Reasons For Failure Research Articles

BN SO20 - Day-case laparoscopic cholecystectomy: Predictors of failure

Abstract Background Laparoscopic Cholecystectomy (LC) is the main treatment option for symptomatic gallstone disease. It is commonly performed as a day case operation and Getting It Right First Time (GIRFT) have suggested that this should be the default position for all trusts. NHSE Model Hospital analyses hospital metrics and sets national benchmarks. They suggest that the day case rate for LC should be greater than 71.4%. The aim of our study is to analyse all elective LC’s over a two year period and identify factors that increase the likelihood of day-case failure and the common reasons for this. Method All patients who had LC between 1st July 2020 and 30th June 2022 were identified. All emergency cholecystectomies were excluded from analysis. Patient and operative details were retrieved from their electronic record and a Charlson co-morbidity index was calculated. Statistical analysis was performed using SPSS with Chi-squared tests performed for categorical data and ANOVA for continuous data. Odds ratios with 95% confidence intervals were calculated. Statistical significance was taken as p<0.05. Results 788 patients had elective cholecystectomies with 74.0% being successful day-case. Factors increasing day-case failure included: Admission with gallbladder disease within past year (OR 3.15 (2.26-4.37), CBD diameter>8mm (OR 2.17(1.44-3.26), thick-walled gallbladder (OR 2.20(1.59-3.04), on-table cholangiogram (OR 4.16 (2.21-7.84), sub-total cholecystectomy (OR 30.6(9.19-102) and male sex (OR 1.55(1.11-2.18). Patients who failed day-case had higher mean age (59 vs 49) and higher co-morbidity index (2.16 vs 1.44). The most common reasons for day-case failure were complex procedure (41%), and symptom control (35%). Only 20% had planned admissions. 30-day morbidity and re-admission rate were higher for failed day-case patients. Conclusion Our hospital complies with the day case benchmark set out by Model Hospital. Furthermore, only 5.2% of patients undergoing elective cholecystectomy had a pre-operative decision for an inpatient stay demonstrating that day case is the default for the vast majority of patients. Despite this, improvement could still be made with post-operative symptom control to try and increase this number further.

The Emerging Role of IGF2BP2 in Cancer Therapy Resistance: From Molecular Mechanism to Future Potential

Tumor resistance is one of the primary reasons for cancer treatment failure, significantly limiting the options and efficacy of cancer therapies. Therefore, overcoming resistance has become a critical factor in improving cancer treatment outcomes. IGF2BP2, as a reader of m6A methylation, plays a pivotal role in the post-transcriptional regulation of RNA through the methylation of m6A sites. It not only contributes to cancer initiation and progression but also plays a key role in tumor drug resistance. This review provides a comprehensive summary of the mechanisms by which IGF2BP2 contributes to therapy resistance, with the aim of improving the efficacy of chemotherapy in cancer treatment. Advancing research in this area is crucial for developing more effective therapies that could significantly improve the quality of life for cancer patients.

Current state and perspectives of CAR T cell therapy in central nervous system diseases

Abstract B cell-directed CAR T cell therapy has fundamentally changed the treatment of hematological malignancies and its scope of application is rapidly expanding to include other diseases such as solid tumors or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include limited access of current therapies to the CNS, as well as enormous inter- and intraindividual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option to overcome this problem and to tackle pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has lately revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further perspective, pre-clinical data reveal potential benefits of CAR T cell therapy also in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as the extension to target different antigens or the variation of the modified T cell subtype, new and promising fields of application for CAR T cells are rapidly opening up. These innovations offer the potencial to address the complex pathophysiological properties of CNS diseases. To optimally utilize CAR T cell therapy for CNS diseases in the future while minimizing therapy risks, there is a need for further mechanistic research as well as prospective controlled trials to seriously assess the disease and patient-specific risk-benefit ratio.

