Effective Therapy Research Articles

Flexible Development Programs for Antibacterial Drugs to Address Unmet Medical Needs.

The US Food and Drug Administration recognizes the unmet medical need for antibacterial drugs to treat serious bacterial diseases caused by resistant pathogens for which effective therapies are limited or lacking. The agency also recognizes that designing and conducting clinical trials to assess the safety and efficacy of drugs to treat resistant infections is challenging, especially for drugs only active against a single or a few bacterial species, and that a more flexible development program might be appropriate. In this article, we discuss several regulatory considerations for flexible development programs for antibacterial drugs intended to meet an unmet medical need. As an example, we use the recent approval of sulbactam for injection and durlobactam for injection (XACDURO) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.

Targeted nanomedicine for reprogramming the tumor innate immune system: From bench to bedside

Tumor-associated innate immune cells such as tumor-associated macrophages, neutrophils, dendritic cells play a crucial role in tumor progression, angiogenesis and metastasis. These cells also control the efficacy of chemotherapy and immunotherapy by inducing drug resistance and immunosuppression, leading to therapeutic failures. Therefore, targeting the tumor-associated innate immune cells has gained high attention for the development of effective cancer therapy. Nanomedicine based strategies to target these cells are highly relevant and can be used to reprogram these cells. In this review, we discuss the fundamental roles of the tumor-associated innate immune cells in the tumor microenvironment and different strategies to modulate them. Then, nanomedicine-based strategies to target different tumor innate immune cells are explained in detail. While the clinical development of the targeted nanomedicine remains a great challenge in practice, we have provided our perspectives on various factors such as pharmaceutical aspects, preclinical testing and biological aspects which are crucial to consider before translating these targeting strategies to clinics.

Exploring the Therapeutic Potential of Ginkgo biloba Polyphenols in Targeting Biomarkers of Colorectal Cancer: An In-silico Evaluation.

Colorectal cancer (CRC) is a major contributor to cancer-related deaths worldwide, driving the need for effective anticancer therapies with fewer side effects. The exploration of Ginkgo biloba, a natural source, offers a hopeful avenue for novel treatments targeting key colorectal biomarkers involved in CRC treatment. The aim of this study was to explore the binding affinity of natural molecules derived from G. biloba to essential biomarkers associated with CRC, including Kirsten rat sarcoma virus, neuroblastoma RAS mutations, serine/threonine-protein kinase B-Raf, phosphatidylinositol 3'-kinase, and deleted colorectal cancer, using molecular docking. The focus of this research was to evaluate how effectively these molecules bind to specified targets in order to identify potential inhibitors for the treatment of CRC. A total of 152 polyphenolic compounds from G. biloba were selected and subjected to molecular docking simulations to evaluate their interactions with CRC-related biomarkers. The docking results were analysed to identify ligands exhibiting strong affinities towards the targeted genes, suggesting potential inhibitory effects. Docking simulations unveiled the strong binding affinities between selected polyphenolic compounds derived from G. biloba and genes associated with CRC. The complex glycoside structures that are found in flavonols are of significant importance. These compounds, including derivatives with distinctive arrangements, exhibited promising docking scores, signifying substantial interactions with the targeted biomarkers. The study demonstrates the potential of G. biloba-derived molecules as effective anticancer agents for colorectal cancer. The identified ligands exhibit strong interactions with crucial CRC-related biomarkers, suggesting potential inhibition ability. Further in vitro and in vivo investigations are needed to validate and build upon these promising findings, advancing the development of novel and efficient CRC therapies.

Fecal microbiota transplantation against moderate-to-severe atopic dermatitis: A randomized, double-blind controlled explorer trial.

