundant microorganisms and their general functions in carbon and nitrogen utilization were discussed. Denitrification and L-glutamate formation were identified as two main nitrogen pathways. The cooccurrence network connecting various genera and multiple functions was revealed. Subtilisin was one important PLA degrading enzymes in the system.

GAD1 ameliorates glioma progression through regulating cuproptosis via RAS/MAPK pathway.

Glioma represents a primary malignant tumor occurring in the central nervous system. Glutamate decarboxylase (GAD1) plays a significant role in tumor development; however, its function of GAD1 and underlying mechanisms in glioma progression remain unclear. Differentially expressed genes (DEGs) obtained from the GSE12657 and GSE15209 datasets that intersected with cuproptosis-related genes and pivot genes were identified using comprehensive bioinformatics methods. The elesclomol (ES) treatment was used to induce cuproptosis in U251 cells, which was validated by detecting intracellular copper levels and cuproptosis marker expression. Lentivirus-mediated gene overexpression was performed to explore the effects of GAD1 using functional assays in vitro and in a mouse xenograft model. The RAS agonist ML098 was used to verify the effect of GAD1 on the RAS/MAPK pathway in glioma cells. A total of 87 cuproptosis-related DEGs and seven hub genes were obtained, with five genes upregulated and two were downregulated in gliomas. Overexpression of GAD1 inhibited proliferation, invasion, and migration, promoted apoptosis of glioma cells, and suppressed tumorigenesis in vivo. In addition, GAD1 overexpression enhanced the sensitivity of glioma cells to cuproptosis. Additionally, ML098 treatment attenuated the inhibitory effect of GAD1 overexpression on the malignant phenotype of ES-treated cells. GAD1 plays an anti-oncogenic role in glioma by regulating apoptosis via inhibition of the RAS/MAPK pathway.

Antifungal activities of Equol against Candida albicans in vitro and in vivo.

Candida albicans is an opportunistic fungal pathogen that can cause systemic infections in immunocompromised individuals. Morphological transition and biofilm formation are major virulence factors of C. albicans. Moreover, biofilm enhances resistance to antifungal agents. Therefore, it is urgent to identify new and effective compounds to target the biofilm of C. albicans. In the present study, the antifungal activities of equol against C. albicans were investigated. In vitro, the microdilution analysis and spot assay result showed that equol exhibited potent inhibitory activities against C. albicans. Further investigations confirmed that the antifungal effects of equol involved interference with the transition from yeast to hypha and biofilm formation of C. albicans. In addition, transcriptome sequencing and reverse transcription-quantitative PCR (qRT-PCR) analysis showed that equol significantly downregulated the expression of several genes in the Ras1-cAMP-PKA pathway related to hyphae and biofilm formation and significantly upregulated the expression of the negative transcriptional repressors RFG1 and TUP1. Moreover, equol effectively reduced the production of cAMP, a key messenger in the Ras1-cAMP-PKA pathway, while supplementation with cAMP partly rescued the equol-induced defects in hyphal development. Furthermore, in a mouse model of systemic candidiasis (SC), equol treatment significantly decreased the fungal burden (liver, kidneys, and lung) in mice and local tissue damage, while enhancing the production of interleukin-10 (IL-10). Together, these findings confirm that equol is a potentially effective agent for treatment of SC.

The RAL Small G Proteins Are Clinically Relevant Targets in Triple Negative Breast Cancer.

Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS effectors RALA and RALB, which are overexpressed in BC, as tractable molecular targets in these subtypes. While analysis of the breast cancer patient sample data suggests that the RALs are associated with poor outcome in both TNBC and HER2+ BC, our in vivo and in vitro experimental findings revealed the RALs to be essential in only the TNBC cell lines. While testing the response of the BC cell lines to the RAL inhibitors RBC8 and BQU57, we observed no correlation between drug efficacy and cell line dependency on RAL expression for survival, suggesting that these compounds kill via off-target effects. Finally, we report the discovery of a new small molecule inhibitor, OSURALi, which exhibits strong RAL binding, effectively inhibits RAL activation, and is significantly more toxic to RAL-dependent TNBC cells than RAL-independent HER2+ and normal cell lines. These results support the RALs as viable molecular targets in TNBC and the further investigation of OSURALi as a therapeutic agent.

