Multiple Clinical Trials Research Articles

Topology and Mechanism of Broadband and Fast Multi‐Characteristic Opsin for Neuromodulation

Abstract Optogenetics has enabled targeted manipulation of neural circuits, offering insights into the intricacies of brain function and paving the way for potential therapeutic applications in neurological disorders. Multi‐characteristic Opsin (MCO) is an optogenetics therapy candidate that is undergoing multiple clinical trials, including randomized control trials. However, its cellular topography and mechanism of action have remained unknown. Here, we reveal the biophysical characteristics of the MCO molecule, including its unique structure and function, using a combination of predictive protein modeling, western blotting‐based protease protection assay, and electrophysiology. MCO’s first extracellular subunit forms a cation‐channel pore, while the second subunit is partially embedded in the membrane, extending to the third intracellular cytoplasmic subunit. Functional studies using whole‐cell recordings showed that MCO is activated by broadband visible light with fast on‐off kinetics with high photosensitivity, and large dynamic range across the visible spectrum, enabling best‐in‐class light‐activation of MCO‐expressing cells. Further, multi‐electrode array recording confirmed multi‐color light‐activation of MCO‐expressing neurons in the retina. The unique topological and functional activation features of fused MCO protein represent novel findings linking the in‐vitro and in‐vivo efficacy of this opsin, which is particularly important for neuromodulation leading to vision restoration in retinal degenerative diseases and other neurological therapies.

Human pluripotent stem cell-based cardiac repair: Lessons learned and challenges ahead.

Human pluripotent stem cell-based cardiac repair: Lessons learned and challenges ahead.

Uncovering a bias in estimated treatment effects on PIRA in multiple sclerosis clinical trials.

Uncovering a bias in estimated treatment effects on PIRA in multiple sclerosis clinical trials.

Escalation and de-escalation in surgery for gastric cancer.

Surgical resection remains the cornerstone of curative treatment for gastric cancer, providing effective local control. Recent advances in systemic therapies and the development of various surgical technologies have significantly transformed treatment strategies for this disease. Multiple clinical trials of gastric cancer surgery have demonstrated that extended surgical procedures do not improve survival outcomes, whereas minimally invasive approaches-such as conventional laparoscopic and robot-assisted surgeries-, have been shown to offer favorable safety and efficacy. Moreover, with an aging patient population and substantial progress in multidisciplinary treatments, including immunotherapy, the role of surgery is being reassessed, even for patient groups deemed unsuitable for surgical intervention, such as older patients and those with initially unresectable advanced gastric cancer. Furthermore, the introduction of novel diagnostic technologies has expanded the potential for individualized surgical decision-making by enabling more precise assessment of residual diseases. This review examines the current evidence and future perspectives on gastric cancer surgery, focusing on surgical escalation and de-escalation. Four key aspects are addressed: (1) surgical approach, (2) extent of lymphadenectomy, (3) extent of resection, and (4) surgical indications. These insights aim to inform optimal surgical strategies for gastric cancer in the era of evolving treatment paradigms.

Stem Cell Therapy in Ischemic Heart Failure.

Stem cells have emerged as a promising therapeutic approach for ischemic heart failure, with multiple preclinical and clinical trials demonstrating encouraging outcomes. However, limitations and challenges encountered during clinical trials or follow-up periods hinder stem cell therapy's clinical translation for heart failure. In this review, we will elaborate on the applications of stem cell-based therapy, the main subtypes and fundamental properties of stem cells, and the mechanisms by which stem cells exert their effects in ischemic heart failure, such as remuscularization, paracrine effects, autocrine effects, and endocrine-like effects. We will also demonstrate and explain the extensive clinical trials of stem cell therapy in ischemic heart failure, focusing on safety, efficacy, and primary and secondary outcome measures. To improve transplanted stem cells' viability and retention rates, we will discuss various delivery routes and advanced biomaterials used to encapsulate stem cells, such as injectable hydrogels, cardiac patches, and cell sheets. Several challenges severely obstruct the clinical translation of stem cell therapy for ischemic heart failure, including immunological rejection, post-transplantation hypoxia, inflammatory reactions, the maturity of transplanted stem cells, and cost. Finally, we will focus on the prospects of stem cell-based therapy for ischemic heart failure, emphasizing the ongoing need for further research to address existing challenges and establish clearer avenues toward clinical application.