Fecal microbiota transplantation (FMT) is a novel treatment for inflammatory diseases. Herein, we assess its safety, efficacy, and immunological impact in patients with moderate-to-severe atopic dermatitis (AD). In this randomized, double-blind, placebo-controlled clinical trial, we performed the efficacy and safety assessment of FMT for moderate-to-severe adult patients with AD. All patients received FMT or placebo once a week for 3 weeks, in addition to their standard background treatments. Patients underwent disease severity assessments at weeks 0, 1, 2, 4, 8, 12, and 16, and blood and fecal samples were collected for immunologic analysis and metagenomic shotgun sequencing, respectively. Safety was monitored throughout the trial. Improvements in eczema area and severity index (EASI) scores and percentage of patients achieving EASI 50 (50% reduction in EASI score) were greater in patients treated with FMT than in placebo-treated patients. No serious adverse reactions occurred during the trial. FMT treatment decreased the Th2 and Th17 cell proportions among the peripheral blood mononuclear cells, and the levels of TNF-α, and total IgE in serum. By contrast, the expression levels of IL-12p70 and perforin on NK cells were increased. Moreover, FMT altered the abundance of species and functional pathways of the gut microbiota in the patients, especially the abundance of Megamonas funiformis and the pathway for 1,4-dihydroxy-6-naphthoate biosynthesis II. FMT was a safe and effective therapy in moderate-to-severe adult patients with AD; the treatment changed the gut microbiota compositions and functions.

Unveiling environmental transmission risks: comparative analysis of azole resistance in Aspergillus fumigatus clinical and environmental isolates from Yunnan, China.

Azole resistance in Aspergillus fumigatus poses a significant clinical challenge globally. Our previous epidemiological analysis revealed a remarkably high frequency (~80%) of azole-resistant A. fumigatus in Yunnan's greenhouse environments, prompting increased local and regional research for targeted control strategies. In this study, we analyzed 94 clinical A. fumigatus isolates from Yunnan, comparing their susceptibility profiles and genotypic characteristics with environmental strains previously isolated. While the overall frequency of azole resistance in clinical isolates was lower than that in environmental samples, a significant prevalence of cross-resistance, with varying resistance patterns based on minimum inhibitory concentration (MIC) levels was observed, which exceeded rates in other regions of China. Specific mutation combinations in the cyp51A gene were linked to elevated MIC values in clinical and/or environmental samples, while some resistant strains with wild-type cyp51A remain unexplained, indicating a need for further investigation into their resistance mechanisms. The differences in unique genetic elements and the distinct genetic differentiation observed between clinical and environmental isolates can be attributed to Yunnan's unique geomorphology and potential genotype importation from other provinces and abroad. Extensive allele exchanges and sharing contributed to the selection of azole-resistant clinical isolates, suggesting a common environmental origin, and the transmission routes of local drug-resistant strains cannot be excluded. These findings emphasize the imperative for regional and targeted surveillance to monitor resistance trends and guide effective antifungal therapy, and management strategies to mitigate invasive aspergillosis risk in this region.IMPORTANCEAzole resistance in Aspergillus fumigatus is a major global health concern, with particularly high rates (~80%) observed in Yunnan's greenhouse environments. This study compares azole resistance in 94 clinical isolates from Yunnan with environmental strains, revealing lower clinical resistance but significant cross-resistance and distinct resistance patterns. Specific mutations in the cyp51A gene were associated with elevated minimum inhibitory concentration values, though some resistant strains had wild-type cyp51A, highlighting the need for further research. The unique genetic profiles and potential external genotype influences in Yunnan emphasize the need for targeted regional surveillance. Effective monitoring and control strategies are essential to manage and mitigate the risk of invasive aspergillosis.

Functional outcomes in children and adolescents with neurodisability accessing music therapy: A scoping review.

