Potential Therapy Research Articles

Lysosome-Mitochondria Cascade Targeting Nanoparticle Drives Robust Pyroptosis for Cancer Immunotherapy.

The subcellular distribution of cargoes plays a crucial role in determining cell fate and therapeutic efficacy. However, achieving the precise delivery of therapeutics to specific intracellular targets remains a significant challenge. Here, we present a trimodular and acid/enzyme-gated nanoplatform (TAEN) that undergoes disassembly within acidic endosomes and then is cleaved by lysosomal cathepsin B to facilitate efficient and targeted transport of released cargoes into mitochondria compartments. By utilizing this nanovehicle, we successfully achieve selective sorting of photosensitizer molecules into mitochondria with a colocalization coefficient of up to 0.98, leading to the generation of reactive oxygen species stress specifically within the mitochondria for potent pyroptosis-based cancer therapy. The induction of mitochondrial stress triggers the intrinsic apoptotic pathway as well as caspase-3/gasdermin-E (GSDME) cascade, resulting in an enhanced cancer cell killing efficacy by nearly 2 orders of magnitude as compared to lysosomal stress. Furthermore, due to its superior capability to stimulate both innate and adaptive immune responses, our mitochondria-sorted nanophotosensitizer exhibits robust antitumor immune efficacy in multiple tumor-bearing mice models. This study not only provides insights into engineering nanomedicines for subcellular targeted delivery but also offers a valuable toolkit for advanced research in the field of nanobiology at subcellular resolution.

Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities

Chimeric antigen receptor (CAR)-T-cell therapy has revolutionized cellular immunotherapy, demonstrating remarkable efficacy in hematological cancers. However, its application in solid tumors faces significant challenges, including limited T-cell infiltration and tumor-induced immunosuppression. Given the prominent role of macrophages in the tumor microenvironment, their phenotypic plasticity and inherent antitumor properties, such as phagocytosis, offer a promising avenue for therapeutic intervention. This study focuses on the development of a second generation of CAR macrophages (CAR-Ms). We elucidated the role of the proprotein convertase furin in macrophages, demonstrating its overexpression in the presence of tumor cells. Importantly, furin inhibition maintains a proinflammatory macrophage phenotype, potentially redirecting them towards an antitumor state. Compared to furin-expressing counterparts, furin-inhibited CAR-Ms exhibited heightened antitumor phagocytic activity against breast cancer cells and ex vivo patient-derived tumoroids. Notably, they sustained a persistent proinflammatory profile, indicative of enhanced tumoricidal potential. Additionally, furin-inhibited CAR-Ms secreted factors that promote T-cell activation, offering a means to modulate the tumor microenvironment. In summary, our work highlights the translational potential of furin-inhibited CAR-Ms as a potent cellular therapy to mitigate macrophage exhaustion within the tumor environment. By capitalizing on macrophage-mediated antitumor responses, these findings pave the way for the development of second-generation CAR-M therapeutic strategies tailored for solid tumors.

Necroptosis and autophagy in cisplatinum-triggered nephrotoxicity: Novel insights regarding their prognostic and diagnostic potential

Necroptosis is an innovative class of programmed autophagy (Atg) and necrosis; considered as a type of homeostatic housekeeping machinery that have observed an escalating concern due to its power in alleviating Cisplatinum-induced nephrotoxicity. This article elucidated in details the prospective role of both autophagy and necroptosis on Cisplatinum-triggered nephrotoxicity and investigating more potent therapy via lactoferrin and Ti-NPS conjugation. Cisplatinum is a commonly used chemotherapeutic drug; one of the limiting adverse actions of cisplatinum is renal toxicity. Upon cisplatinum administration, autophagy is highly stimulated in the kidney to shield against nephrotoxicity. Atg is a lysosomal degradation process which discards detorirated proteins to retain cell homeostasis. This article summarizes necroptosis progress in reconizing cisplatinum nephrotoxicity and debates how this progress can help in discovering more potent therapy via lactoferrin and Ti-NPS conjugation via monitoring autophagy and apoptotic biomarkers X-box-binding protein 1 (XBP), C/EBP homologous protein (CHOP), hypoxanthine phosphoribosyltransferase-1 (HPRT), FKBP prolyl isomerase 1B (FKBP), Cellular myelocytomatosis oncogene (C-myc), tumor suppressor gene (P53) and tumor necrosis factor (TNF-α). Cisplatinum nephrotoxicity was conducted in rat model via an oral dose of (2mg/kg BW) for one month furthermore a comparative study was conducted among TiNPs-loaded Cisplatinum and Lactoferrin loaded Cisplatinum. Loaded drug delivery system counteracted Cisplatinum triggered nephrotoxicity via controlling autophagy and apoptotic XBP, CHOP, HPRT, FKBP, C-myc, P53 and TNF-α signaling pathway.