2061-LB: Diabetes Staging System (DSS)—A Novel Approach to Improve SGLT2i/GLP-1RA Use and CVD/CKD Outcomes in DM2

Introduction and Objective: Multiple clinical trials in DM2 patients have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like-peptide-1 agonist (GLP-1a) decrease cardiovascular disease (CVD) mortality and progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). But overall use of these agents is low (SGLT2i 11%, GLP-1a 8%) in Veterans DM2 patients with CVD/CKD. The Diabetes Staging System (DSS) is a novel DM2 staging system patterned after TNM cancer staging that links SGTLT2i/GLP-1a use to specific DM2 stages which are based on number of macrovascular/microvascular complications. Methods: A 6-month pilot study implemented DSS in VA primary care clinics in the Greenville VA. Study visits were at baseline and 6-months. Primary outcome: % of Veteran DM2 patients w/ CVD/CKD on SGLT2i/GLP-1a. Secondary outcomes: Weight, blood pressure, hemoglobin A1C, glomerular filtration rate (GFR), and medication adherence. Inclusion criteria: Male or female Veterans, age 18-75, with DM2 and ≥1 CV event and/or CKD and not on SGLT2i/GLP-1a. Exclusion criteria: Veterans with contraindications to SGLT2i/GLP-1 and/or a serious mental health disorder. Results: Primary outcome: Baseline visit: After baseline visit, 14/14 patients were prescribed at least one of the medications with 12/14 prescribed SGLT2i and 2/14 prescribed GLP-1a. 6-Month visit: We found 13/14 (93%) patients to still be on at least one of the medications at 6 months. Secondary outcomes: At 6 months compared to baseline, weight (216 lbs ± 41 → 213 lbs ± 39), blood pressure (141/76 ± 20/10 → 132/73± 17/10), A1C (7.7% ± 1.5% → 7.4%± 0.8%) modestly decreased but GFR was stable (64 ml/min ± 17 → 64 ml/min ± 19). Medication possession ratio was ≥80% in all 13 patients indicating medication adherence. Conclusion: DSS increased SGLT2i/GLP-1a use and medication adherence in Veterans DM2 patients and may offer a novel approach to improving CVD/CKD outcomes in primary care where the vast majority of DM2 patients are managed. Disclosure M. Dar: Research Support; Boehringer-Ingelheim, Nestlé Health Science. J. Zhang: None. A. Ashline: None. S. Kota: None. S. Woolson: None. N. Majette: None. H.B. Bosworth: Research Support; ESPERION Therapeutics, Inc., Sanofi, Pfizer Inc, Novo Nordisk, Improved Patient Outcomes, Otsuka America Pharmaceutical, Inc, elton john foundation, walmart, Boehringer-Ingelheim. Funding Department of Veteran Affairs

Pooled biomarker analysis of the association of baseline T regulatory cells with response and T-cell recovery profiles with blinatumomab treatment.

Blinatumomab, a bispecific T-cell engager, requires the activity of CD3+ T-cells for tumor lysis. This pooled analysis aimed to re-examine baseline T regulatory cells (Tregs) as a biomarker of blinatumomab efficacy across multiple clinical trials and provide insights into peripheral T-cell dynamics during blinatumomab therapy in hematological malignancies. Tregs and peripheral T-cells were enumerated by fluorescence-activated cell sorting and were statistically evaluated using the Wilcoxon rank-sum test and linear mixed effect modeling, respectively. Comparable baseline percentages of Tregs were observed in responders and non-responders of blinatumomab treatment (N = 325) in adults with leukemia or lymphoma. Peripheral T-cell count recovery occurred early during blinatumomab dosing, and before blinatumomab-free interval in patients (N = 233) from 4 clinical trials. The pooled analysis revealed that baseline Treg levels do not serve as a predictive marker for blinatumomab response and that there is rapid peripheral T-cell recovery following blinatumomab dosing. These results suggest that patients with varying levels of Tregs can benefit from blinatumomab treatment and that blinatumomab-free intervals of 7 days may suffice in blinatumomab treatment regimens.

