Failure Of Therapy Research Articles

Role of ABCC5 in cancer drug resistance and its potential as a therapeutic target

Over 90% of treatment failures in cancer therapy can be attributed to multidrug resistance (MDR), which can develop intracellularly or through various routes. Numerous pathways contribute to treatment resistance in cancer, but one of the most significant pathways is intracellular drug efflux and reduced drug concentrations within cells, which are controlled by overexpressed drug efflux pumps. As a member of the family of ABC transporter proteins, ABCC5 (ATP Binding Cassette Subfamily C Member 5) reduces the intracellular concentration of a drug and its subsequent effectiveness using an ATP-dependent method to pump the drug out of the cell. Numerous studies have demonstrated that ABCC5 is strongly linked to both poor prognosis and poor treatment response. In addition, elevated ABCC5 expression is noted in a wide variety of malignancies. Given that ABCC5 is regulated by several pathways in a broad range of cancer types, it is a prospective target for cancer treatment. This review examined the expression, structure, function, and role of ABCC5 in various cancer types.

Mechanism of CXCL8 regulation of methionine metabolism to promote angiogenesis in gliomas

BackgroundGliomas are the most common malignant brain tumors characterized by angiogenesis and invasive growth. A detailed understanding of its molecular characteristics could provide potential therapeutic targets. In the present study, we sought to explore the key gene CXCL8 in methionine metabolism in gliomas and its potential role in angiogenesis.MethodsU251 glioma cells were divided into control and methionine-restriction tolerant (constructed with 1/4 of the standard level of methionine in the culture medium) groups for transcriptome and metabolome analysis. To confirm the functions and mechanism of CXCL8 in glioma, heat map, volcano map, Go enrichment, gene set enrichment analysis (GSEA), protein–protein interaction network analysis, RT-PCR, western blotting assays, chicken embryo chorioallantoic membrane (CAM) test, chicken embryo yolk sac membrane (YSM) test and transplantation tumor nude mice model were performed. The TCGA database, CGGA database and clinical tissue samples were used to analyze CXCL8’s significance on prognosis for patients with glioma.ResultsCXCL8 expression was significantly up-regulated in methionine-restricted tolerance cells, it also activated vascular system development and triggered angiogenesis. CXCL8 expression is negatively correlated with survival prognosis in gliomas.ConclusionsGlioma cells promote angiogenesis in methionine-restricted environments through the activation of CXCL8, compensating for nutrient deprivation, and possibly contributing to the failure of antiangiogenic therapy.

Clinical significance of appendicoliths in conservative treatment of acute complicated appendicitis patients with peri-appendiceal abscess: a single-center retrospective study

Background: This study aimed to analyze the clinical data of patients who received conservative treatment for acute complicated appendicitis with peri-appendiceal abscess, identify factors influencing the success rate, and improve treatment strategies. Methods: The clinical data of acute complicated appendicitis patients with peri-appendiceal abscess who received conservative treatment at the Department of Emergency Surgery, Zhongshan Hospital, Fudan University, from January 2016 to March 2023, were retrospectively analyzed. Results: A total of 80 patients were included in our study. Patients were divided into two groups based on the outcomes of ultrasound-guided drainage: The Drainage group (n=28) and the Antibiotic group (n=52). The baseline characteristics of the two groups were comparable. In the Antibiotic group, the surgery rate was 30.4% for patients with an appendicolith and 6.9% for those without. In the Drainage group, the surgery rate was 33.3% for patients with an appendicolith and 27.3% for those without. The presence of an appendicolith significantly correlated with the need for surgery in the Antibiotic group (P=0.026), but not in the Drainage group (P=0.771). For patients who underwent surgery, the incidence of surgical site infections did not differ significantly (P=0.656), and the median length of postoperative hospital stay was similar between the groups (4.0 days vs. 3.0 days, P=0.337). Conclusion: The presence of an appendicolith is a risk factor for the failure of antibiotic therapy alone in acute complicated appendicitis patients with peri-appendiceal abscess. However, it does not affect the surgical rate in those who underwent successful drainage.