Синергическая эффективность низкоинтенсивной экстракорпоральной ударно-волновой терапии и обогащенной тромбоцитами плазмы при эректильной дисфункции

Erectile dysfunction (ED), an unusual sexual condition in which the person fails to attain or sustain an erectile penis, severely impacts personal relationships, confidence, and efficiency. To date, low-intensity extracorporeal shock wave therapy (Li-ESWT) is an option to manage ED; however, it is associated with adverse events such as bruising, redness, and pain. Hence, in this study, we applied platelet-rich plasma (PRP), a blood-derived biomaterial containing cargo of growth factors, to enhance the therapeutic efficacy of Li-ESWT on ED. We assessed the synergistic effect of PRP+Li-ESWT, in which Li-ESWT was extracorporeally applied simultaneously with PRP. They were evaluated clinically at 22 ± 2, 50 ± 2 and 78 ± 2 days. Statistical analysis was performed using a non-parametric test, Friedman repeated measures as an alternative non-parametric test of ANOVA test. The international index of erectile function (IIEF-5) and erection hardness score (EHS) were recorded. IIEF-5 score in the pre-treated group was 8.36 ± 1.44. After 22 ± 2 days of synergistic PRP+Li-ESWT treatment, the score was 14.45 ± 2.12 (p < 0.028). This score further increased to 15.45 ± 1.93 (p < 0.008) and 16.18 ± 1.48 (p < 0.001) after 50 ± 2 days and 78 ± 2 days of treatment, respectively. The mean pre-treated EHS was 1.64 ± 0.20 (p < 0.002), which increased to 2.81 ± 0.26 (p < 0.002), 3.09 ± 0.25 (p < 0.0002) and 3.18 ± 0.12 (p < 0.000) on day 22 ± 2, 50 ± 2 and 78 ± 2 days, respectively. Conclusively, our study demonstrated potent synergistic therapy of PRP+Li-ESWT in ED treatment by improving IIEF-5 and EHS scores. However, extensive mechanism-based clinical studies are needed to reach a consensus.

Innovations in mRNA-based cancer immunotherapy: Challenges and future directions

Messenger RNA (mRNA) vaccines have quickly become a potent tool in cancer immunotherapy, with the potential to personalise cancer treatment and get around many of the drawbacks of conventional therapies. With an emphasis on their processes, technological developments, and clinical applications, this study examines the scientific breakthroughs and difficulties surrounding mRNA cancer vaccines. We begin by investigating the ways in which mRNA vaccines work to stimulate the immune system, encode antigens specific to tumours, and elicit a potent anti-tumor response. We also look at the variety of mRNA vaccines which are currently being deployed and emphasize their successes in clinical studies, especially when combined with immune checkpoint inhibitors. The effectiveness and safety of these vaccines have been significantly increased by technological developments, such as enhancements in mRNA stability, design, and delivery systems (such as lipid nanoparticles and polyplexes). Emerging technologies like circular RNA and self-amplifying present promising opportunities for enduring and more potent therapies. But there are still limitations with mRNA vaccines, such as stability, immunogenicity, degradation, and effective in vivo delivery. Concerns about possible adverse effects and safety in long-term applications are also covered in this review. Despite these obstacles, novel approaches are being developed to boost antigen expression, optimize delivery systems, and improve mRNA stability, establishing mRNA vaccines as a crucial component of tailored cancer immunotherapy. These developments provide the foundation for upcoming advances in mRNA vaccine technology and represent a major breakthrough in the fight against cancer.