Meta-analysis of the cardiovascular adverse effects of bispecific antibodies in malignant hematology therapies.

e14503 Background: Bispecific antibodies (BsAbs), recombinant molecules that target two distinct antigens or epitopes, are a promising therapeutic option for relapsed or refractory (R/R) hematologic malignancies, including acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and B-cell lymphoma. While BsAbs have shown significant efficacy in managing hematologic malignancies, toxicities must be carefully monitored and their safety profiles require further investigation. Notably, cardiovascular adverse effects have not been extensively studied despite reported incidents in BsAbs such as blinatumomab and teclistamab. This meta-analysis aims to investigate the cardiovascular toxicities associated with seven BsAbs across multiple clinical trials. Methods: A systematic literature review identified seven BsAbs and their associated randomized control clinical trials. The BsAbs in this analysis were blinatumomab, elranatamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, and teclistamab and only monotherapy regimens were included. 37 clinical trials were analyzed (6 Phase I, 12 Phase I/II, 15 Phase II, 1 Phase II/III, 3 Phase III). Cardiovascular adverse events that were analyzed include arrhythmias, heart failure, blood pressure changes, and myocardial infarctions. All cardiac adverse events were pooled and studied collectively. A meta-analysis was performed using the R meta package. Proportions and 95% confidence intervals (CI) were calculated for each study. A random-effects model was utilized. Heterogeneity was assessed using the I 2 statistic. Results: A total of 3758 patients were included. Significant occurrence rates were 10.2% tachycardia (95% CI 7.6-13.5%, p < 0.05, I 2 = 64.9%), 12.6% cardiac arrhythmias (95% CI 7.8-19.7%, p = 0.05, I 2 = 50.1%), and 13.3% hypotension (95% CI 10-17.3%, p < 0.05, I 2 = 76.9%). Other rates were 1.5% acute myocardial infarction (95% CI 0.7-3.1%, p = 0.5, I 2 = 0%), 1.3% atrial fibrillation (95% CI 0.4-4.4%, p = 0.062, I 2 = 52.5%), 8% hypertension (95% CI 5.8-11%, p = 0.19, I 2 = 27.5%), and 1.4% heart failure (95% CI 0.3-5.8%, p = 0.085, I 2 = 48.3%). Blinatumomab was the most represented BsAb during analysis, followed by mosunetuzumab, elranatamab, and teclistamab. Conclusions: As BsAbs have demonstrated promising efficacy and increased use in the treatment of R/R hematologic malignancies, a wide variety of cardiac toxicities have been observed in these patients and more data on these toxicities are documented. This meta-analysis has identified tachycardia, cardiac arrhythmias, and hypotension as the most significant cardiac adverse events in a pooled analysis of multiple BsAbs. Practicing oncologists, cardiologists, and pharmacists need not only to be aware of these potential toxicities, but also to establish strategies for cardiac monitoring, prevention and management in order to provide quality care to cancer patients.

Efficacy and safety of envafolimab plus platinum-based chemotherapy as neoadjuvant therapy in resectable stage IIb-IIIb NSCLC: A single-arm, prospective, exploratory study.