To determine the evidence for functional outcomes experienced by a population with paediatric neurodisability (such as acquired brain injury, cerebral palsy, spinal cord injury, and other neurological disorders), who access music therapy through neurorehabilitation services across the rehabilitation spectrum. Using scoping review methodology of the JBI and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), a systematic search was conducted across eight databases and expert knowledge users were consulted. Articles were screened by title and abstract, and data from eligible studies were categorized using the International Classification of Functioning, Disability and Health: Children and Youth version (ICF-CY). From 1726 records identified, 53 eligible primary sources were included in the synthesis. Most literature (n = 30) related to children and adolescents with an acquired or traumatic brain injury. Physical functionwas the most frequently reported outcome across sources(n = 27), followed by communication (n = 25), social (n = 22), cognitive (n = 17), emotional (n = 13), psychological (n = 13), behavioural (n = 8), and sensory (n = 5). Evidence for functional outcomes experienced by children and adolescents accessing music therapy as part of their neurorehabilitation is limited. More than half of the included sources were clinical descriptions with small samples. High-quality studies involving children, adolescents, families, and interprofessional teams are needed to identify the most effective music therapy methods and techniques for functional outcomes in paediatric neurodisability.

Emerging CART Therapies for Pediatric Acute Myeloid Leukemia.

The prognosis of children with acute myeloid leukemia (AML) has improved incrementally over the last decades. However, at relapse, overall survival (OS) ∼40% to 50% and is even lower for patients with chemorefractory disease. Effective and less-toxic therapies are urgently needed for these children. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies. CART therapies are being developed for AML on the basis of the results obtained for other hematologic malignancies. The biggest challenge of CART therapy for AML is to identify a specific target antigen, since antigens expressed in AML cells are usually shared with healthy hematopoietic stem cells. An overview of prospects of CART in pediatric AML, focused on the common antigens targeted by CART in AML that have been tested or are currently under investigation, is provided in this manuscript.

Discovery and Total Synthesis of Anhydrotuberosin as a STING Antagonist for Treating Autoimmune Diseases

Excessive activation of the stimulator of the interferon gene (STING) pathway has been identified as a significant contributor to various autoimmune diseases, such as STING‐associated vasculopathy with infantile‐onset (SAVI) and inflammatory bowel disease (IBD). However, discovering effective STING antagonists for treating STING‐mediated autoimmune disorders remains challenging. Herein, we identified the natural product anhydrotuberosin (ATS) as a potent STING antagonist by a high‐throughput chemical screen and follow‐up biological validations. However, the limited supply from natural product isolation impeded the pharmacological evaluations of ATS. Accordingly, we developed a concise and scalable total synthesis of ATS in 6 steps. Enabled by total synthesis, we further extensively investigated ATS’s mode of action and evaluated its therapeutic potential. Remarkably, ATS inhibits STING signaling in PBMCs derived from three SAVI patients. ATS showed decent pharmacokinetic parameters and strongly alleviated tissue inflammation in DSS‐induced IBD colitis and Trex1‐/‐ autoimmune animal models with low toxicity. Collectively, this research lays the foundation for developing novel STING antagonists as an effective therapy for autoinflammatory and autoimmune diseases.

Noninvasive identification of ANOCA endotypes by stepwise, multi-stress, multi-marker stress echocardiography