Resurrecting p53 by an Artificial Nano-Protein for Potent Photodynamic Retinoblastoma Therapy.

The treatment of retinoblastoma (RB), a formidable eye cancer that affects infants and children, is not only aimed at saving lives but at preserving ocular function, maintaining optimal visual acuity, and enhancing the overall quality of life. Photodynamic therapy has already been established as a secure and dependable therapeutic modality for the treatment of ocular diseases that effectively preserves ocular function; however, it fails to provide satisfactory outcomes against RB. To address this formidable challenge, groundbreaking advancement is aspired by delving into the genetic characteristics of RB, which initially involves the wild-type p53 pathway but is subsequently suppressed by MDM2 and MDMX. In this study, an artificial nanoprotein (ANP) is developed through the fusion of human serum albumin with a potent MDM2/MDMX degrading peptide and the porphyrin-photosensitizer verteporfin (VP). ANP effectively dismantles MDM2/MDMX proteins within the ubiquitin-proteasome degradation pathway and triggers VP-PDT-mediated cell death through mitochondrial impairment. Remarkably, ANP exhibited remarkable therapeutic efficacy in both subcutaneous and in situ RB mouse models, while maintaining a highly favorable biosafety profile. Collectively, ANP not only provides compelling evidence for sensitizing photodynamic RB therapy by reactivating p53, but also serves as an exceptionally potent photosensitizer with promising potential for clinical translation in RB treatment.

Lenvatinib-activated NDUFA4L2/IL33/PADI4 pathway induces neutrophil extracellular traps that inhibit cuproptosis in hepatocellular carcinoma.

Lenvatinib is a potent first-line therapy for patients with hepatocellular carcinoma (HCC), but it also increased the number of neutrophils in HCC tumor microenvironment. CitH3, MPO-DNA, elastase and MPO activity were measured for assessing neutrophil extracellular traps (NETs) in vivo and in vitro. Cell cuproptosis was assessed by measurement of copper content, FDX1, and pyruvate. The functions of lenvatinib, DNase I, interleukin 33 (IL33) neutralizing antibody and GPX4 in tumor growth were explored in mice. Lenvatinib induced NETs in the HCC tumor microenvironment via HCC cells, but not through the direct stimulation of neutrophils. In addition, NET clearance by DNase I improves the efficacy of lenvatinib therapy in HCC mouse models. Mechanistically, lenvatinib promoted the expression and secretion of IL33 by HCC cells that triggered NET formation. Moreover, IL33 knockdown in Hepa1-6 cells improved lenvatinib efficacy in Hepa1-6-bearing HCC model mice and reduced NET formation in the tumor microenvironment. Subsequently, lenvatinib increased IL33 production by increasing the NDUFA4L2 expression in HCC cells. Furthermore, we found that IL33 triggered NET formation in neutrophils by increasing the protein expression of PADI4 via the Akt/mTOR signaling pathway. Rapamycin inhibition of mTOR reduced PADI4 expression and NET formation. Consistently, PADI4 inhibition by the selective PAD4 inhibitor GSK484 hydrochloride (GSK484) improved lenvatinib response to HCC therapy. Importantly, NETs contribute to lenvatinib resistance by inhibiting cuproptosis, but not apoptosis, pyroptosis, or ferroptosis in HCC cells. Treatment with GSK484 reversed the inhibitory effects of NETs on cuproptosis and sensitized the HCC cells to lenvatinib. Our study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resistance in HCC.

The Efficacy of Metacognitive Therapy on Social Avoidance and Distress, and Academic Persistence Among Students with Exam Anxiety