Analyzing sedimentation patterns in the Naumure Multipurpose Project (NMP) reservoir using 1D HEC-RAS modeling.

Naumure Multipurpose Project (NMP) featuring a 169 m high Concrete Face Rock Filled Dam (CFRD) is the proposed reservoir project in the West Rapti River with an installed capacity of 218.34 MW. Most of the rivers in Nepal carry significant sediment loads that will consequently catalyze reservoir sedimentation. This phenomenon prevails as the primary factor in reducing reservoirs useful life, making ineffective for both flood control and hydroelectricity generation. Ultimately, such process of sedimentation has adverse impacts on projects economic feasibility and long-term sustainability. Therefore, the objective of this research was to examine the expected sediment deposition pattern in the NMP reservoir throughout its operational period by employing 1D HEC-RAS model to simulate the sedimentation process. The model was simulated for 10, 20, 30, 40 and 50 years. Yang's equation as a sediment transport function, Active layer as a bed sorting method and Toffaleti as a fall velocity method were best suited for the river reach. The delta deposition was formed between 11 km and 22 km upstream of the dam region in the Jhimruk river, with the sediment deposition depth reaching peaks of about 23 m, 38 m, 39 m, 41 m and 49 m in 10, 20, 30, 40 and 50 years, respectively. Similarly, the delta deposition was formed between 13 km and 33 km upstream of dam region in the Madi river, with the sediment deposition depth reaching peaks of about 47 m, 62 m, 60 m, 68 m and 75 m in 10, 20, 30, 40 and 50 years respectively. Headcutting of delta deposition occurred between 20 and 30 year due to high flood during low stage of reservoir. Furthermore, the study revealed that about 6.22%, 11.61%, 15.94%, 22.96% and 25.65% of the storage capacity of NMP reservoir will be depleted in 10, 20, 30, 40 and 50 years respectively.

A multi-docking strategy for robotic LAR and deep pelvic surgery with the Hugo RAS system: experience from a tertiary referral center.

INTRODUCTION: In June 2023, our institution adopted the Medtronic Hugo RAS system for colorectal procedures. This system's independent robotic arms enable personalized docking configurations. This study presents our refined multi-docking strategy for robotic low anterior resection (LAR) and deep pelvic procedures, designed to maximize the Hugo RAS system's potential in rectal surgery, and evaluates the associated learning curve. METHODS: This retrospective analysis included 31 robotic LAR procedures performed with the Hugo RAS system using our novel multi-docking strategy. Docking times were the primary outcome. The Mann-Kendall test, Spearman's correlation, and cumulative sum (CUSUM) analysis were used to assess the learning curve and efficiency gains associated with the strategy. RESULTS: Docking times showed a significant negative trend (p < 0.01), indicating improved efficiency with experience. CUSUM analysis confirmed a distinct learning curve, with proficiency achieved around the 15th procedure. The median docking time was 6 min, comparable to other robotic platforms after proficiency. CONCLUSION: This study demonstrates the feasibility and effectiveness of a multi-docking strategy in robotic LAR using the Hugo RAS system. Our personalized approach, capitalizing on the system's unique features, resulted in efficient docking times and streamlined surgical workflow. This approach may be particularly beneficial for surgeons transitioning from laparoscopic to robotic surgery, facilitating a smoother adoption of the new technology. Further research is needed to validate the generalizability of these findings across different surgical settings and experience levels.

Medtronic's Hugo™ robotic surgery system for robot-assisted radical prostatectomy: a systematic review of current worldwide experiences.