DDDR-01. TUMOR ASSOCIATED MACROPHAGES VIS-À-VIS TMZ RESISTANCE IN PTEN-DEFICIENT GLIOMA

Abstract Drug resistance is one of the most important obstacles during chemotherapy. Currently temozolomide (TMZ) is still first line chemotherapy agent for gliomas, while drug resistance is one of the main reasons for chemotherapy failure. It has been reported that tumor-associated macrophages (TAMs) could be related to drug resistance, and thus we have investigated the association between TAMs and TMZ response in gliomas. Firstly, our study have found that PTEN-deficient glioma can specifically induce a large number of M2 phenotype TAMs, which can attenuate the TMZ-mediated the killing effect on glioma cells. Further search for the possible mechanism, we have found TAMs may secrete cytokine IL-6 in PTEN-deficient gliomas, which in turn mediate TMZ resistance. We also revealed that IL-6 highly secreted by TAMs can enhance the stemness of glioma cells through activation of the JAK-STAT3 signaling pathway in PTEN-deficient glioma cells. Secondly, have found valproic acid (VPA) can promote the transformation of TAMs from M2 to M1, reduce its IL-6 secretion, and in turn enhancing sensitivity of TMZ in PTEN-deficient gliomas. Our study revealed that TMZ resistance may modulated through soluble factors released by TAMs. Conventional anti-epilepsy drug- VPA may enhance TMZ sensitivity in PTEN-deficient gliomas, and worth to further clinical investigation. Keywords: PTEN-deficient gliomas; tumor-associated macrophages; valproic acid; temozolomide resistance

CTNI-15. A PERIOPERATIVE STUDY OF SAFUSIDENIB IN PATIENTS WITH IDH1 MUTATED GLIOMA

Abstract BACKGROUND IDH mutations cause aberrant accumulation of (R)-2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis through abnormal hypermethylation of histones and DNA as well as suppression of normal cellular differentiation. IDH inhibition significantly improves progression free survival in patients with IDH mutant WHO grade 2 glioma, however most patients progress, and there is a lack of understanding on mechanistic reasons for failure. METHODS We tested Safusidenib, an oral, blood brain barrier penetrant IDH1 R132X enzyme inhibitor in a single arm, open label perioperative study. Patients with IDH1 mutated glioma, treatment naïve to radiation or chemotherapy, received Safusidenib (250 mg BID) for four weeks following surgical biopsy and prior to definitive resection (Part A). After resection patients continued Safusidenib until toxicity or progression (Part B). Translational endpoints include paired whole genome transcriptome sequencing (WGTS), single nuclei RNA sequencing (snRNAseq), spatial transcriptomics and spatial metabolomics as well as longitudinal sampling of blood and CSF for circulating tumour DNA (ctDNA). Here we are reporting Part A of the study. RESULTS As of May/27/2024 10 patients (mean age 37, 40% female) have been enrolled: seven with astrocytoma, three with oligodendroglioma; six had prior surgical resection. Pharmacokinetic sampling showed a mean tumor concentration 2457 ng/mL (range 957.0 – 4810) with tumor:plasma ratio 0.33. Consistent with mechanism, tumor 2-HG reduced 86% from biopsy (mean 75.0μM, range 7.8-203) to surgery (10.3μM, range 2.3 – 30.8), as well as identification of novel biomarkers of response. Paired tumour snRNAseq reveals transcriptional shift with changing cell-to-cell communication, and increased immune infiltration post-treatment, validated by spatial transcriptomics. Additionally, we find reduced heterogeneity consistent with a more differentiated tumour state. Treatment was well tolerated with ongoing follow-up. CONCLUSIONS This innovative trial facilitates intra-patient comparisons and confirmation of the on-target effects of Safusidenib, enhancing understanding of the mechanisms of response and resistance. The approach serves as a proof of concept for advancing drug development in glioma through perioperative trials.