The impact of preoperative four-chamber strain on failure of the maze IV procedure for atrial fibrillation: insights from conventional and speckle-tracking echocardiography

Abstract Background Prior studies have linked decreased left atrial (LA) and left ventricular (LV) function to the failure of both catheter ablation and surgery for atrial fibrillation (AF). Yet, the effects of right atrial (RA) and right ventricular (RV) function on the failure of interventional therapy remain unexplored. This study evaluates four-chamber strain parameters using conventional echocardiography and speckle-tracking analysis to evaluate the contributions of preoperative left heart and right heart function to the failure of surgery for atrial fibrillation. Methods We retrospectively analyzed 821 patients who had surgical AF ablation, using pre- and postoperative data from electronic records to assess AF recurrence and thromboembolic events. Of these, 531 had LA ablation only and 290 had bi-atrial Maze-IV procedures. Four-chamber strain was evaluated via speckle-tracking on preoperative echos with TomTec Arena, excluding low-quality images. Univariate and multivariate logistic regression analyses were conducted to assess the influence of AF duration, LV ejection fraction, age, and gender on post-PAF surgery AF recurrence, thromboembolic events with results shown as odds ratios (ORs) in the table. An OR over 1.00 indicates a higher recurrence risk per variable increment. SAS software was used for all statistical analysis. Results In our cohort with a median age of 67.4±11.0 (46.2% female), unadjusted analyses revealed that increased LA and RA volumes and decreased RV free wall strain were significantly associated with AF recurrence post-surgical ablation. Conversely, each unit decrease in LA and RA peak reservoir strain corresponded to a 6% increase in the risk of AF recurrence, indicating an inverse relationship. Adjusted analyses for LA and RA end diastolic volumes and strain values showed a similar direction of association with AF recurrence, though these were not statistically significant. Similarly, lower LA and RA peak strains and larger atrial volumes were suggestive of an increased risk for postoperative thromboembolic stroke, but did not reach statistical significance, potentially due to the low event rate (1.8% of the cohort). Conclusion Conventional echocardiography offers a practical tool for identifying patients at high risk for AF recurrence and potential thromboembolic events after AF ablation surgery. Our study confirms that reduced preoperative LA, RA and RV strain values and enlarged volumes of LA and RA are strongly associated with AF recurrence following surgical ablation. Additionally, RA strain and volume are as predictive as LA metrics, underscoring their importance in risk stratification. These echocardiographic parameters may also hold value in forecasting the likelihood of postoperative stroke.

Efficacy and safety of catheter ablation for paroxysmal atrial fibrillation as first-line therapy vs. after drug failure -analysis from Japan Nationwide Ablation (J-AB) Registry-

