Effective Therapy Research Articles

Construction of machine learning models of lipid metabolism-related long non-coding RNA in lung adenocarcinoma is associated with microenvironmental heterogeneity and immunotherapy

Using various bioinformatics tools, we constructed a prognostic model integrating the expression profiles of lipid metabolization-related lncRNAs and clinical features. Our study discovered that various lipid metabolism-related lncRNAs were linked to the prognosis of lung adenocarcinoma. The link between immune cell infiltration in the tumour microenvironment and the expression level of lncRNAs involved with lipid metabolism was also investigated. Our findings suggest that there is a complex interplay between lipid metabolism, microenvironmental heterogeneity, and immunotherapy in lung adenocarcinoma. Furthermore, the study has significant clinical implications for the development of effective therapies for patients with lung adenocarcinoma by investigating the potential of these lncRNAs as biomarkers for anticipating the response to immunotherapy. Finally, our study emphasises the significance of continued analysis of lncRNAs associated with lipid metabolism in tumours to better understand the mechanisms behind the incidence and progression of lung adenocarcinoma. Several of the strengths of our work are the extensive analysis of the relationship between lipid metabolism and lncRNAs in lung adenocarcinoma and the utilization of a sizable sample size from the TCGA-LUAD cohort. However, there are also some limitations. Firstly, the mechanisms of how these lncRNAs interact with lipid metabolism pathways and immune response require further investigation. Secondly, our study was based on bioinformatics analysis and lacked experimental verification. Finally, our study was limited to the TCGA-LUAD cohort and further validation using other independent cohorts is required. In conclusion, our study provides a comprehensive and systematic analysis of lncRNAs associated with lipid metabolism in lung adenocarcinoma. Lung cancer patients may benefit from using identified lncRNAs as therapeutic targets and prognostic biomarkers. Validating these findings and confirming the potential therapeutic applications of these lncRNAs will require more mechanistic research.

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.

Gallic acid enhances GVL effects of T cells without exacerbating GVHD after haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for acute myeloid leukaemia (AML), predominantly due to its potent graft-versus-leukaemia (GVL) effect. However, leukaemia relapse remains a major obstacle to the success of allo-HSCT. In this study, we demonstrated that gallic acid (GA), a natural dietary compound, can enhance T-cell-mediated GVL effects both invitro and invivo. GA-treated T cells exhibited increased activation and elevated secretion of cytotoxic cytokines, leading to the apoptosis of AML cells in co-culture systems invitro. In a non-irradiated leukaemia mouse model, we showed that GA treatment prolonged the survival of leukaemic mice and reduced leukaemia cell infiltration. Further analysis revealed that GA treatment increased T-cell activation and tumour necrosis factor-α secretion. Moreover, integrated transcriptomic and proteomic analyses indicated that GA augments T-cell-mediated GVL effects through the activation of the MAPK and NF-κB pathways. Blocking these pathways individually diminished the protective effect of GA in AML model mice. Importantly, GA administration did not accelerate graft-versus-host disease (GVHD) progression in a mouse model. In conclusion, our study revealed that GA can enhance the GVL effects of T cells without exacerbating GVHD, offering insights into its potential to improve outcomes for patients after HSCT.

Contemporary Approaches to Wound Burn Healing

The World Health Organization (WHO) reports that over 11 million individuals get burns annually, resulting in 180,000 fatalities. A burn is a condition resulting by heat, chemical agents, electrical currents, or other forces that inflict tissue damage. Burns primarily impact the skin, however they may also include deeper structures, including bones and muscles. Upon combustion, the skin forfeits its primary functions, including protection against the external environment, infections, moisture evaporation, and thermal regulation. Based on the burn's stage, the patient's health, and the burn's etiology, it is essential to choose the most suitable therapy. Personalization and interdisciplinary teamwork are essential for the effective therapy of burn victims. This thorough study compiles and examines the existing treatment modalities, emphasizing current advancements in topical therapies, wound debridement, dressings, skin grafting, nutritional support, pain management, and scar tissue therapy.

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.

Prevalence of metabolic dysfunction-associated steatotic liver disease in people living with HIV and on antiretroviral treatment: A systematic review and meta-analysis protocol.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common hepatic condition globally. The prevalence of MASLD continues to increase, paralleling the consistent rising rates of risk factors such as obesity and type 2 diabetes. Literature suggests that human immunodeficiency virus-infected (HIV-infected) individuals may have an increased risk of developing MASLD due to a complex interplay of factors including antiretroviral therapy. Since the development and widespread use of effective antiretroviral therapy (ART), HIV-induced liver disease has continued to be the predominant cause of liver-related morbidity and mortality. This protocol serves to narrate the methods that will be employed in conducting the published literature search for the systematic review and meta-analysis which will report on the global prevalence of MASLD on people living with HIV and on ARV treatment. The search of literature will be done using search engines or electronic databases including PubMed, Google Scholar, African Journal Online, and ResearchGate. Specific keywords will be used to search literature that has reported on the prevalence of MASLD among HIV patients receiving antiretroviral treatment, this will ensure the reproducibility of the study. Cross-sectional and longitudinal observational studies, retrospective cohort studies, clinical trial studies, meta-analyses, and systematic reviews that were published in the English language from 1990 to 2024 will be included. Animal studies will be excluded. Three independent reviewers will conduct the selection process and select studies that meet the eligibility criteria. A quality assessment tool, Downs and Blacks will be used to assess the risk of bias of the selected studies. A review manager will be used for meta-analysis of collected data and the Grading of Recommendations Assessment, Development, and Evaluation tool will assess the strength of evidence. The review will not require ethical clearance as it will only include data that is publicly available in published reports. The results of this review will be disseminated through publications. This study is registered with PROSPERO (CRD42024516814).