Risk factors for puncture-related complications after cerebrovascular angiography and neuroendovascular intervention with distal transradial approach

Background and purposeTo determine the risk factors for puncture-related complications after the distal transradial approach (dTRA) for cerebrovascular angiography and neuroendovascular intervention and to explore the incidence and potential mechanisms of procedural failure and puncture-related complications.Materials and methodsFrom February to November 2023, 62 patients underwent dTRA in our department. Demographic, clinical, and procedural data were collected retrospectively. Postoperative puncture-related complications were defined as a syndrome of major hematoma, minor hematoma, arterial spasm/occlusion, arteriovenous fistula, pseudoaneurysm, and neuropathy. Univariate and multivariate logistic regressions were performed to identify significant factors contributing to puncture-related complications.ResultsForty-five diagnostic cerebral angiograms and 17 neurointerventions were performed or attempted with dTRA in 62 patients. Procedural success was achieved via dTRA in 47 (75.8%) patients, whereas 15 (24.2%) required conversion to other approaches. Reasons for failure included puncture failure (n = 8), inability to cannulate due to arterial spasm (n = 6), and inadequate catheter support of the left vertebral artery (n = 1). 17.0% (8/47) of patients had postoperative puncture-related complications. Minor hematoma occurred in 8.5% (4/47) of patients, arterial spasm/occlusion in 6.3% (3/47), and neuropathy in 2.1% (1/47). No major complications were observed. On stepwise multivariable regression analysis, BMI (OR = 0.70, 95%CI 0.513 to 0.958; p = 0.026) was an independent risk factor for puncture-related complications, with a cut-off of 24.8 kg/m2 (sensitivity 66.7% and specificity 87.5%).ConclusionOur cohort is the first study of risk factors for puncture-related complications after neurointerventional interventions with dTRA. This study has shown that a low BMI (< 24.8 kg/m2) is independently associated with the development of puncture-related complications.

MGST1 facilitates novel KRASG12D inhibitor resistance in KRASG12D-mutated pancreatic ductal adenocarcinoma by inhibiting ferroptosis

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a low 5-year survival rate. Treatment options for PDAC patients are limited. Recent studies have shown promising results with MRTX1133, a KRASG12D inhibitor that demonstrated potent antitumor activity in various types of tumors with KRASG12D mutation. Resistance to KRAS inhibitors is frequently occurred and one of the main reasons for treatment failure. Understanding resistance mechanisms to novel KRAS inhibitors is crucial to ensure sustained and durable remissions.MethodsTwo KRASG12D inhibitor MRTX1133-resistant PDAC cell lines were established in vitro. The resistance mechanisms to KRASG12D inhibitor MRTX1133 against PDAC in vitro and in vivo were characterized by RNA sequencing, reverse transcript polymerase chain reaction, cytotoxicity test, plasmid transfection, lentivirus transfection, lipid peroxidation detection, malondialdehyde levels detection, glutathione levels detection, western blot, immunofluorescence, nude mice tumorigenesis experiment and immunohistochemistry.ResultsThe bioinformatics analysis and transcriptome sequencing showed that ferroptosis was involved in the resistant effect of the KRASG12D inhibitor treatment, and MGST1 was the key molecule against MRTX1133-induced ferroptosis. Increased expression of MGST1 weakened the cytotoxicity of MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis in KRASG12D inhibitor-resistant PDAC cells. Knockdown or overexpression of MGST1 conferred sensitivity or resistance to KRASG12D inhibitor MRTX1133, respectively. Mechanismly, increased nuclear localization and higher levels of active β-catenin were observed in MRTX1133-resistant PDAC cells, which contributed to higher MGST1 expression. Knockdown of CTNNB1 or TCF4 can decreased MGST1 expression. Additionally, we found that PKF-118-310, an antagonist of β-catenin/Tcf4 complex, repressed MGST1 expression. In both in vitro and in vivo models, a synergistic effect was observed when combining MRTX1133 and PKF-118-310 in KRASG12D inhibitor MRTX1133-resistant PDAC cells and tumors.ConclusionOur data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations.Graphical

Transcatheter mitral replacement: what are the outcomes of un-eligible patients compared to treated?