Abstract Background Catheter ablation is an effective rhythm control therapy for atrial fibrillation (AF). Recent advancements in technology have improved the efficacy and safety of this procedure. Current European Society of Cardiology and Japanese Circulation Society guidelines recommend that catheter ablation (CA) for patients with paroxysmal AF (PAF) after failure of drug therapy is classified as Class I, and CA as first-line therapy is categorized as Class IIa. However, there are limited clinical studies directly comparing these groups. Objective This study aimed to compare the efficacy and safety of CA as first-line therapy vs. those after failed drug therapy using data from the Japan Nationwide Ablation (J-AB) Registry led by the Japanese Heart Rhythm Society. Methods Detailed data of patients who underwent catheter ablation for PAF extracted from the J-AB registry were analyzed. Patients were divided into two groups: those who underwent CA as first-line therapy (First-line group) or those who underwent CA after failed drug therapy (Drug failure group). Patients’ characteristics, efficacy and safety of CA were compared between the two groups. Efficacy was assessed by evaluating the recurrence rate of any atrial arrhythmia within one year after the 90-day blanking period, and major safety outcomes were set as severe bleeding complication, stroke, and gastrointestinal disorders during the perioperative period. Result This analysis included 5,011 cases with a median age of 69 years (range 61-75) and 35% females. Comparing patient characteristics between the first-line therapy group (n = 3,447) and the drug failure group (n = 1,564), there are no statistically significant differences between the two groups except in left atrium diameter in echocardiogram (LAD) (38 [34-42] mm vs. 38 [34-43] mm, P <0.001), serum creatinine levels (0.8 [0.7-1.0] mg/dl vs. 0.9 [0.7-1.0] mg/dl, P <0.001), and beta-blocker usage (38.2% vs. 46.7%, P <0.01). A total of 501 recurrence events were observed in this analysis during a median follow-up of 365 [254-390] days. Recurrence rates did not statistically differ between the two groups (log-rank P=0.49). After adjusting for contributing factors with age, gender, body mass index, LAD, and left ventricular ejection fraction in echocardiogram using a multivariate Cox proportional hazards model, efficacy outcomes showed no significant difference between the two groups (adjusted hazard ratio; 1.06 95% confidence interval; 0.88-1.28, P = 0.55). Besides, the two groups had no significant difference in major safety outcomes. Conclusions Catheter ablation as the first-line therapy for paroxysmal atrial fibrillation showed a similar recurrence rate of atrial arrhythmias and adverse events compared to those who underwent catheter ablation after drug failure.

Cardiovascular risks of PD1 inhibitor therapy in cancer: impact of prior ischemic events on heart failure - a retrospective cohort study

Abstract Introduction Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but concerns remain about their cardiac risks. Limited recent basic evidence suggests a possible link between ICIs that target PD1 and adverse cardiac events such as heart failure. Purpose This study explores the connection between PD1 inhibitor therapy and incident heart failure in cancer patients. Methods In our retrospective study at a tertiary medical center, 1,671 cancer patients receiving PD1 inhibitors were analyzed. Individuals with a history of heart failure, who developed myocarditis on PD-1, or had missing data were excluded. Data from pharmacy records and the Research Patient Data Registry provided clinical and ICI-related details. Cases were defined as patients who developed incident heart failure after ICI started. Controls were patients who did not develop incident heart failure after ICI start. Sensitivity analyses, including propensity score matching and comparison with non-ICI-treated cancer patients, ensured result robustness. Multivariate logistic regressions were performed. Results Among 1,671 ICI treated patients, 109 (6.5%) developed heart failure without evidence of myocarditis over a median follow-up of 332.0 days. In both the full cohort and the 3:1 matched cohort (n=380), multivariate logistic regression showed increased odds of incident heart failure in patients with prior ischemic cardiac events: 2.34 (95%CI 1.26-4.16, p=0.005) and 2.11 (95%CI 1.05-4.2, p=0.033) respectively. Among the non-ICI treated cancer patients, multivariate logistic regression found no association between prior ischemic events and incident heart failure (1.23, 95%CI 0.53-2.63, p=0.6), but hypertension showed an association (1.74, 95%CI 1.07-2.87, p=0.027). Conclusion This study emphasizes vigilance for cardiovascular complications in PD1 inhibitor-treated cancer patients. The incidence of heart failure was 6.5% over a follow-up period of less than 1 year. Prior ischemic events correlate with increased heart failure risk, suggesting a need for nuanced patient management. Understanding ICIs' cardiovascular safety is crucial for risk assessment, treatment optimization, and patient well-being.

Arrhythmogenic right ventricular cardiomyopathy: the importance of biventricular strain in risk-stratification