Abstract Background Angina with non-obstructive coronary artery disease (ANOCA) is increasingly recognized in clinical practice, but effective therapy is difficult due to the heterogenity of pathophysiological substrates: organic coronary microvascular dysfunction (CMD), functional (vasospastic) CMD, epicardial artery vasospasm, non-cardiac chest pain. Current guidelines recommend invasive coronary function testing with the inherent cost of catheterization time, radiation exposure, iodinated contrast effects and risks of invasive procedures. Objective To evaluate the feasibility of a step-wise, multi-marker, multi-stress assessment of ANOCA patients by stress echocardiography (SE). Methods In a prospective study design, we enrolled 54 ANOCA patients (age =54±14 years, 14 men, 25 %), without significant coronary artery disease (CAD) on invasive or noninvasive angiography. In all patients hyperventilation (HYPER) test (30 deep breaths/min for 5 min) was performed, followed by semi-supine exercise (EX) if negative. All patients underwent adenosine (ADO) test with coronary flow velocity reserve (CFVR) measurement in the mid-distal left anterior descending artery (LAD). Positivity criteria were a coronary flow velocity (CFV) decrease during HYPER despite the increase in the double product (DP) indicating functional CMD i.e. vasoconstriction); the presence of inducible regional wall motion abnormality (RWMA) with HYPER-EX (microvascular/epicardial spasm), and CFVR ≤2.0 with ADO hyperemia (organic CMD). Results Fifty one pts (94%) had normal increase in CFV at ADO: CFV rest 0.264±0.078 vs ADO 0.608±0.133, p<0.001, while 3pts (5%) showed decrease in CFV at ADO suggesting organic CMD. Double product (DP) increased during HYPER (rest 10061 ±2406 vs. HYPER 13580 ±3356, p<0.001). Twenty-nine pts (53%) showed a paradoxical vasoconstrictor response during HYPER despite the increase in DP (CFV decreased during HYPER: CFV rest 0.261±0.059 vs HYP 0.216±0.057, p<0.001). With HYPER-EX, RWMA was induced in 15 patients (27%), while 7 patients had also RWMA during HYPER. Conclusion In patients with ANOCA, a stepwise multi-marker (CFVR and RWMA) and multi-stress (ADO, HYPER and EX) SE identifies CMD phenotypes and actionable therapeutic targets. According to our results functional vasospastic CMD (paradoxical decrease of CFV with HYPER), is more frequent than organic CMD (reduced CFVR with ADO) in patients with ANOCA. Inducible RWMA with HYPER-EX indicate severe vasoconstrictor response.

Invasive disease-free survival and brain metastasis rates in patients treated with neoadjuvant chemotherapy with trastuzumab and pertuzumab

Patients with HER2(+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD). We analyzed IDFS and brain metastasis (BM) rates in patients with HER2(+) EBC treated with NAST and report the outcomes of patients with HER2(−) RD. Patients with HER2(+) EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. IDFS was defined as the time from surgery until first occurrence of invasive breast cancer recurrence, distant recurrence, or death from any cause. The total cohort was 594 patients. pCR (ypT0/isN0) was achieved in 325(55%) and RD was seen in 269(45%) patients. In 269 patients with RD, 45(17%) did not have HER2 retesting and were excluded. In the remaining 224 patients, 143(64%) were HER2(+) and 81(36%) were HER2(−). With a median follow up of 24 months, 8 patients developed BM at initial recurrence, 4/325(1.2%) with pCR and 4/143(2.8%) with HER2(+) RD. IDFS events occurred in 22/594(3%) patients; 14/269(5%) in RD and 8/325(2%) in pCR (p = 0.04). There was no difference in IDFS between 9/143(6%) patients with HER2(+) RD or 5/81(6%) with HER2(−) RD (p = 0.10). Patients with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2(+) status; IDFS events appeared similar in those with HER2(+) RD versus those with HER2(−) RD. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adjuvant setting to minimize BM risk.

Infection management in the extravascular implantable cardioverter defibrillator: experience from the EV ICD Pivotal study