Abstract Background/Introduction Transcatheter mitral valve replacement (TMVR) is emerging in recent years as a promising tool to treat mitral regurgitation, however its applicability in the real world remains limited. Purpose The aim of the study is to assess the real-world screening success rate of TMVR in native anatomy and the 1-year outcomes of both accepted and refused patients as well as clinical results. Methods Retrospective analysis was performed on all patients screened for TMVR at our Valve Center, eligible for 1-year follow-up. In-hospital data of all patients admitted to our Department are prospectively collected. Follow-up was done through outpatient visits and/or telephone calls. Results Out of 3400 patients referred to mitral treatment at our department between January 2016-January 2022, 92 were submitted to screening for TMVR. Among these, 48 patients (49%) were accepted and treated with TMVR while 44 (44.8%) were refused (RG). The main reasons for rejection were anatomy unfeasibility in 25 patients (59%) and frailty in 5(11%). Main reasons for anatomy unfeasibility were risk LVOT obstruction (n=15; 60%), annular dimension (n=8; 33%) and ventricular dimension (n=2; 8,3%).Major baseline characteristics between groups were similar including age (85 vs 84), STS (12 vs 13), ejection fraction and LVEDD. However, refused patients had higher filtration rate than TMVR (80 vs 45 ml/min respectively (p=0.001)).All patients accepted were treated with TMVR: 7 patients received Tiara and 24 Tendyne. Procedure success in the TMVR group was 96% (46/48). Patients refused from TMVR were treated with Mitraclip in 5(11%) cases, 37(84%) were left in medical therapy and 2 (4,5%) underwent surgery. 1-year overall survival 65.2±51.3 vs 54.8±36.5 in TMVR and refused group respectively (p=0.002)(Figure 1). 6 deaths (2 cardiac, 33%) occurred in the TMVR compared to 37 (32 cardiac, 86%) in the refused group. Freedom from Cardiac death was 98±19% TMVR vs 75±65% (p&amp;lt;0.001)(Figure 2). NYHA class improved in 98% of cases in TMVR group but worsened in 80% in refused group, (p&amp;lt;0.001). TMVR screening failure is associated with increased cardiac death (HR 12 [1,51;95], p&amp;lt;0,019) and death for any causes (HR 17,5 [6,02;51], p&amp;lt;0,001). Conclusion(s) In the present experience, approximately 50% of patients screened for TMVR were accepted. The most frequent reasons for screening failure were anatomical issues. With a baseline similar clinical profile, treatment with TMVR provided significant 1-year survival and symptoms improvement compared to those of patients refused, whose prognosis is indeed remarkably poor. These data underline the importance of proper patient selection for TMVR to achieve good outcomes but also the need for technological improvement of devices to expand the proportion of patients who can be treated. Given the small numbers currently available, more data are needed to confirm the present findings, which must be considered hypothesis-generating.Figure 1Figure 2

A Probability-Based Model for Course Completion Prediction in Online Asynchronous Learning

The sheer scale of Massive Open Online Courses (MOOCs), presents a significant challenge in delivering personalized learning experiences and effective student support. With vast participation numbers, it becomes difficult for instructors to track individual progress, pinpoint specific areas where students struggle, and understand the underlying reasons for failure to complete the course. This lack of individualized attention can lead to disengagement and higher dropout rates. A probability-based analysis offers a solution by generating student-specific predictions about their likelihood of completion. This empowers educators to proactively identify those at risk, tailor interventions, optimize resource allocation, and potentially improve the overall learning experience within the MOOC environment. This study focuses on developing a robust predictive framework to accurately estimate the probability of students completing an introductory programming course offered on the Open Learning Platform of the University of Moratuwa, Sri Lanka. The approach began with a classification model to determine the likelihood of course completion. Building upon this, a regression model was developed to generate a specific probability percentage representing the chance of a student successfully completing the course within a designated time frame. Initial findings suggested that predictions from the classification model achieved the highest accuracy when students have completed approximately 42.8% of the course materials. It is anticipated that further refinements to the methodology will improve the reliability of the predictions. A crucial aspect of this research involves determining the optimal percentage of course progress needed to yield reliable probability predictions. This is investigated through systematic analysis and experimentations including incremental model testing. The dataset encompasses diverse demographic and educational variables, enabling the identification of influential factors affecting course completion. This study provides insights on developing personalized learning strategies, intervention tactics and academic planning within online asynchronous education.