Abstract Background Despite Arrhythmogenic right ventricular cardiomyopathy (ARVC) being a predominant right ventricle (RV) disease, concomitant left ventricle (LV) involvement has been recognized. ARVC diagnosis is made through the RV-centric 2010 Task Force Criteria (TFC), but previous studies already suggested the use of echocardiographic strain measures to better depict RV and LV dysfunction in these patients. No data however is available on the additional value of combining biventricular strain in ARVC for risk stratification. Purpose To assess the prognostic value of measuring both LV global longitudinal strain (GLS) and RV free wall strain (FWLS) analysis in patients with ARVC. Methods A total of 204 patients who met the TFC for the ARVC spectrum were included. Patients were categorized based on a cut-off of -18% for strain impairment in both ventricles. The end-point was a composite of all-cause mortality, arrhythmic events, ICD therapy and heart failure events. Results Patients (age 41 ± 17 years, 55% males) were divided into impaired (n=33), discordant (either RV or LV impaired, n=70), and normal (n=101) strain groups (Fig. 1A). Definite and borderline ARVC were diagnosed in 78% and 39%, respectively, at the time of first available echocardiography. During a follow-up of 87 [24-136] months, 60 (29%) experienced the combined outcome, and a significant difference in event-free survival was observed (p<0.001) between the 3 groups (Fig. 1B). In the multivariate analysis (Fig. 2), the strain grouping remained associated with outcome (p=0.040) after adjusting for age, gender, history of syncope and definite ARVC diagnosis, which were also significantly associated with the endpoint at the univariate analysis. A sub-analysis including only definite and borderline ARVC patients confirmed that the strain grouping was an independent predictor of the composite endpoint (p=0.027). Conclusion Biventricular involvement by strain analysis has additional prognostic value in ARVC patients and outcome is worse for those with both RV and LV involvement.Strain groups and Kaplan Meier curvesMultivariate analysis

Predicting High-Flow Nasal Cannula Oxygen Therapy Failure in Patients With Acute Hypoxaemic Respiratory Failure Using Machine Learning: Model Development and External Validation.

To develop and validate a prediction model for high-flow nasal cannula (HFNC) failure in patients with acute hypoxaemic respiratory failure (AHRF). AHRF accounts for a major proportion of intensive care unit (ICU) admissions and is associated with high mortality. HFNC is a non-invasive respiratory support technique that can improve patient oxygenation. However, HFNC failure, defined as the need for escalation to invasive mechanical ventilation, can lead to delayed intubation, prolonged mechanical ventilation and increased risk of mortality. Timely and accurate prediction of HFNC failure has important clinical implications. Machine learning (ML) can improve clinical prediction. Multicentre observational study. This study analysed 581 patients from an academic medical centre in Boston and 180 patients from Guangzhou, China treated with HFNC for AHRF. The Boston dataset was randomly divided into a training set (90%, n = 522) and an internal validation set (10%, n = 59), and the model was externally validated using the Guangzhou dataset (n = 180). A random forest (RF)-based feature selection method was used to identify predictive factors. Nine machine learning algorithms were selected to build the predictive model. The area under the receiver operating characteristic curve (AUC) and performance evaluation parameters were used to evaluate the models. The final model included 38 features selected using the RF method, with additional input from clinical specialists. Models based on ensemble learning outperformed other models (internal validation AUC: 0.83; external validation AUC: 0.75). Important predictors of HFNC failure include Glasgow Coma Scale scores and Sequential Organ Failure Assessment scores, albumin levels measured during HFNC treatment, ROX index at ICU admission and sepsis. This study developed an interpretable ML model that accurately predicts the risk of HFNC failure in patients with AHRF. Clinicians and nurses can use ML models for early risk assessment and decision support in AHRF patients receiving HFNC. TRIPOD checklist for prediction model studies was followed in this study. Patients were involved in the sample of the study.

Clinical evaluation of sintilimab in conjunction with bevacizumab for advanced colorectal cancer with microsatellite stable-type after failure of first-line therapy

Clinical evaluation of sintilimab in conjunction with bevacizumab for advanced colorectal cancer with microsatellite stable-type after failure of first-line therapy

Extramammary Paget's disease treated with of anti-programmed cell death protein 1 therapy after docetaxel therapy failure.