Background: Attendance in educational settings such as schools is often accompanied by varying levels of anxiety for many students. One of the most significant types of anxiety in educational environments is exam anxiety. Objectives: This study aimed to investigate the efficacy of metacognitive therapy on social avoidance, distress, and academic persistence among students with exam anxiety in 2023. Methods: This quasi-experimental study utilized a pretest-posttest design to assess the efficacy of metacognitive therapy for female students with exam anxiety. All female second-grade high school students in Ahvaz city who reported experiencing exam anxiety during the 2022 - 2023 academic year were included in the study sample. A purposive sample of 36 female students was randomly divided into two groups: An experimental group receiving metacognitive therapy and a control group. The experimental group participated in seven 60-minute sessions of metacognitive therapy, conducted twice a week. The control group did not receive any intervention during the study period. The Social Avoidance and Distress Scale (SADS) and Academic Persistence Scale (APS) were administered to both groups before and after the intervention. Data were analyzed using analysis of covariance to control for baseline differences. Results: Metacognitive therapy was effective in reducing social avoidance and distress, as well as in improving academic persistence in high school students (P < 0.001). Specifically, the mean social avoidance and distress score decreased significantly from 19.67 ±1.68 to 10.11 ±2.13 in the metacognitive therapy group. Additionally, the mean academic persistence score increased significantly from 9.39 ±1.78 to 23.72 ±3.10 in the metacognitive therapy group. Conclusions: Metacognitive therapy effectively reduced social avoidance and distress while increasing academic persistence in female students with exam anxiety. This study highlights the therapy's potential as a valuable intervention for improving the overall well-being and academic performance of students facing similar challenges.

Stem cell exosomes: New hope for recovery from diabetic brain hemorrhage.

Recent advancements in stem cell-derived exosome therapy for diabetic brain hemorrhage are discussed in this editorial, which highlights this therapy's potential for revolutionizing diabetic brain hemorrhage treatment. The paper offers compelling evidence that exosomes can effectively reduce neuroinflammation and promote recovery from diabetic brain hemorrhage. Although these findings are promising, further research is warranted to fully understand the underlying mechanisms and to validate the therapeutic potential of exosomes in clinical settings. The findings of this study indicate that continued exploration should be conducted into exosome-based therapies as a novel approach to managing diabetic brain hemorrhage.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Educational competencies for telehealth physical therapy: Results of a modified Delphi process.

Telehealth is becoming more prevalent in physical therapy, involving a whole host of clinical services. These services are often provided without structured training in telehealth, and no formal curricula currently exist for this purpose. To develop a set of educational competencies (ECs) to guide instruction of telehealth-related skills in entry-level programs (i.e., Doctor of Physical Therapy), existing programs (i.e., residencies and fellowships), and potential future post-graduate programs specific to telehealth physical therapy. Physical therapists and physical therapist assistants from diverse geographic locations and practice areas were invited to participate on an expert panel. A modified Delphi process was then used to evaluate the acceptability of draft ECs gathered from the extant literature by a steering group. Draft ECs were presented to the expert panel on a questionnaire, which asked expert participants to rate each draft EC according to applicability and clarity. Draft ECs were accepted if they met a priori established criteria for acceptability and clarity. Unendorsed ECs were revised by the steering group according to open-ended comments from respondents and presented during a subsequent round. Three rounds of surveys were undertaken. Thirty-eight participants formed the expert panel; 38 participants completed the Round 1 survey, 28 participants completed the Round 2 survey, and 24 participants completed the Round 3 survey. Delphi group members approved 48 ECs in the first round, 23 ECs in the second round, and 2 ECs in the third round. There were 4 ECs that remained unendorsed after the modified Delphi process. Endorsed ECs spanned 7 conceptual areas. Distinct sets of ECs characterized expected end points of first professional degree, existing residency and fellowship, and potential future telehealth physical therapy post-graduate program. Consensus-based ECs identified in this study may guide instruction in knowledge and skills relevant to physical therapy telehealth.

Changes in Glycosylation on the Cell Surface Result in Highly Potent and Long-Lasting Allogeneic CAR-T Therapy in Patients

Changes in Glycosylation on the Cell Surface Result in Highly Potent and Long-Lasting Allogeneic CAR-T Therapy in Patients

Cancer and Autoimmune Diseases as Two Sides of Chronic Inflammation - and the Method of Therapy.