Abstract Background The extravascular implantable cardioverter defibrillator (EV ICD) has recently emerged as an option for guideline indicated ICD patients. Results from the EV ICD Pilot and Pivotal studies demonstrated that the device can provide safe and effective therapy through chronic follow up. Lead placement outside the vasculature has the potential to reduce systemic infections. Infection occurrence and management details from the Pivotal are reported. Purpose To report on details of infection occurrence and management from the EV ICD Pivotal study. Methods The EV ICD Pivotal study was an international, prospective, single-arm, premarket clinical study. Patients with a class I or IIa indication for a single-chamber ICD per ESC or ACC/AHA/HRS guidelines were enrolled. Results In the EV ICD Pivotal study, 316 patients had an implant attempt, (74.7% male, age 53.8±13.1 years, 82% primary prevention, LVEF of 38.9%±15.4%, and NYHA Class I [23.7%] or II/III [65.5%]), of which 15 had a system or procedure-related infection (4.7%, 9 - 737 days post-implant) through an average 16.2 months follow-up. Of these infections, 8 were classified as major complications, 3 as minor, and 4 as observations. Most (n=9) infections were addressed through medication with or without wound care (2.8% of patients) while 6 (1.9% of patients) resulted in system removal. There was a single lead-related infection addressed through system explant. However, there were no reports of mediastinitis, sepsis, or endocarditis. No system removal resulted in sequelae. Conclusions Infection rates observed in the EV ICD Pivotal study were similar to those reported in the subcutaneous implantable cardioverter defibrillator. The results from this study support that EV ICD related infections are treatable with antibiotic therapy or system removal. No system or procedure-related systemic infections such as mediastinitis, sepsis, or endocarditis have been reported in the Pivotal study.

The CNP analogue vosoritide reduces arrhythmia in diabetic cardiomyopathy via cGMP-dependent PDE2 stimulation on cellular and organ level

Abstract Background Detrimental arrhythmia occurs frequently in patients with diabetic cardiomyopathy (DiabCM), but safe and effective therapies are limited. Diabetes-associated neuropathological alterations increase the sympathetic tone, leading to hyperactivation of β-adrenoceptor-mediated cAMP signalling in cardiomyocytes (CM). Increased activity of deleterious cAMP-dependent kinases causes pro-arrhythmic dysregulation of intracellular Ca2+ homeostasis. Phosphodiesterases (PDE) can reduce cAMP levels. Exceptionally, the cAMP-hydrolysing activity of PDE2 can be cGMP-dependently increased by C-type natriuretic peptide (CNP). Thus, the CNP analogue vosoritide (approved for the treatment of achondroplasia) might mediate this cGMP/cAMP crosstalk, reducing arrhythmia. Purpose Here, we aim to study whether the cGMP-dependent activation of PDE2 by vosoritide (VO) is sufficient to reduce arrhythmia and arrhythmogenic triggers in DiabCM. Methods Diabetes was induced by 5 consecutive injections of streptozotocin (50 mg/kg) in control (WT) mice and mice with a CM-specific PDE2 knockout (KO). All experiments were performed 5 weeks later. Cardiac function was characterised by echocardiography. Primary ventricular CM were isolated to assess protein expression and phosphorylation levels by Western blot (WB) and cAMP levels by ELISA. Patch-clamp and Ca2+ imaging experiments were used to investigate pro-arrhythmic triggers. Arrhythmic events were quantified in ex vivo perfused hearts after ischaemia-reperfusion (I/R) injury. Results Compared to healthy controls, diabetic animals showed impaired systolic function with a ~9 % reduction in ejection fraction. The significant increase in E/E’ ratio by ~34 % indicated a diastolic dysfunction. Interestingly, the cardiac function was further worsened in diabetic PDE2 KO. WB analysis revealed upregulation of the CNP receptor NPR-B and PDE2 in diabetic CM and altered regulation of proteins involved in cAMP-dependent Ca2+ cycling such as protein kinase A, Ca2+/calmodulin-dependent kinase II and phospholamban. Interestingly, VO significantly reduced isoprenaline (Iso)-induced cAMP levels in diabetic CM. The effect of VO was prevented by specific PDE2 inhibition with BAY 60-7550 (BAY). Furthermore, VO was able to reduce the Iso-induced increase in L-type Ca2+ current, whereas BAY or genetic PDE2 deletion counteracted this effect. Accordingly, VO significantly decreased the Iso-triggered Ca2+ spark frequency by ~40 %. Concomitant PDE2 inhibition or PDE2 KO prevented this anti-arrhythmic effect. Finally, ECG analysis revealed that VO clearly reduced arrhythmia development after I/R in ex vivo perfused diabetic hearts via PDE2 activation. Conclusion Our data indicate that vosoritide-induced PDE2 stimulation may attenuate abnormal cardiac Ca2+ cycling and thereby reduce arrhythmia in diabetic hearts. Thus, vosoritide may be repurposed as a novel anti-arrhythmic drug in DiabCM.