Extramammary Paget's disease (EMPD) is a rare skin cancer with no standard treatment for advanced-stage disease. Although docetaxel-based chemotherapy is common, no standard treatment exists. Pembrolizumab is approved for solid tumors with a high tumor mutation burden (TMB) and/or high microsatellite instability, and nivolumab was approved in Japan in February 2024 for unresectable advanced or recurrent epithelial skin malignancies. However, there is a lack of real-world data regarding the efficacy of anti-programmed cell death protein 1 (PD-1) therapy for EMPD. We present the case details of three EMPD patients treated with anti-PD-1 therapy after docetaxel treatment, with TMB values of 17.8, 14.3, and 5.0 mut/Mb, respectively, and we review similar reported cases. Even in the cases with a high TMB, the response to anti-PD-1 therapy was not sufficient. Most cases involve second-line or later treatments, so further research is needed to determine the precise effectiveness of anti-PD-1 therapy as a first-line treatment.

Recent Advancement in Drug Designing as Small Molecules in Targeted Cancer Therapy: Challenges and Future Directions.

The adverse outcome that patients experience as a result of anti-cancer therapy failure is primarily caused by metastasis. Making cancer a chronic disease with regular but controlled relapses is the real issue in increasing cancer patient lifespans. This can only be achieved by developing efficient therapeutic techniques that target critical targets in the metastatic process. New targeted therapy medications continue to emerge, and research into the molecular targeted therapy of tumors is flourishing. The ineffectiveness of conventional chemotherapy in targeting metastatic cells is primarily due to its ability to promote the selection of chemo-resistant cell populations that engage in epithelial-to-mesenchymal transition (EMT), which in turn encourages the colonization of distant sites and maintains the initial metastatic process. In considering this circumstance, research into a broad range of small molecules and biologics has been initiated to develop anti-metastatic medications that target particular targets implicated in the different stages of metastasis. With their ability to concentrate on cancer cells while avoiding normal cells, tar-geted medications offer a promising alternative to conventional chemotherapy that is both highly effective and relatively safe. Many obstacles, including an inadequate response rate and drug resistance, persist for small-molecule targeted anti-cancer medications, despite significant ad-vancements in this area. We encouraged small-molecule-focused anti-cancer therapy develop-ment by extensively assessing them by target classification. We reviewed current challenges, listed licenced drugs and key drug candidates in clinical trials for each target, and made sugges-tions for improving anti-cancer drug research and development. This review aims to discuss pre-sent and future small molecule inhibitor research and development for cancer treatment.

Relationship Between The Compliance of Antiretroviral Therapy and The Occurrence of Underweight Conditions, Calf Circumference, Handgrip Strength, and Triceps Skinfold in HIV/AIDS Patients at RSSA Malang

Background: Human Immunodeficiency Virus or commonly known as HIV is a virus that infects CD4 cells thereby impaired the human immune system. The number of new HIV cases in Indonesia in 2019 was reported to have reached 50,282 cases and tends to increase from year to year. What often happens in people with HIV/AIDS (PLWHA) tends to experience weight loss accompanied by opportunistic infections that do not occur in normal people. Adherence to therapy is the main factor that must be emphasized by PLWHA in order to achieve treatment success. However, ARV therapy adherence rates are reported to be <80%. This number can be a predictor of therapy failure. One indicator of the success of therapy is when there is clinical improvement in the patient's condition, such as no opportunistic infections or weight gain. Aim: The aim of this study was to determine whether there is a relationship between adherence to antiretroviral therapy and underweight conditions in HIV/AIDS patients. Methods: This study used a cross sectional design with an analytical observational nature and the research subjects were patients at RSSA Malang who visited from June to August 2023. Results: The results of the study showed that there was a significant relationship between adherence to taking ARVs and being underweight (p=0.018) and there was no significant relationship between adherence to taking ARVs with calf circumference, handgrip strength, and triceps skinfold. Conclusion: The conclusion of this study is that the more compliant the patient is with ARV therapy, the higher the increase in body mass index and the smaller the possibility of becoming underweight.