e20510 Background: Multiple clinical trials have reported the striking benefit for PD-1/PD-L1 monoclonal antibody combined with chemotherapy neoadjuvant therapy for non-small cell lung cancer (NSCLC), while the efficacy of subcutaneous injection of anti-PD-L1 Envafolimab combined with chemotherapy neoadjuvant therapy for NSCLC patients has not been demonstrated yet. Envafolimab is a novel recombinant protein of a humanized camel-derived single-domain anti-PD-L1 antibody fused with a human IgG1 Fc fragment designed for subcutaneous injection, making it easy to administer and improving patient compliance. This study aims to investigate the efficacy and safety of Envafolimab plus platinum-based chemotherapy as neoadjuvant therapy in resectable stage IIB-IIIB NSCLC. Methods: In this prospective, open-label, single-arm study aims to enroll histologically confirmed, potentially resectable stage IIB-IIIB NSCLC patients. Eligible patients will receive concurrent 300 mg Envafolimab and chemotherapy (cisplatin 50~100mg/m 2 or carboplatin AUC = 4~6 plus pemetrexed 500mg/m 2 or docetaxel 60-75mg/m 2 ) on day 1 for three 21-day cycles. Radical surgery was scheduled within 4-6 weeks after the last dose of neoadjuvant therapy, followed by optional adjuvant therapy. Follow up will last for three years unless the subject withdraws. The primary endpoint was major pathological response (MPR) rate. The secondary endpoints included R0 resection rate, pathological complete response (pCR) rate, and safety. Results: Between May 2024 and October 2025, 15 patients were enrolled, and included for efficacy and safety analysis. Neoadjuvant treatment was started in 15 patients. Surgery was done in 5 patients. MPR was achieved in 2 patients. R0 resection was achieved in 2 patients. pCR was achieved in 1 patients. No unacceptable toxicity or treatment-related deaths occurred. Conclusions: As of the data reporting date, Envafolimab in combination with platinum-based chemotherapy demonstrated a robust preliminary MPR in Neoadjuvant Therapy of NSCLC patients with manageable safety profile. In consist with the results from intravenous anti-PD-1 antibody plus chemotherapy in NSCLC patients, subcutaneous injection of envafolimab with chemotherapy provided a more convenient dose regimen in this population. Clinical trial information: 2400079595 .

Outcomes for adults with KMT2A-r acute myeloid leukemia treated with venetoclax plus azacitidine (Ven/Aza) or intensive chemotherapy (IC): A single-center retrospective study.

e18537 Background: KMT2A-rearranged acute myeloid leukemia (KMT2A-r AML) is known for adverse outcomes due to aggressive disease presentation and high relapse rates. Oral menin inhibitors are being studied in combination with frontline chemotherapy regimens. However, baseline data regarding outcomes for KMT2A-r AML treated with Ven/Aza is limited. Here, we conducted a study to assess outcomes in newly diagnosed KMT2A-r AML treated with Ven/Aza or IC. Methods: We retrospectively analyzed outcomes for adults with KMT2A-r AML who received Ven/Aza or IC as their first therapy. Phenotype was assessed by Hematopathology by morphologic review and flow cytometry. A monocytic phenotype was defined by >20% monocytic differentiation within the blast population on morphology and expression of at least 2 of the following: CD14, CD64, CD11b, and CD11c. Responses were recorded based on 2022 ELN criteria. Statistical analyses were performed on R v4.4.2. Results: This study included 34 pts with KMT2A-r AML, with 50% receiving Ven/Aza (n = 17) and 50% receiving IC (n = 17). The median age was 46 (19-78) years (y), with the IC cohort being relatively younger (41 vs 57y for Ven/Aza; p = 0.01). 76% of pts had de novo AML, while 24% had therapy-related AML (t-AML). Most pts (79%) had a monocytic phenotype. The composite complete remission (CRc) rate was 35% in pts who received Aza/Ven and 82% in pts who received IC (p=0.005). Among the entire cohort, the median overall survival (mOS) was 17 months (mo) (95% CI 8.4 mo, NR), and the median event-free survival (mEFS) was 5.2 mo (3.7 mo, NR). The mOS was 8.8 mo (3.5 mo, NR) in pts treated with Ven/Aza and 37 mo (9.3 mo, NR) in pts treated with IC (p=0.27). The mEFS was 3.8 mo (2.0 mo, NR) in pts treated with Ven/Aza and 37 mo (4.6 mo, NR) in pts treated with IC (p=0.072). In multivariate analyses, Allo-HSCT was associated with a reduced risk of relapse (HR 0.09 (95% CI 0.03–0.33, p < 0.001)) and decreased risk of death (HR 0.17 (95% CI 0.05–0.52, p < 0.001)). t-AML was associated with an increased risk of death with a HR of 3.03 (95% CI 1.16–7.95, p = 0.02). Conclusions: Our results demonstrate that KMT2A-r is associated with a monocytic phenotype and highlights poor outcomes in KMT2A-r AML when treated with Ven/Aza as frontline therapy. Allo-HSCT independently improves the likelihood for long term survival. Whether the addition of a menin inhibitor to frontline chemotherapy will improve outcomes is being assessed in multiple clinical trials. Characteristics and responses for KMT2A-r AML. Variables Ven/AzaN = 17 IC 1 N = 17 P-value Median age, yrs 57 41 0.01 t-AML, n (%) 6 (35) 2 (12) 0.2 Monocytic phenotype, n (%) 12 (71) 15 (88) 0.4 Response, n (%)- CR- CRi- No response- UnknownCRc (CR + CRi) 5 (33)1 (6.7)9 (60)26 (35) 13 (81)1 (6.3)2 (13)114 (82) 0.007 0.005 1 IC regimens included 7+3 (n=13), 7+3 with midostaurin (n=1), FLAG-Ida+Ven (n=3).