Chronic inflammation is associated with a prolonged increase in various inflammatory factors. According to clinical data, it can be linked with both cancer and autoimmune diseases in the same patients. This raises the critical question of how chronic inflammation relates to seemingly opposing diseases - tumors, in which there is immunosuppression, and autoimmune diseases, in which there is over-activation of the immune system. In this review, we consider chronic inflammation as a prerequisite for both immune suppression and an increased likelihood of autoimmune damage. We also discuss potential disease-modifying therapies targeting chronic inflammation, which can be helpful for both cancer and autoimmunity. On the one hand, pro-inflammatory factors persisting in the areas of chronic inflammation stimulate the production of anti-inflammatory factors due to a negative feedback loop, eliciting immune suppression. On the other hand, chronic inflammation can bring the baseline immunity closer to the threshold level required for triggering an autoimmune response using the bystander activation of immune cells. Focusing on the role of chronic inflammation in cancer and autoimmune diseases may open prospects for more intensive drug discovery for chronic inflammation.

Short review of diagnosis and revascularization for thromboangiitis obliterans

This short review focuses on recent diagnostic criteria and outcomes after revascularization in thromboangiitis obliterans (TAO, Buerger disease). The incidence and disease have decreased worldwide, including in Eastern Asia, except in regions where inexpensive tobacco products are widely consumed. However, the global epidemiology remains unclear due to the lack of definitive diagnostic biomarkers. Clinical diagnostic criteria are also not standardized but have been updated according to medical advances and current patient characteristics. Notably, neither of the two recently proposed criteria excludes patients with risk factors for atherosclerosis, as these conditions may coexist with TAO and are often seen in young patients. Young age at onset is no longer essential. Objective test findings are required, and typical vascular imaging findings are essential for definitive diagnosis. Suspected diagnosis is allowed for patients who have difficulty undergoing tests. Revascularization for TAO is typically directed at below-the-knee lesions, which are characterized by poor distal runoff, associated inflammation, and prone to spasm. Recently, both bypass surgery (BS) and endovascular treatment (EVT) have shown improved outcomes. Two studies on BS published after 2000 reported primary patency rates exceeding 50% at 3 years. A systematic review and meta-analysis of EVT, which mostly consisted of balloon angioplasty, revealed that multiple reinterventions were often required; however, the secondary patency and limb salvage rates at 3 years were comparable to those of BS. Short-term arterial patency, whether achieved by BS or EVT, can be sufficient for ulcer healing. Given that TAO is a highly thrombogenic condition, the administration of potent antithrombotic therapy during and after revascularization is crucial to maintain arterial patency.

Early Mixed Donor Chimerism is a Strong Negative Prognostic Indicator in Allogeneic Stem Cell Transplant for AML and MDS

Allogeneic bone marrow transplantation remains the most potent curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) due to the graft-versus-tumor effect provided by donor cells. Donor chimerism is utilized early after transplantation to evaluate engraftment and to monitor the persistence of donor hematopoiesis. Literature is conflicting regarding to the prognostic utility of early mixed donor chimerism, chimerism kinetic patterns as well as factors associated with it and we sought to clarify this uncertainty. In this single-centre retrospective analysis, 141 adults aged 18 years of age or older with AML (n = 104) and MDS (n = 37) who received their first transplant from HLA matched related, matched unrelated or mismatched related (haploidentical) donors between 2016 and 2022 and had at least day 30 chimerism measured were included. Approximately 30% received post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis and 67% of subjects received reduced-intensity conditioning. Chimerism was measured using STR-PCR from unfractionated peripheral blood mononuclear cells (whole blood; WB) and CD3+ (T cell; TC) compartment at each time point. Complete donor chimerism was defined as ≥95% whereas <95% defined as mixed. Competing risk analysis was used to estimate cumulative incidence of relapse with kinetic calculations completed using an increment factor. Kaplan-Meier was used for overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to explore prognostic factors for OS and RFS. Both day 30 mixed WB and TC donor chimerism were individually associated with an increased risk of relapse and worse overall and relapse-free survival at days 30, 60 and 90 post-transplant. Day 30 mixed WB was more specific for relapse (86%), while mixed TC was more sensitive (67%). Complete day 30 chimerism had a negative predictive value of 63% and 70% and positive predictive value of 57% and 67% for WB and TC, respectively. Day 30 WB and TC donor chimerism of <88.92% and 89.29% had specificities of 79.17% and 82.19% although sensitivities only approximated 50%. Evaluating the kinetics of chimerism over the first 90 days provided additional information for prognosticating relapse than absolute chimerism values at individual time points in both WB day 30 to 90 [HR, 1.75 (95% CI, 1.04 to 2.94); P < .035] and TC day 60 to 90 [HR, 1.32 (95% CI, 1.03, 1.69); P < .29]. Twice as many patients with complete chimerism developed acute GVHD compared to those with mixed chimerism. Factors that were found to be associated with day 30 mixed TC chimerism were donor source, ATG GVHD prophylaxis, myeloablative conditioning and female sex, while only donor source was associated with mixed WB. Both TC and WB day 30 mixed chimerism were associated with an increased risk of relapse. Early mixed WB and TC chimerism is strongly associated with a worse overall and relapse-free survival. The serial measurement of chimerism early post-transplant for monitoring chimerism kinetics provides additional prognostic information beyond the absolute donor chimerism value at a single time point. Haploidentical stem cell transplants were associated with a lower likelihood of mixed chimerism than other donor sources.