Upadacitinib in patients with difficult-to treat Crohn’s disease

Abstract Background Upadacitinib has been approved to treat adults with moderate-to-severe Crohn’s disease (CD). Only a few studies have evaluated the effectiveness and safety of the drug in clinical practice, with even fewer focusing on patients with difficult-to-treat CD. Therefore, this study assessed the effectiveness and safety of upadacitinib in CD patients for whom all other available therapies had failed. Methods Patients with moderate-to-severe CD who had received upadacitinib after exhausting other treatments were included. The primary endpoint was corticosteroid-free clinical remission. Secondary endpoints included clinical response, biochemical remission, transmural response, transmural healing, deep remission, and continuation of therapy. Results The study included 64 CD patients. After 12 weeks, 51.6% of patients achieved steroid-free clinical remission, and 71.8% showed a clinical response. Biochemical remission was observed in 36.2% of patients, and transmural healing in 28.8%. At 24 weeks, clinical remission was achieved in 78% of patients continuing therapy. Therapy was discontinued before the end of the induction period in 14 patients (21.9%) due to therapy failure or adverse events. Conclusions This study highlights the efficacy of upadacitinib in CD patients for whom multiple drugs have failed, providing real-world evidence supporting its use in patients with moderate-to-severe CD unresponsive to other therapies.

Comparison of Vicious Effect of Oral Pantoprazole and Famotidine on New Bone Formation in Patients With Lumbar Spine Fusion Surgery: A Randomized Control Trial

Background and Aim: Due to the increasing use of proton pump inhibitors (PPIs) and their side effects for bone repair and the high percentage of therapy failure in lumbar fusion surgery, especially in various animal studies, the goal of this study was to appraise the consequence of pantoprazole and famotidine on new bone formation in patients experiencing spinal fusion surgery. Methods and Materials/Patients: In this double-blind clinical trial, eighty patients participated based on the inclusion and exclusion criteria, of whom 40 cases received pantoprazole (group P) and 40 received famotidine (group F) for eight weeks. They were followed up for three, six, and twelve months after surgery for cage subsidence, screw loosening, and visual analogue scale (VAS), Oswestry disability index (ODI), Brantigan, Steffee, Fraser (BSF), and Lenke classification for grading their bone formation. A P<0.05 was considered significant. Results: The rate of fusion based on the Lenke score was lower in the group receiving pantoprazole six and 12 months after the surgery compared to group F (the frequency of Lenke grades C and D were 35% and 25% compared to the famotidine group 12.5% and 12.5%, respectively; P=0.042). The VAS Mean±SD score in group F was lower than group P after 12 months (2.48±1.06 and 1.83±0.55, respectively; P=0.008). There was no pharmacologically significant association between subsidence (P=0.43), loosening (P=0.13), ODI (P=0.31), and BSF (P=0.77) 3, 6 and 12 months post-operation. Conclusion: Affording to the preliminary conclusions of this study, the use of pump inhibitors, such as pantoprazole is more destructive for the ossification process in candidates for spinal fusion requiring the chronic use of drugs for controlling their gastric acid secretion, and H2-blocking drugs, such as famotidine are preferable in this situation after further investigations.

Antibiotic Susceptibility-Guided Concomitant Therapy Regimen with Vonoprazan, High-Dose Amoxicillin, Clarithromycin, and Metronidazole for Helicobacter pylori Eradication as Fourth-Line Regimen: An Interventional Study.

Twenty patients who underwent three rounds of eradication therapies (first- or second-line 7-day triple therapy consisting of amoxicillin and clarithromycin, or metronidazole- and sitafloxacin-based third-line therapy) and had failed eradication based on a urea breath test or fecal antigen test were recruited. All patients underwent endoscopic examination and culture tests before starting eradication therapy. The intervention was concomitant therapy consisting of vonoprazan 20 mg bid, amoxicillin 500 mg qid, clarithromycin 400 mg bid, and metronidazole 250 mg bid for 14 days, which were modified based on the susceptibility test, and the resistant drugs were removed from the regimen. Patients with negative culture results were treated with quadruple therapy. The primary outcome was the eradication rate (UMIN000025765, jRCTs 031180208). The eradication rate of susceptibility-testing-based fourth-line eradication therapy was 63.2% (95%CI: 38.4-83.7%) in intent-to-treat analysis and 70.6% (95%CI: 44.0-89.7%) in per-protocol analysis. Thirteen patients received quadruple therapy, with eradication rates of 61.5% and 75.0%, respectively. No serious adverse events were reported. This vonoprazan-based concomitant therapy modified by the susceptibility test is a potential option as fourth-line eradication after first-line clarithromycin-based 7-day triple, second-line metronidazole-based 7-day triple, and third-line sitafloxacin-based 7-day triple therapy failure.