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.

Effectiveness of Mindfulness Therapy as a Complement to Pharmacological Treatment in the Control of Blood Pressure in Hypertensive Adults: A Quasi-Experimental Study in Lima, Peru.

To evaluate the effectiveness of mindfulness therapy as an adjunct to pharmacological treatment for improving blood pressure (BP) control in hypertensive adult patients at a health center in Lima, Peru. This study employed a quasi-experimental design with a quantitative and longitudinal cohort approach. The participants included 50 adults who were diagnosed with hypertension and who regularly attended the health center in the Villa El Salvador district of Lima, Peru. The data were collected using three instruments: the Depression Anxiety Stress Scale (DASS 21), validated in Peru; a sociodemographic questionnaire; and a BP recording sheet. The Wilcoxon test was utilized to assess the effectiveness of mindfulness therapy on BP control, while the nonparametric Friedman test was used to evaluate the effectiveness of mindfulness therapy considering confounding factors. Therapy resulted in favorable outcomes for BP control. After eight sessions, the average systolic BP decreased from 122.8 to 115.0mm Hg (a reduction of 7%), and the average diastolic BP decreased from 78.1 to 69.9mm Hg (a reduction of 11%). Mindfulness is an effective complementary therapy for controlling BP in hypertensive adults. It also helps reduce confounding factors such as stress, anxiety, and depression.

CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury.

Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear. The expression of FAP (fibroblast activation protein) was studied in mouse hearts after I/R. FAP CAR-Ms were generated to target FAP-expressing cardiac fibroblasts in mouse hearts after I/R. The phagocytosis activity of FAP CAR-Ms was tested in vitro. The efficacy and safety of FAP CAR-Ms in treating I/R were evaluated in vivo. FAP was significantly upregulated in activated cardiac fibroblasts as early as 3 days after I/R. Upon demonstrating their ability to engulf FAP-overexpressing fibroblasts, we intravenously administered FAP CAR-Ms to mice at 3 days after I/R and found that FAP CAR-Ms significantly improved cardiac function and reduced myocardial fibrosis in mice after I/R. No toxicities associated with FAP CAR-Ms were detected in the heart or other organs at 2 weeks after I/R. Finally, we found that FAP CAR-Ms conferred long-term cardioprotection against I/R. Our proof-of-concept study demonstrates the therapeutic potential of FAP CAR-Ms in alleviating myocardial I/R and potentially opens new avenues for the treatment of a range of heart diseases that include a fibrotic phenotype.