Endoscopic dacrocystorhinostomy: Reasons for failure and possible solutions.

Endoscopic dacryocystorhinostomy is a well-established procedure with high success rate. There are multiple causes of failure of this procedure which affect surgical success. To analyze causes of failure in endoscopic dacryocystorhinostomy and ascertain methods to overcome causes of failure. After approval from the Institutional Review Board a retrospective review of 119 patients was undertaken over an 11-year period from 2008 to 2018. A tertiary care hospital in North India. Patients presenting to the Otorhinolaryngology out-patient department and diagnosed as failed endoscopic dacryocystorhinostomy cases. After thorough preoperative workup consisting of history, examination and diagnostic nasal endoscopy, patients underwent revision endoscopic dacryocystorhinostomy. After exclusion of 2 cases, 117 patients were included in the study. The mean age at presentation was 31.4 years. Number of previous surgeries: 92 patients had had one surgery, 20 patients had had two surgeries, 5 patients had had three surgeries and 9 patients had had multiple surgeries before presentation. All patients (100%) had epiphora, 75 (64.1%) patients had associated discharge and 4 (3.4%) had persistent medial canthal swelling. Duration of symptoms following previous surgery was 1-6 weeks. Commonest cause of failure was incomplete sac exposure in 117/117 cases (100%). Other causes were cicatricial closure of ostium in 47 (40.1%), synechiae in 20 (17%), canalicular obstruction in 4(3.4%), lacrimal sac diverticulum in 3 (2.5%), nasal polyps in 2 (1.7%), concha with adhesion in 2 (1.7%), septal deviation in 2 (1.7%) cases. Meticulous and thorough sac exposure is the most important factor affecting surgical success. Comprehensive preoperative assessment of cases, meticulous surgical technique, and postoperative follow up are needed for successful outcomes.

Leveraging how animals learn in conservation science: Behavioral responses of reintroduced bison to management interventions

AbstractReintroduction programs have increased amid unprecedented biodiversity loss, yet the success of these programs lag. A prominent reason for program failure is dispersal beyond the planned range of the population. Management techniques, such as hazing, can be used to prevent movement beyond set boundaries, but to be effective long‐term, the animals must learn to avoid the areas where they are hazed. Although concepts of animal learning have been used to improve reintroduction programs, learning is not often explicitly tested or used as an indicator of program success. We used a conservation behavior framework to evaluate how a range of management techniques influenced learning in a reintroduced population of bison in Banff National Park, Canada. We hypothesized exposure to stronger negative stimuli would enhance learning, leading to more pronounced behavioral responses. Specifically, we tested the degree to which management actions (i.e., drift fence encounters, foot, horseback, helicopter, and combined hazing) elicited behavioral responses and how they facilitated learning. Consistent with our predictions, drift fence interactions and foot and horseback hazing elicited fewer behavioral responses of a smaller magnitude than helicopter hazing or combined methods, suggesting these techniques cause less disturbance to the bison. Bison continually returned to locations where they encountered management actions that caused the least disturbance, demonstrating a lack of associative learning. Bison appeared to form negative associations with locations where they were hazed via helicopter or combined methods, however, and rarely returned to these locations. Evaluating management techniques is essential for improving conservation success. We demonstrate that by bridging the fields of conservation biology and animal learning, we can understand how management techniques influence learning and behavior thereby facilitating effective conservation plans that incorporate disruption levels of the animals, financial costs, and overall effectiveness. Effective conservation plans, in turn, improve our likelihood of successfully managing and recovering species.

Matrix-bound nanovesicles alleviate particulate-induced periprosthetic osteolysis.