Efficacy of Second-Line Biological Therapies in Moderate to Severe Ulcerative Colitis Patients with Prior Failure of Anti-Tumor Necrosis Factor Therapy: A Multi-Center Study.

Few studies have compared the efficacy and safety of second-line biological therapies in ulcerative colitis (UC) patients with prior exposure to anti-tumor necrosis factor (TNF) therapy. We aim to compare the efficacy and safety between ustekinumab, vedolizumab, and tofacitinib, a current option as second-line biological therapy with different mechanisms in those patients. This retrospective multi-center study was conducted across five institutions from 2011 to 2022. We enrolled patients with moderate to severe UC who failed anti-TNF therapy and subsequently received ustekinumab, vedolizumab, or tofacitinib as second-line biological therapy. The outcomes were analyzed for clinical response/remission and endoscopic improvement/remission rates after induction therapy, drug persistency, and adverse events. A total of 70 UC patients were included and grouped into ustekinumab (11 patients), vedolizumab (40 patients), and tofacitinib (19 patients) treatments. The clinical response/remission rates after induction therapy were similar between ustekinumab (90.9/81.8%), vedolizumab (92.5/65.0%), and tofacitinib (94.7/73.7%). There were no significant differences in the endoscopic improvement/remission rates between the three groups: 90.9/18.2% for ustekinumab, 72.5/12.5% for vedolizumab, and 84.2/26.3% for tofacitinib. Drug persistence was similar across the three agents (p = 0.130). Three patients of the tofacitinib group experienced adverse events (herpes zoster and hypertriglyceridemia). Based on real-world data, second-line biological therapy with ustekinumab, vedolizumab, and tofacitinib showed comparable efficacy in patients with moderate to severe UC with prior exposure to anti-TNF therapy.

Transmitted drug resistance and molecular transmission network among treatment-naive HIV-1 patients in Wenzhou, China, 2020–2023

BackgroundTransmitted drug resistance (TDR) increases the risk of antiretroviral therapy (ART) failure in HIV-1 patients. This study investigated the molecular epidemiology of TDR and its transmission networks among newly diagnosed HIV-1 patients in Wenzhou, China.MethodsWe enrolled 1878 ART-naive HIV-1 patients from January 2020 to October 2023. TDR was evaluated using the Stanford University HIV Drug Resistance Database. We performed phylogenetic analysis, genotyping, transmission clustering, and population-based TDR-related factor analysis.ResultsAmong 1782 patients with successful genotyping, TDR prevalence was 5.7%. Multivariable analysis identified CRF08_BC subtype (adjusted odds ratio [aOR] 18.59, 95% CI 3.79-336.18, p = 0.004), CD4 > 500 cells/mm³ (aOR 2.19, 95% CI 1.16–4.03, p = 0.013), and year 2023 (aOR 1.83, 95% CI 1.11–4.89, p = 0.039) as factors associated with higher TDR risk. The most prevalent NNRTI mutations were K103N, E138A, and V179E. Seven TDR transmission clusters were identified, notably one with V179D that expanded during 2020–2023.ConclusionsWhile TDR prevalence in Wenzhou remained lower than in other Chinese regions, an upward trend was observed. Most resistant individuals were in transmission clusters, predominantly middle-aged and elderly. NNRTI resistance was severe and concentrated in efavirenz, nevirapine, and rilpivirine. Enhanced HIV surveillance and wider free antiretroviral options are crucial to control drug-resistant HIV spread in Wenzhou.