Urology's pioneering role in surgical innovations, from cystoscopy to laparoscopic surgery, culminated in the twenty-first-century advent of robotic surgery. The dominant da Vinci® system faced new competition following its 2019 patent expiration. Medtronic's Hugo™ system emerged. Its growing global adoption, especially in robot-assisted radical prostatectomy (RARP), necessitates a systematic review, evaluating safety, feasibility, and comparison with established systems. A comprehensive search identified eligible studies of the Hugo™ robotic platform for RARP, presenting their current experiences. Following systematic screening, quality of eligible studies was assessed using ROBINS-I. Results then underwent a narrative synthesis. This systematic review analysed 19 eligible studies, consisting of 9 comparative and 10 single arm studies. Due to the non-randomised nature of the studies, a moderate risk of bias was concluded in most. On account of the high heterogeneity between studies, a narrative synthesis of data was enacted; categorised into themes relating to operative timings, transfer of skills, patient demographics, plus safety and feasibility. Eligible studies demonstrated the promise of the Hugo™ platform within these themes, in comparison to currently available platforms. Despite a paucity of high-quality randomised controlled trials, available evidence indicates Hugo™ as a promising, safe alternative for RARP. Positive experiences across diverse centres and surgeons revealed minimal differences in surgical outcomes compared to the established da Vinci® system, fostering global Hugo™ adoption. Despite evidence demonstrating Hugo™ safety and comparability, the review underscores the scarcity of high-quality evidence, attributing it to early stage implementation challenges.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of developing cancer-related lymphedema following axillary lymph node dissection (ALND).

Purpose: Patients undergoing axillary lymph node dissection (ALND) for breast cancer face a high risk of lymphedema, further increased by high body mass index (BMI) and insulin resistance. GLP-1 receptor agonists (GLP-1RAs) have the potential to reduce these risk factors, but their role in lymphedema has never been investigated. The purpose of this study was to determine if GLP-RAs can reduce the risk of lymphedema in patients undergoing ALND. Methods: All patients who underwent ALND at a tertiary cancer center between 2010 and 2023 were reviewed. Patients with less than 2 years of follow-up from the time of ALND were excluded. Race, BMI, radiation, chemotherapy history, pre-existing diagnosis of diabetes, lymphedema development after ALND, and the use of GLP-1RAs were analyzed. Multivariate logistic regression analysis was performed to assess if there was a significant reduction in the risk of developing lymphedema after ALND. A sub-group analysis of non-diabetic patients was also performed. Results: 3,830 patients who underwent ALND were included, 76 of which were treated with. GLP-1 RAs. The incidence of lymphedema in the GLP-1 RA cohort was 6.6% (5 patients). Compared to 28.5% (1,071 patients) in the non-GLP-1 RA cohort. On multivariate regression analysis, patients who were treated with GLP-1 RA were 86% less likely to develop lymphedema compared to the non-GLP-1 RA cohort (OR 0.14, 95% CI 0.04-0.32, p < 0.0001). A BMI of 25 kg/m 2 or greater was a statistically significant risk factor for developing lymphedema with an odds ratio of 1.34 (95% CI 1.16-1.56, p < 0.0001). Diabetes was associated with lymphedema development that closely approached statistical significance (OR 1.32, 95% CI 0.97-1.78, p = 0.06). A subgroup analysis solely on non-diabetic patients showed similar results. The odds of developing lymphedema were 84% lower for patients without diabetes treated with GLP1-RAs compared to those who did not receive GLP-1 RAs (OR 0.16, 95% CI 0.05-0.40, p < 0.0001). Conclusion: GLP1-RAs appear to significantly reduce the risk of lymphedema in patientsundergoing ALND. The mechanism of action may be multifactorial and not limited to weight reduction and insulin resistance. Future prospective analysis is warranted to clarify the role of GLP-1RAs in reducing lymphedema risk.

Genetic Polymorphisms of Angiotensin-Converting Enzyme 1 (ACE1) and ACE2 Associated With Severe Acute Respiratory Syndrome COVID-19 in the Palestinian Population.