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.

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.

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.

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.

Different treatments in chronic thromboembolic pulmonary hypertension: comparison of strategies in the Italian centre real-world experience

Abstract Rationale Pulmonary endarterectomy (PEA) has been the most effective therapy for chronic thromboembolic pulmonary hypertension (CTEPH). However, there is a substantial proportion of patients declared not operable in whom other treatment strategies are available: medical therapy and balloon pulmonary angioplasty (BPA). We aimed to compare different CTEPH treatment strategies effect in real-world setting. Methods All CTEPH referred to our Centre were included. We compare the short-term clinical, functional, exercise and haemodynamic effect of medical therapy (irrespective of subsequent treatment strategies), PEA and BPA (irrespective of previous/subsequent treatment strategies); we also describe the long-term outcome of the different patient groups. Results We included 467 patients (39% were treated only with medical therapy, 43% underwent PEA, 13% underwent BPA and 5% were not treated with any therapy). Patients treated only with medical therapy were the oldest; compared to patients undergoing PEA, they had a lower exercise capacity, a higher risk profile and gained a lower haemodynamic, functional and survival benefit from the treatment. Patients undergoing BPA had a lower haemodynamic improvement but a comparable functional, exercise and risk improvement and a similar survival compared to patients undergoing PEA; their survival is anyway better than patients undergoing only medical treatment. Untreated historical control patients had the worst survival. Conclusions We confirm the superiority of PEA compared to any alternative treatment in CTEPH and we observe that BPA, in patients declared not operable or with persistent/recurrent PH after PEA, leads to a better outcome than medical therapy alone.

Comparative Analysis of Osteoarthritis Therapeutics: A Justification for Harnessing Retrospective Strategies via an Inverted Pyramid Model Approach

In this review, we seek to explore two distinct approaches to the clinical management of OA: a prospective approach, addressing primarily one’s genetic predisposition to OA and generating early intervention options, and the retrospective approach, aimed at halting or reversing OA progression post-symptom onset. The clinical management of OA remains challenging, largely due to the limited availability of preventative treatments and failure of existing therapies to modify or reverse the underlying pathophysiology. The prospective approach involves the identification of genetic markers associated with OA and utilizes in vitro and in vivo models to characterize the underlying disease mechanism. Further, this approach focuses on identifying genetic predispositions and unique molecular subtypes of OA to develop individualized treatment plans based on patient genotypes. While the current literature investigating this strategy has been notable, this approach faces substantial challenges, such as extensive time burdens and utilization of extensive genetic testing that may not be economically feasible. Additionally, there is questionable justification for such extensive investigations, given OA’s relatively low mortality rates and burden when contrasted with diseases like specific forms of cancer, which rely heavily on the prospective approach. Alternatively, the retrospective approach primarily focuses on intervention following symptom onset and aims to utilize novel therapeutics to slow or reverse the inflammatory cascade typically seen in disease progression. These treatments, like Hippo pathway inhibitors, have shown initial promise in halting OA progression and alleviating OA symptomology by modulating cellular processes to preserve articular cartilage. In comparison to the prospective approach, the retrospective strategy is likely more cost-effective, more widely applicable, and does not necessitate thorough and invasive genetic screening. However, this approach must still be weighed against the typical natural history of disease progression, which frequently results in total knee arthroplasty and unacceptable outcomes for 15–20% of patients. From a comparative analysis of these two approaches, this review argues that the retrospective strategy, with ideally lower time and economic burden and greater accessibility, offers a more reasonable and effective solution in the context of OA management. Using a similar approach to other management of chronic diseases, we suggest an “Inverted Pyramid” model algorithm, a structured research and development regimen that prioritizes generating widely effective therapies first, with subsequent refinement of treatments based on the development of patient resistance to these therapies. We argue that this strategy may reduce the need for total knee arthroplasty while improving patient outcomes and accessibility.

Transcatheter mitral edge-to-edge repair in patients with prior cancer diagnosis

Abstract Background Transcatheter edge-to-edge repair (TEER) is a safe and effective therapy for mitral regurgitation (MR). Despite oncological patients have an increased risk of functional and organic MR due to cardiotoxic treatment exposure, the use of TEER in this setting remains underexplored. Purpose To evaluate the safety and efficacy of TEER in patients with MR and prior cancer diagnosis. Methods Observational, retrospective, multicenter study based on the Spanish national TEER registry. Patients from those centers providing oncological specific data were included in this analysis. Patients with and without history of cancer were propensity score matched (PSM) in a 1:1 ratio. The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 1 year. Results A total of 1237 patients with MR who underwent TEER between 2010 and 2022 across 14 centers in Spain were included. The mean age was 73 ± 11 years and 34% were female. MR etiology was functional in 58%, organic in 27% and mixed in 15%. Of them, 164 had a history of cancer. Baseline characteristics of the unmatched cohort are shown in Figure 1. Median time from cancer diagnosis to TEER was 7 (3-17) years and the most common cancer types were breast (20%), leukemia/lymphoma (19%) and colorectal (11%). PSM resulted in 163 pairs with a good balance of baseline characteristics (Figure 1). Procedural success rate was high and similar between the groups (93% vs 96%, p=0.217), as were periprocedural complication rates (Figure 2A). The primary efficacy endpoint occurred in 38 (23%) patients in the cancer group and 29 (18%) patients in the control group (Hazard ratio 1.36, CI 95% 0.84 to 2.20, p= 0.214) (Figure 2B). Conclusion In routine practice, a notable proportion of patients undergoing mitral TEER have a prior cancer diagnosis. Immediate and 1-year clinical outcomes appear comparable to those observed in non-cancer patients. These findings suggest that mitral TEER should not be withheld from this growing population.