Aseptic loosening of orthopedic implants is an inflammatory disease characterized by immune cell activation, chronic inflammation, and destruction of periprosthetic bone, and is one of the leading reasons for prosthetic failure, affecting 12% of total joint arthroplasty patients. Matrix-bound nanovesicles (MBVs) are a subclass of extracellular vesicle recently shown to mitigate inflammation in preclinical models of rheumatoid arthritis and influenza-mediated "cytokine storm." The molecular mechanism of these anti-inflammatory properties is only partially understood. The objective of the present study was to investigate the effects of MBV on RANKL-induced osteoclast formation in vitro and particulate-induced osteolysis in vivo. Results showed that MBV attenuated osteoclast differentiation and activity by suppressing the NF-κB signaling pathway and downstream NFATc1, DC-STAMP, c-Src, and cathepsin K expression. In vivo, local administration of MBV attenuated ultrahigh molecular weight polyethylene particle-induced osteolysis, bone reconstruction, and periosteal inflammation. The results suggest that MBV may be a therapeutic option for preventing periprosthetic loosening.

Hierarchical Classification of Factors Associated With Noninvasive Prenatal Testing Failures and Its Impact on Pregnancy Outcomes

Abstract Objective To conduct a hierarchical classification analysis of the nonreportable results of noninvasive prenatal testing in an attempt to reduce failure rates and provide pregnant women with accurate information to alleviate their anxiety. Methods In this study, 30,039 singleton pregnancies who underwent noninvasive prenatal testing in a single center from May 2019 to April 2022 were collected, and 811 samples with initial noninvasive prenatal testing failure were retrospectively analyzed. Grouping was based on the reasons for initial test failure; tracking the noninvasive prenatal testing results and prenatal diagnosis results (if any) of the “z-scores in the gray area” group and analyzing the possible influencing factors of the “low fetal fraction” group in the pre-experimental and experimental period by using one-way analysis of variance, Mann-Whitney U test, and χ2 test; and tracking the pregnancy outcomes of the test failures samples to analyze the risk of perinatal complications and adverse pregnancy outcomes of the different types of test failures. Results None of the samples' initial nonresults because of z-scores in the gray area were ultimately found to have chromosomal aneuploidy. However, pregnancy complications (P = 0.018) and a high likelihood of adverse pregnancy outcomes (P = 0.048) may still occur. Maternal gestational age (P &lt; 0.001), body mass index (P &lt; 0.001), library concentration (P &lt; 0.001), and fetal gender (P &lt; 0.001) were considered to be the associated factors for the initial low fetal fraction results. This may be associated with pregnancy complications (P &lt; 0.001) and a high likelihood of adverse pregnancy outcomes (P = 0.034). The body mass index (P = 0.015) and time between draws (P = 0.001) were associated with the second test’s success. The incidence of low fetal fraction samples was more frequent with blood collection tubes of the G type than with the K type (P &lt; 0.001). Conclusion Initial nonresults because of z-scores in the gray area did not imply an increased risk of aneuploidy, but vigilance is needed for an increased risk of pregnancy complications and adverse pregnancy outcomes. Because of the low fetal fraction, the initial absence of results may be related to the assay method, as well as the effect of blood collection tubes and the need to be alert to the risk of pregnancy complications and adverse pregnancy outcomes.

Intralymphatic Immunotherapy with Ultrasound Guidance Seems to Be Associated with Improved Clinical Effect in Canine Atopic Dermatitis-A Retrospective Study of 109 Cases.

Background: Intralymphatic immunotherapy (ILIT) has been used successfully in both human and veterinary medicine as a safe and effective treatment for allergic diseases. Initially, ILIT was administered by ultrasound guidance, but palpation-based injections have become more popular among veterinary dermatologists. Data from human medicine, however, show that precise injection into the lymph node is mandatory, and injection quality clearly correlates with clinical response. Hypothesis: Our aim was to assess the impact of the injection method (ultrasound guidance versus palpation-based guidance) on clinical response in dogs with atopic dermatitis. Methods: A total of 129 canine atopic dermatitis (CAD) cases treated with ILIT between 2014 and 2022 were retrieved from the hospital clinical database. The included dogs had to receive at least three intralymphatic injections administered either by palpation or ultrasound guidance. Those cases were retrospectively assessed and compared regarding clinical response to ILIT. Results: In total, 84 dogs received ILIT by ultrasound guidance, and in 25 dogs, ILIT was injected based on palpation. The success rate of ILIT was significantly higher in the ultrasound guidance group when compared to palpation-based injections. Conclusions: Low-quality injections must be considered as a possible reason for ILIT failure in dogs. Further prospective and controlled studies are necessary to confirm these results.