Survival and safety of two year-fixed duration vs continuous immune checkpoint inhibitor therapy in advanced or metastatic NSCLC: A systematic review.

8584 Background: The optimal duration of immune checkpoint inhibitor (ICI) therapy in advanced or metastatic non-small cell lung cancer (NSCLC) is unknown. While multiple randomized clinical trials (RCTs) have shown the benefit of ICI-based regimens over chemotherapy, they were not designed to test optimal duration of ICI. Most trials opted to continue ICI indefinitely or stopping at two years if no progressive disease or treatment limiting immune-related adverse events (irAEs) emerged. There is concern for increased cumulative risk of irAEs with indefinite treatment. Methods: A systematic review of randomized controlled trials (RCTs) and real-world evidence (RWE) studies was performed for adult patients with advanced/metastatic NSCLC treated with ICI therapy (alone or in combination) up to August 24, 2024. Studies were included if they specifically reported on patients who completed a minimum of 2 years of therapy. Databases, conference abstracts and clinical trials were queried. Patients were divided into two cohorts: a two year-fixed cohort where ICI therapy was discontinued after 2 years, and a continuous cohort where ICI therapy was continued beyond 2 years. Results: The database search identified 8741 records of which 174 articles were screened. The final qualitative analysis included 20 studies (11 RCTs and 9 RWE studies) and 5027 patients. There were 23 cohorts that belonged to the 2 year-fixed group (N=2051) and 7 that belonged to the continuous group (N=2976). Outcomes of patients in the 2 year-fixed arms from RCTs were excellent with 5-year overall survival (OS) rates in the range of 69-83%. This was supported by RWEs which showed similar OS rates. Continuous treatment with ICIs had similar OS rates in both RCTs and RWE and was comparable to the 2 year-fixed arms. Four RWE studies compared hazard ratios (HR) for survival outcomes among 2 year-fixed vs continuous arms and did not find any statistically significant difference. Patients that completed 2 years of therapy in RCTs tended to have greater rates of irAEs compared to the baseline population but lower rates of grade 3 or 4 events. Three out of four RWEs reported higher rates of irAEs in the continuous vs 2 year-fixed arms. These findings were likely associated with longer exposure to immunotherapy. A large proportion of patients that developed progressive disease after the 2 year-mark in both 2 year-fixed and continuous arms was alive at data cut-off. Many of these were re-challenged with ICI therapy. Data from RWEs showed that larger/academic centers tended to favor 2 year-fixed therapy whereas the reverse was true for community centers. Conclusions: Survival outcomes after ICI discontinuation at 2 years are comparable to continuous therapy in advanced/metastatic NSCLC. Immune-related adverse events tend to accumulate over time. Progressive disease is often localized and amenable to ICI re-challenge.