Applicability of VICTORION-1 PREVENT Criteria to the US Population

Abstract Background VICTORION-1 PREVENT (V-1P) is an ongoing randomized clinical trial comparing inclisiran sodium 300mg every six months with placebo for primary prevention in patients with high cardiovascular (CV) risk. Purpose We evaluated the generalizability of V-1P trial enrollment criteria to the US population to understand the demographic and CV health characteristics of the trial target population. Methods We included data from the National Health and Nutrition Examination Survey (N=25,531, 2015-March 2020), a nationally representative sample of the US population. Enrollment criteria similar to V-1P were applied. Nonpregnant adults 40-79 years with low-density lipoprotein cholesterol (LDL-C) of 70-189 mg/dL were included. 10-year risk for CV disease was determined using the American Heart Association race-free 10-year PREVENT risk equations. Individuals with 10-year risk >20% or 7.5%-19.9% with two risk enhancing factors at baseline were included. Risk enhancing factors included elevated high sensitivity C-reactive protein (≥2 mg/L), inflammatory arthritis, estimated glomerular filtration rate <60 ml/min/1.73 m2, metabolic syndrome, or early family history of CV disease. Patients with history of atherosclerotic CV disease or liver disease were excluded. Estimates of demographics and health characteristics were nationally representative using survey weights. Results Among US adults, 21,576,506 (standard error [SE]: ±1,258,255) meet eligibility criteria for V-1P (weighted estimate). This represents 8.8% of all US adults or 15.1% of US adults 30-79 years. The V-1P eligible population had a mean age of 65.3 years (SE: ±0.5 years), and 55.0% (SE: ±2.5%) were female. Compared with the US adult population (≥18 years), V-1P eligible population had a higher mean body mass index (32.6 ± 0.3 kg/m2 vs 29.5 ± 0.2 kg/m2) and higher rates of obesity (61.0% ± 2.1% vs 40.0% ± 1.1%) (Table). V-1P eligible population also had higher mean systolic blood pressure (133.9 ± 1.0 mmHg vs 121.7 ± 0.3 mmHg), similar mean diastolic blood pressure (72.6 ± 0.8 mmHg vs 71.8 ± 0.2 mmHg), and higher rates of hypertension (85.8% ± 2.0% vs 45.9% ± 1.1%). Mean hemoglobin A1c percent (6.3 ± 0.1 vs 5.7 ± 0.02), fasting blood sugar (127.7 ± 1.9 mg/dL vs 109.2 ± 0.6 mg/dL), and diabetes rates (39.7% ± 2.6% vs 13.1% ± 0.7%) were higher in the V-1P eligible population. Mean low-density lipoprotein cholesterol (115.8 ± 1.5 mg/dL vs 110.2 ± 0.8 mg/dL) and fasting triglycerides (137.6 ± 5.0 mg/dL vs 110.4 ± 1.7 mg/dL) were higher, while mean high-density lipoprotein cholesterol was lower (49.9 ± 0.8 mg/dL vs 54.8 ± 0.4 mg/dL). The distribution of key CV risk factors is shown in the Figure. Conclusion V-1P enrollment criteria apply to many patients. These patients have significant cardiometabolic risk factor burden, and effective preventive therapies could have substantial health impact.

Spleen-Targeted mRNA Vaccine Doped with Manganese Adjuvant for Robust Anticancer Immunity In Vivo.

The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn2+) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this "All-in-One" mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.

Association between preprocedural thromboembolic or bleeding events under oral anticoagulation therapy and mid-term outcomes after percutaneous left atrial appendage closure

Abstract Background Currently, no consensus has been established on the most effective antithrombotic therapy to prevent thromboembolic and bleeding events in patients undergoing percutaneous left atrial appendage closure (LAAC). Methods We retrospectively investigated the incidence of device-related thrombosis (DRT), thromboembolic events, and bleeding events in patients who underwent LAAC from September 2019 to October 2022. After categorizing patients into groups based on preprocedural thromboembolic or bleeding events under oral anticoagulation (OAC) therapy, we compared the incidence of DRT and prognosis according to the postprocedural antithrombotic therapy. Results In patients who received the conventional antithrombotic therapy (OAC with and without single antiplatelet therapy for 45 days after LAAC and dual-antiplatelet therapy from 45 days to 6 months followed by single antiplatelet therapy), preprocedural thromboembolic events despite OAC were independently associated with DRT or postprocedural thromboembolic events at the 3-year follow-up (hazard ratio [HR] 4.55; 95% confidence interval [CI] 1.32–15.6; P = 0.016), whereas preprocedural bleeding events were independently associated with postprocedural bleeding events (HR 8.01, 95% CI 1.45–58.3; P = 0.036). Continuation of OAC for 12 months among patients who developed preprocedural thromboembolic events during OAC significantly decreased the incidence of DRT or postoperative thromboembolic events (P = 0.002) with no increase in the bleeding events (P = 0.522). Conclusions Preprocedural thromboembolic and bleeding events can predict adverse events after LAAC with conventional antiplatelet-based antithrombotic therapy. Patients who develop thromboembolic events under continuous OAC may benefit from continuous OAC for 1 year after LAAC.