Gastric Cancer Actively Remodels Mechanical Microenvironment to Promote Chemotherapy Resistance via MSCs-Mediated Mitochondrial Transfer.

Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA-resistant GC patients and analyzed tumor tissues by single-cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis-independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), whichcould repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical-related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical-related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.

Ureteric stenting outside of the operation theatre: challenges and opportunities.

To evaluate the safety, efficacy, tolerability, and cost-effectiveness of bedside or office-based ureteric stent insertion. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols (PRISMA-P) and A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 guidelines, we searched PubMed/the Medical Literature Analysis and Retrieval System Online (MEDLINE), the Excerpta Medica dataBASE (EMBASE), Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and Dimensions for English-language studies from 1978 to April 2023. Inclusion criteria focused on primary ureteric stent placements outside of the operating theatre (OT). A total of 15 studies involving 2072 stents were included. Success rates for correctly positioned stents in bedside or office-based insertions ranged from 60% to 95.8%, with most studies reporting ≥80% success rates. Common failure reasons included impacted stones and difficulty identifying the ureteric orifice. Pain and tolerability were assessed using various methods, with validated tools indicating moderate pain levels, but most patients would undergo the procedure again under local anaesthesia. Complication rates were generally low, with minor complications such as haematuria or postoperative fever being the most common. Procedural costs were significantly lower in non-OT settings, with estimates indicating savings of up to four-fold. Bedside or office-based ureteric stent insertion is a viable alternative to OT procedures, offering high success rates, manageable pain levels, low complication rates, and substantial cost savings. This approach is particularly advantageous in settings with limited OT access, highlighting its potential for broader adoption in urological practice. Future research should focus on standardising pain assessment methods and randomised studies.

Pressures on Egyptian Red Sea fisheries from the artisan fishers’ perspective

The Egyptian Red Sea (ERS) supports artisanal, commercial and recreational fisheries, managed using a summertime closure, not applied to recreational fishing. Stock status is little known and management options are severely limited. To inform future management, we report the results of a questionnaire survey of artisan fishers from four Red Sea ports, collecting basic socioeconomic and fisheries data: fleet characteristics, self-reported landings, plus attitudes towards current management. Relationships among catches, technical and social categories and categorised attitudes were analysed using ordinal and multinomial logistic regressions. Median income of ERS artisanal fishers was 54% of the mean income from work in rural Egypt in 2020. Almost all respondents reported declining catches (61% blamed “overfishing”) and most were pessimistic (43% expected to remain fishing in 10 years time). The seasonal closure was poorly supported by artisanal fishers: 75% claimed it contributed to declining resources. The timing of the closure, intended to protect spawning fish, aligned with published spawning seasons for some, but not all important species. 66% of fishers identified this mismatch as the reason for policy failure. High dissatisfaction rates risk non-compliance: e.g. 23% of those interviewed switched to ‘recreational’ fishing during the closed season. Most artisan fishers of the ERS are in a precarious economic position, facing a declining resource, under management that few support, with concerns about the long term future for their livelihood. We suggest transition to a participatory approach with data-driven co-management as a long term solution.

Failure analysis on cracking and leakage of 304 stainless steel flange in petrochemical butyl device

Abstract During the pressure test process in a petrochemical butyl device in China, it was found that the 304 stainless steel flange of the ethylene pipeline appeared to be cracking and leakage. This article analyzed the reasons for failure using macroscopic inspection, chemical composition analysis, metallographic structure analysis, scanning electron microscope, energy dispersive spectroscopy, mechanical properties test, and intergranular corrosion test. The results show that the carbon content of the flange base material exceeds the standard, many carbides precipitate at the grain boundary, the material itself is seriously sensitized, and the intergranular corrosion resistance is reduced. At the same time, under corrosive media such as sulfur and chlorine and high stress, the flange displays stress corrosion cracking, which leads to cracking and leakage failure. This article reports the reasons for the failure of the flange, and some reasonable suggestions are put forward to avoid similar leakage accidents.