Bringing Pain Neuroscience Into the Arena: A Call to Action in Sports Rehabilitation

SYNOPSIS: The study of pain continues to evolve by leaps and bounds. In the last 2 decades, multiple observational studies, clinical trials, and evidence syntheses have attempted to shed light on the relevance of the biopsychosocial model in musculoskeletal rehabilitation. In sports, pain is an area of significant interest for many researchers, sports clinicians, and, of course, athletes. Pain neuroscience is a constantly growing area of research, with important advances in musculoskeletal rehabilitation. We have information about the importance of some pain neuroscience-related mechanisms such as central sensitization, conditioned pain modulation, and temporal summation of pain in people with chronic pain. However, the number of studies evaluating different areas of pain neuroscience in athletes with chronic pain remains limited. We make a call for action to researchers to expand and improve the quality of research specifically addressing pain neuroscience-related mechanisms in athletes, to better understand and manage their pain experiences. JOSPT Methods 2025;1(2):40-43. Epub 23 April 2025. doi:10.2519/josptmethods.2025.0158

Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence.

Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence.

Inhibitory pattern recognition receptors: lessons from LAIR1.

Many inhibitory receptors that regulate immune cell function recognize a limited number of specific ligands. However, a subgroup of so-called inhibitory pattern recognition receptors (iPRRs) can bind a much larger array of ligands of structural similarity. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is one such iPRR that is expressed by most immune cells and recognizes a common structural pattern present in collagens and collagen domain-containing proteins. LAIR1 signalling regulates diverse immune cell populations and is currently the focus of multiple clinical trials for the treatment of cancer. We here review the current literature on LAIR1, as a prototypic example of how inhibitory PRRs contribute to immune balance and of how these receptors are regulated. We discuss the function of LAIR1 in homeostasis, infection, inflammation and cancer, and consider the advantages and potential pitfalls of targeting this receptor in human disease.

Estimate hazard ratios in small clinical trials without reported hazard ratios

BackgroundFor survival studies, pooling hazard ratios (HRs) across multiple clinical trials through meta-analysis is commonly performed to achieve widely accepted and robust conclusions. However, clinical trials sometimes do not report HRs.MethodsWe developed a new, simple approach to estimate HRs by reconstructing life tables from Kaplan–Meier (KM) curves, particularly for small clinical trials. First, we extracted the time points and survival rates from the published KM curves. Then, we reconstructed the life table by reverse derivation of its parameters, using time points and survival rates extracted from the KM curves. Finally, we replotted the KM curves using the Kaplan–Meier method and estimated the HRs via the Cox regression method by SPSS software, using the survival data from the reconstructed life table.ResultsThe estimated HRs of 3 examples were 0.510 (95% CI 0.272–0.958, P = 0.036), 2.472 (95% CI 1.548–3.949, P < 0.001), and 0.591 (95% CI 0.291–1.199, P = 0.145), compared with the original HRs of 0.51 (95% CI 0.27–0.96, P = 0.04), 2.33 (95% CI 1.45–3.73, P < 0.001), and 0.62 (95% CI 0.31–1.26, P = 0.18), respectively.ConclusionsThis simple approach allows for the estimate of HRs from published KM curves in small survival studies without reported HRs, facilitating their inclusion in meta-analyses. This increases the overall sample size and enhances the reliability of synthesized clinical evidence.

Cracking the Code of Colorectal Cancer Screening: An Overview With a Focus on Current and Emerging Screening Methods.

Colorectal cancer (CRC) is a common cancer that affects the colon and rectum. It is a major cause of cancer-related mortality. A complicated interaction between environmental and genetic factors, such as age, diet, gut microbiota, obesity, chronic inflammation, and familial predisposition, appears to contribute to the pathophysiology of colorectal cancer. A multidisciplinary strategy is necessary for the effective care of CRC, including early detection through screening, surgical resection, chemotherapy, radiation therapy, and targeted medicines. The slow progression of CRC through various stages gives us, physicians, leverage and a chance to promptly and adequately screen a patient and give them a better chance at life. There are multiple clinical trials being conducted to find better and the best screening and treatment modalities. Existing and emerging screening tests can be broadly divided into blood-based, stool-based and direct imaging-based screening tests. Colonoscopy is the gold standard. However, numerous emerging screening tests are changing the face of colon cancer screening. This review aims to highlight the background of CRC, including its etiopathogenesis, risk factors, and clinical features. It will also shed light on the existing and emerging screening techniques that will decide the future of this deadly cancer. In addition, the management section of this article will provide a summary of suggestions, including radiation and medical and surgical treatment modalities that may benefit physicians in managing this challenging condition. We conducted a comprehensive literature search in PubMed-indexed journals using the terms "Colorectal Cancer," "Etiopathogenesis of CRC," and "Emerging screening and treatment modalities in CRC." We explored the literature on the background of CRC, its pathogenesis, the importance of screening, screening modalities and comparisons amongst each one, and treatment options for this challenging cancer. We used peer-reviewed original research articles and systematic reviews published in English, conducted from 2015 to the present time, to reflect the developments in colorectal cancer. Studies with uncertain methodological details and outcomes were excluded.