Epidemiological and virological characteristics of people living with HIV on antiretroviral treatment for more than 6 months in virological failure in Brazzaville, Republic of Congo

Introduction. Virological failure is one of the main causes of failing to treat, and better management of HIV infection requires understanding and controlling the factors that contribute to this phenomenon. The main objective was to characterize the patients of the active file of the Brazzaville Outpatient Treatment Center in virological failure to identify predictive factors leading to virological failure. Methods. Conducted between June and December 2020, this was a cross-sectional study. Patients enrolled were HIV-1-infected patients from the Brazzaville Outpatient Treatment Center receiving a potent combination therapy for at least 6 months but experiencing virological failure. Viral load was measured using the automated Abbott Real-time HIV-1 m2000rt System. Sociodemographic and clinical data were collected from a computerized patient record software called Santia. For the identification of the independent predictors of virological failure, statistical analysis was performed. Results. A total of 109 patients with virological failure were recruited. The median age of the patients was 45 years (interquartile range: 37–52 years) and women were more represented (74%). More than half of the patients had World Health Organization stage IV HIV and the median duration of antiretroviral treatment was 96 months. The most followed treatment regimen was AZT+3TC+EFV (or nevirapine) with 48%, while the median viral load was 12985 copies ml−1. Conclusion. In our study, we did not identify any sociodemographic or clinical variables predictive of virological failure. However, we felt that it would be desirable to carry out a study with temporal follow-up and the possibility of sequencing in order to identify the different circulating genotypes and resistance mutations.

Afatinib boosts CAR-T cell antitumor therapeutic efficacy via metabolism and fate reprogramming

BackgroundChimeric antigen receptor T (CAR-T) cell therapy has been shown remarkable efficacy in the treatment of hematological malignancies in recent years. However, a considerable proportion of patients would experience tumor...

Full-active pharmaceutical ingredient nanosensitizer for augmented photoimmunotherapy by synergistic mitochondria targeting and immunogenic death inducing.

The precise and effective activation of the immune response is crucial in promising therapy curing cancer. Photoimmunotherapy (PIT) is an emerging strategy for precise regulation and highly spatiotemporal selectivity. However, this approach faces a significant challenge due to the off-target effect and the immunosuppressive microenvironment. To address this challenge, a nanoscale full-active pharmaceutical ingredient (API) photo-immune stimulator was developed. This formulation overcomes the limitations of PIT by strengthening the ability to penetrate tumors deeply and inducing precise and potent mitochondria-targeted dual-mode photodynamic therapy and photothermal therapy. Along with inhibiting overexpressed Hsp90, this nanosensitizer in turn improves the immunosuppressive microenvironment. Ultimately, this mitochondria-targeted PIT demonstrated potent antitumor efficacy, achieving a remarkable inhibition rate of ≥95% for both established primary tumors and distant abscopal tumors. In conclusion, this novel self-delivery full-API nanosystem enhances the efficacy of phototherapy and reprograms the immunosuppressive microenvironment, thereby holding great promise in the development of precise and effective immunotherapy.