Large-scale proteomic profiling reveals characteristic HIV-specific druggable protein signatures associated with incident heart failure

Abstract Background Compared with the general population, persons with HIV suffer from an augmented risk of both systolic and diastolic heart failure despite effective antiretroviral therapy [1]. While inflammatory and coagulation markers are thought to be involved in this increased risk, other contributing mechanisms, such as pro-inflammatory protein networks, remain to be elucidated. Purpose To identify novel protein predictors of incident heart failure events in the longitudinal Veterans Aging Cohort Study Biomarker Cohort of United States Veterans with HIV (PLWH; n = 1525) and without HIV (PWoH; n = 853) and to assess the functional relatedness of these proteins in PLWH. Methods We characterized the plasma proteome of PLWH and PWoH using an aptamer-based platform and assessed univariable associations with incident heart failure. Druggable proteins were identified using the Therapeutic Target Database [2]. We built a protein interaction network querying significant proteins (q-value <0.05) using Cytoscape for the Retrieval of Interacting Genes/Proteins (STRING) database [3]. To focus on densely connected core proteins, we used the mcl clustering method and identified a subnetwork of approximately 77 proteins. Over-representation analysis was performed for the core network by identifying enriched gene sets using Gene Ontology biological processes and WikiPathways. Final results are filtered based on a false discovery rate (FDR) threshold of 0.05. Results Of 4926 plasma proteins, 441 proteins in all PLWH and 706 in those with well-controlled HIV (viral load <200 copies/mL) were significantly associated with incident heart failure, compared with only 142 among PWoH (Figure 1A). Of the top 50 proteins most significantly associated with heart failure, 21 were druggable in PLWH and 14 in PWoH; only 5 druggable markers were shared, while 16 were unique to HIV (Table 1). Pleiotrophin, a pro-angiogenic, pro-inflammatory cytokine that induces tumor necrosis factor- (TNF) α, interleukin- (IL) 1β, and IL-6 expression and has been implicated in cardiomyocyte apoptosis [4,5], had the highest hazard ratio (HR) for incident heart failure (HR = 4.7; p = 1.6E-20; q = 1.7E-18) in PLWH. The most significant enriched protein pathway included 36 genes involved in chemotaxis (FDR = 1.3E-30); 3 of the 21 druggable targets (pleiotrophin, ephrin-A5, and ephrin type-A receptor 2) were represented in this pathway (Figure 1B). Ephrin signaling pathways, which are involved in cell adhesion, differentiation, and proliferation [6], have not previously been implicated in heart failure, nor in HIV. Subnetwork analysis of druggable proteins demonstrated that ephrin-signaling, IL-15, and TNF pathways were functionally interconnected (Figure 1C). Conclusions Our findings indicate that there may be unique pro-inflammatory pathways characteristic of HIV-associated cardiomyopathy that merit further study as dedicated pharmacologic targets and/or risk markers in this population.

Current Status of Immunotherapy in Management of Small Bowel Neuroendocrine Tumors.

This study aims to present the current landscape of immunotherapy in the management of small bowel neuroendocrine tumors and identify ongoing and future targets for improved response. Somatostatin analogs and mTOR inhibitors remain cornerstones of non-surgical treatment, and applications of PRRT in SBNET are promising. Several efforts to replicate the success of immunotherapies in other solid tumors have been attempted in SBNET, with limited responses observed with current immune targets, such as PD-1/PD-L1 and CTLA-4. Epigenetic analyses have suggested a potential role for methylation and histone acetylation in SBNET tumorigenesis that warrant greater exploration. While the incidence of SBNET continues to increase, the number of effective therapies is few. Further elucidation of targetable components of the SBNET immune microenvironment with greater modulatory effects is necessary to improve outcomes in this growing patient population.