A Comparison of Conventional Root Canal Sealers With Ones That Use Green Synthesized Nanoparticles for Antimicrobial Activity: Protocol for a Systematic Review.

Root canal failure and secondary endodontic infection are frequent clinical scenarios in dentistry. The main microorganisms implicated in root canal therapy failure are persistent Enterococcus faecalis, Candida albicans, and Staphylococcus aureus. To combat the impact of disease resistance, scientists are concentrating on alternative antimicrobial root canal sealers. Nanomaterials are a recent development in endodontic materials that exhibit great antimicrobial properties, making them an ideal material choice for root canal sealers. This systematic review aims to compare the antimicrobial properties of conventional root canal sealers to those incorporating green synthesized nanoparticles between 2010 and 2024. A well-constructed protocol was established and registered with PROSPERO (CRD42021286373). Ethics approval was obtained from the Biomedical Research and Ethics Committee from the University of the Western Cape (UWC; BM22/1/4). PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) reporting guidelines were followed. The included criteria demonstrate the green synthesized nanoparticles studies where the nanoparticles (NPs) are incorporated in root canal sealers. MeSH (Medical Subject Headings) terms were used for the search strategy of the systematic electronic databases for articles published in English between 2010 and 2024. The selected databases included Scopus, PubMed, Web of Science, Science Direct, EBSCOhost, SpringerLink, and Wiley Online. A quality assessment tool for laboratory studies will be used to critically appraise the included studies. If applicable, statistical measures (mean, SD, etc) will be used for data analysis and presentation of the results. The protocol is registered with PROSPERO. A preliminary search was conducted using a determined search strategy across 8 electronic databases, and the review is now complete. It is anticipated that the results of this systematic review may reveal the increased interest and application for nanoparticle-enhanced root canal sealers. This will aid in the future development of root canal sealants and mitigate the risk of endodontic failure. PROSPERO CRD42021286373; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=286373. DERR1-10.2196/51351.

Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

Sub- and supratherapeutic efavirenz plasma concentrations with risk for HIV therapy failure are mainly genetically explained in Ugandan children: The prospective GENEFA cohort study.

Interindividual variations in efavirenz (EFV) plasma concentrations are extensive, but paediatric data on its consequences for viral control are scarce. The aim of this study was to explore the role of genetic variation in achieving therapeutic efavirenz plasma concentrations in a cohort of Ugandan children and the linkage between genetic CYP2B6 variants, EFV plasma variability, viral resistance and viral outcome. Ninety-nine treatment-naïve children, aged 3-12 years and living with HIV, were followed for 24 weeks after ART initiation assessing mid-dose efavirenz plasma concentrations, HIV RNA, HIV drug resistance and adherence. Polymorphisms in genes coding for drug-metabolizing enzymes were genotyped. Efavirenz concentrations were determined by liquid chromatography coupled with high-resolution tandem mass spectrometry. Metabolizer phenotype was predicted from composite genotypes of CYP2B6 (c.516G>T and c.983 T>C). A mixed effects restricted maximum likelihood regression model was used to identify important factors for efavirenz exposure. Efavirenz plasma concentrations were below the therapeutic interval (1000-4000 mg/mL) in 12-17% and above in 21-24% of measurements. Eight children had persisting subtherapeutic concentrations, five of which failed virologically and three acquired at least one new resistant mutation. Multivariate modelling explained 70% of interindividual variation in plasma concentration, with treatment duration, adherence, CYP2B6c.136A>G, and metabolizer phenotype as independent predictors of EFV concentration. In univariate analysis, metabolizer phenotype explained 50% of interindividual variation. Metabolizer phenotype explained 50% of interindividual variation in efavirenz plasma concentration. Autoinduction was not confirmed and >33% of the concentrations were outside the therapeutic interval. Subtherapeutic concentrations worsened virological resistance and outcomes. Genotype-based dosing may help avert both sub- and supratherapeutic efavirenz plasma concentrations in Ugandan children.