The impact of body mass on cardiovascular outcomes in patients with acute coronary syndrome

Abstract Background Patients with acute coronary syndrome (ACS) and extreme body weights exhibit varying risks of bleeding and thrombotic outcomes. Furthermore, extreme body weights can influence the pharmacodynamic response to potent P2Y12 inhibitors (ticagrelor/prasugrel) and clopidogrel. Purpose This study aims to assess the impact of extreme body weights on cardiovascular outcomes, as well as the comparative efficacy and safety of potent P2Y12 inhibitors versus clopidogrel. Methods Data was extracted from the FORCE-ACS registry, a prospective, multicentre, registry, enrolling patients with ACS. Patients were stratified (in kg/m2) into the categories: underweight (body mass index [BMI] ≤20.0), normal weight (20.1–24.9), overweight (25.0–29.9), class 1 (30.0–34.9) and class 2 obesity (≥35.0). The primary thrombotic endpoint was major adverse cardiac events (MACE), a composite of cardiovascular death, myocardial infarction (MI), or stroke. The primary bleeding endpoint was defined as Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Cox proportional hazard models and Kaplan-Meier survival curves were used to estimate the risk of clinical events across the BMI categories. Restricted cubic splines were made to assess the continuous association of BMI with the risk of the primary endpoints, stratified for P2Y12-inhibitor therapy (potent vs. clopidogrel) and gender. Results The total included population consisted of 5,864 patients with ACS (mean age 65.2 years, 72.4% men), and were stratified into underweight (N=112 [2%]), normal weight (N=1,627 [28%]), overweight (N=2,697 [46%]), class 1 obesity (N=1,081 [18%]) and class 2 obesity (N=347 [6%]). Compared with normal weight (10.8%), the rate of primary bleeding outcome was higher in underweight (15.2%) patients, but lower in the overweight (8.9%), class 1 obesity (7.9%) and class 2 obesity (6.3%) categories. MACE occurred in 9.8% for the underweight group, 7.9% for normal weight, 7.0% for overweight, 8.0% for class, and 6.1% for class 2 obesity. After adjusting for confounding factors such as age, gender, cardiovascular risk factors, access site, and medical therapy, each unit increase in BMI was associated with a decreased bleeding risk (hazard ratio [HR] 0.97, 95% CI 0.95-0.99, p = 0.02), with no significant association found for MACE. Similar findings are demonstrated in the Kaplan Meier analysis (Figure 1A-1B). Subgroup analysis regarding bleeding risk and BMI did not show a significant interaction for potent P2Y12-inhibitor therapy versus clopidogrel and gender (P-value for interaction: 0.04 and 0.32, respectively)(Figure 2A-2D). Conclusions Our findings indicate a stronger correlation between BMI and bleeding risk compared to thrombotic risk, showing an increased risk for bleeding in patients with a low BMI. These results underscore the importance of careful monitoring and tailored interventions to mitigate bleeding risk in underweight patients.

Digital Magnetic Sorting for Fractionating Cell Populations with Variable Antigen Expression in Cell Therapy Process Development

Cellular therapies exhibit immense potential in treating complex diseases with sustained responses. The manufacture of cell therapies involves the purification and engineering of specific cells from a donor or patient to achieve a therapeutic response upon injection. Magnetic cell sorting targeting the presence or absence of surface markers is commonly used for upfront purification. However, emerging research shows that optimal therapeutic phenotypes are characterized not only by the presence or absence of specific antigens but also by antigen density. Unfortunately, current cell purification tools like magnetic or fluorescence-activated cell sorting (FACS) lack the resolution to differentiate populations based on antigen density while maintaining scalability. Utilizing a technique known as digital magnetic sorting (DMS), we demonstrate proof of concept for a scalable, magnetic-based approach to fractionate cell populations based on antigen density level. Targeting CD4 on human leukocytes, DMS demonstrated fractionation into CD4Hi T cells and CD4Low monocytes and neutrophils as quantified by flow cytometry and single-cell RNA seq. DMS also demonstrated high throughput processing at throughputs 3–10× faster than FACS. We believe DMS can be leveraged and scaled to enable antigen density-based sorting in cell therapy manufacturing, leading to the production of more potent and sustainable cellular therapies.