Regulatory Effects of SLC7A2-CPB2 on Lymphangiogenesis: A New Approach to Suppress Lymphatic Metastasis in HNSCC.

Lymph node metastasis (LNM) is a critical factor affecting the outcomes of head and neck squamous cell carcinoma (HNSCC) and the main reason for treatment failure. This study was designed to examine the effects of the key genes involved in the LNM of HNSCC. Tissue samples (HNSCC) were examined by transcriptome sequencing, and the core genes associated with LNM were detected via bioinformatics analysis. The functions of these core genes were then validated using the TCGA biological database and their effects on the propagation, invasion, and metastasis of HNSCC cells were evaluated through cell culture experiments. Moreover, the effect of core gene expression on the LNM capability of HNSCC was confirmed via a footpad xenograft mice model. In the findings, a key gene involved in the LNM of HNSCC was identified as SLC7A2. It was correlated with adverse clinical prognosis and expressed with low expression in HNSCC tissues. As shown in cell culture experiments, FaDu and SCC15 cell growth, invasion, and migration were inhibited when SLC7A2 was overexpressed. Further, cell apoptosis was stimulated, and lymphangiogenesis was suppressed through the downregulation of CPB2 expression. Animal studies demonstrated that the growth and LNM of HNSCC cells were inhibited by SLC7A2 overexpression. It is concluded that SLC7A2 is involved in HNSCC lymphatic metastasis by controlling CPB2 function. The results are anticipated to offer new directions for the effective treatment of HNSCC.

Experimental study on rock drilling vibration of PDC bit in interbedded formations

Mastering the vibration characteristics of PDC bit, especially in interbedded formations, can help to explore reasonable bit failure control measures, achieve bit optimization and drilling optimization. This work used single rocks to construct different types of vertical and horizontal interbedded rocks with different interbedded properties, the experimental study obtained the bit vibration characteristics under single rock, sudden-changed rock, and alternating rock conditions. The vibration acceleration of a single rock is consistent with the rock strength. The acceleration increases with the increase of weight-on-bit and rotary speed, the influence of weight-on-bit is greater than that of rotary speed. The maximum amplitude of accelerations always occurs in the low frequency range of 0∼300 Hz, the difference between rocks is mainly reflected in the high frequency range greater than 400 Hz. When the drill bit suddenly crosses from soft rock to hard rock in the vertical interbedded formation, the acceleration increases rapidly, causing direct impact. When the drill bit suddenly crosses from hard rock to soft rock, the impact and acceleration attenuates slowly, which could cause fatigue damage to the drill bit and induce high-frequency vibration. The rapid and significant change in depth-of-cut is the fundamental reason for the impact generated when the bit crosses through the interlayer, and both the maximum and minimum depth-of-cut occur in the transition region. PDC bit alternately encountered soft and hard rocks in the horizontal interbedded formation, causing intensified vibration. The acceleration is consistent with rock difference. The influence of weight-on-bit on acceleration increases with the increase of rotary speed for horizontal interbedded formation with small rock differences. However, with the increase of weight-on-bit, the influence trend and degree of rotary speed on acceleration remain basically unchanged. The increase in weight-on-bit /rotary speed weakens the effect of rotary speed/ weight-on-bit on acceleration in horizontal interbedded formations with significant rock differences. The research results illustrate that the reason for the abnormal bit failure in interbedded formations is the frequent changes in depth of cut caused by rock mutation and alternation, and the resulting impact. This provides theoretical guidance for the implementation of effective measures such as reasonable cutter arrangement design, pertinent setting of auxiliary structures, and appropriate adjustment of drilling parameters.