As a key enzyme of the renin-angiotensin system (RAS), angiotensin-converting enzyme 2 (ACE2) is a validated receptor for SARS-CoV-2, linking RAS to COVID-19. Functional ACE1/ACE2 gene polymorphisms likely cause an imbalance in the ACE1/ACE2 ratio, triggering RAS imbalance and may contribute to COVID-19 complications. This study aimed to investigate four single nucleotide polymorphisms (SNPs) of ACE1 and ACE2 genes, three for ACE1 (rs4343, rs4342, rs4341) and one for ACE2 (rs2285666), in patients with COVID-19 among the Palestinian population. A total of 130 blood samples were collected, including 50 negative controls without COVID-19 infection, 50 cases with COVID-19 infection but not hospitalized, and 30 patients with severe COVID-19 infection hospitalized in the intensive care unit. Fragments of the ACE1 and ACE2 genes, including the targeted SNPs, were amplified using multiplex PCR and subsequently genotyped by next-generation sequencing with specific virtual probes. Our results revealed that ACE2 rs2285666 GG genotype carriers were more prevalent in COVID-19 patients compared to the control group (P=0.049), while no statistical differences were observed in the distribution of ACE1 (rs4343, rs4342, rs4341) variants between COVID-19 patients and the control group. GA carriers of ACE2, rs2285666, among cases and ICU groups were at lower risk of getting COVID-19 infection (P=0.002 and P=0.013, respectively), and they were unlikely to develop fatigue (P=0.043), headache (P=0.007), loss of smell (P=0.028), and dyspnea (P=0.005). Age and comorbidities such as hypertension and coronary artery disease (CAD) were independent risk factors for COVID-19 disease. Symptoms of COVID-19 patients such as fatigue, headaches, runny noses, and loss of smell were significantly higher in non-hospitalized cases of COVID-19, while dyspnea was more frequent in the ICU patients. In conclusion, these findings indicate that the ACE2 rs2285666 GG genotype is associated with an increased risk of COVID-19 infection. This association suggests a potential genetic predisposition linked to the ACE2 gene, which may influence the susceptibility and severity of the disease.

PRR promotes hypertensive renal injury by activating Wnt/ß-catenin signaling and inflammation infiltration in mice.

Hypertension stands out as a substantial independent risk factor in the progression of chronic kidney disease; however, the exact pathological mechanisms remain elusive. Our preliminary studies find that Wnt/ß-catenin control renin-angiotensin system (RAS) expression, thus playing an important role in the pathogenesis of hypertension and renal fibrosis. As an integral component of the RAS, the (pro)renin receptor (PRR) plays a crucial role in the activation of the RAS and hypertension. Recent studies suggest a reciprocal relationship between PRR and Wnt/ß-catenin signaling, potentially contributing to hypertensive renal fibrosis development. To assess the role of PRR in mediating hypertensive nephropathy, we manipulated this signaling by over expression of PRR ligand or blockade of PRR by siPRR. In vivo, PRR induction promoted hypertension, proteinuria, renal fibrosis, inflammatory response and ß-catenin activation in Ang II induced hypertension mice. Conversely, blockade of PRR inhibited Ang II mediated hypertension, renal fibrosis and inflammation. In vitro, PRR over expression renal tubular cells exacerbated the Ang II induced fibrotic response and inflammation. Moreover, PRR was upregulated in hypertensive nephropathy patients, and correlated with renal function and renal fibrosis. These results indicate that PRR interact with Wnt/ß-catenin signaling promote the progression of hypertensive nephropathy. PRR could be served as a biomarker for the diagnosis and treatment of hypertensive renal fibrosis.

Roles of small GTPases in cardiac hypertrophy (Review).

Cardiac hypertrophy results from the heart reacting and adapting to various pathological stimuli and its persistent development is a major contributing factor to heart failure. However, the molecular mechanisms of cardiac hypertrophy remain unclear. Small GTPases in the Ras, Rho, Rab, Arf and Ran subfamilies exhibit GTPase activity and play crucial roles in regulating various cellular responses. Previous studies have shown that Ras, Rho and Rab are closely linked to cardiac hypertrophy and that their overexpression can induce cardiac hypertrophy. Here, we review the functions of small GTPases in cardiac hypertrophy and provide additional insights and references for the prevention and treatment of cardiac hypertrophy.