Heart failure with preserved ejection fraction therapeutics: in search of the pillars.

Heart failure (HF) affects nearly 8 million individuals in the USA, with approximately half diagnosed with heart failure with preserved ejection fraction (HFpEF). HFpEF is associated with high morbidity and mortality, with fewer than 25% of patients surviving beyond 5years after diagnosis. Historically, poor outcomes have been largely attributed to a lack of effective disease-modifying therapies. However, the past 5years have marked a transformative era in HFpEF management, with multiple landmark clinical trials demonstrating benefits for novel therapeutic classes. These include sodium-glucose cotransporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (Ns-MRAs), and glucagon-like peptide-1 (GLP-1) receptor agonists, particularly for the obesity-related HFpEF phenotype. In this review, we summarize the evolution of HFpEF therapeutics, from traditional heart failure treatments with limited efficacy to emerging targeted therapies, highlighting the latest evidence shaping a modern, comprehensive approach to HFpEF management.

Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response.

The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapueticblockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.

Precision Medicine for Pediatric Glioma and NF1-Associated Tumors: The Role of Small Molecule Inhibitors.

Pediatric gliomas encompass the most common brain tumor in children and are subdivided into pediatric low-grade gliomas (pLGGs) and pediatric high-grade gliomas (pHGGs). The era of molecular diagnosis has shifted the treatment paradigms and management of these patients. RAS/MAPK pathway alterations serve as the driver in the majority of pLGGs, a subset of pHGG and NF1-related plexiform neurofibromas (PNs). The role of small molecule inhibitors in the treatment of these tumors has evolved in the past decade, facilitated through multiple clinical trials and moving into earlier stages of treatment. Although these developments hold promise, questions remain regarding targeted therapy, the long-term toxicities, the duration of treatment and the potential effects on the natural history of the tumor behavior.

Exploration Into Lived Experiences of Multiple Sulfatase Deficiency-Affected Individuals and Their Families.

Despite their importance, rare diseases' impact on patients and families is understudied. This is particularly true for ultrarare disorders, such as multiple sulfatase deficiency (MSD), a pediatric neurodegenerative disorder. To address this gap, we captured caregiver perspectives on how multiple sulfatase deficiency affects their child, themselves, and their families regarding adaptive behaviors and health-related quality of life.Overall, 19 multiple sulfatase deficiency caregivers participated in assessments capturing health outcomes related to daily functional abilities (Vineland Adaptive Behavior Scale-Third Edition [VABS-3]: n = 19), child health-related quality of life (Caregiver Priorities and Child Health Index of Life with Disabilities: n = 12; Pediatric Quality of Life Inventory-generic core scales: n = 13), and caregiver health-related quality of life (Pediatric Quality of Life Inventory-family impact module: n = 12; Traumatic Brain Injury Caregiver Quality of Life: n = 15). The Pediatric Quality of Life Inventory-family impact module results were compared to a data set from metachromatic leukodystrophy (n = 30), a rare disease with an overlapping sulfatase deficiency.The Vineland Adaptive Behavior Scale-Third Edition captured global impairment across domains in multiple sulfatase deficiency. Despite these functional limitations, the Caregiver Priorities and Child Health Index of Life with Disabilities and Pediatric Quality of Life Inventory-generic core scales captured relative preservation of health-related quality of life, especially related to emotional well-being. Compared with the Pediatric Quality of Life Inventory-generic core scales, the Caregiver Priorities and Child Health Index of Life with Disabilities captured a broader spectrum of health-related quality of life across all domains and caregivers' top priorities in disease management and care coordination. The health-related quality of life of caregivers was severely impacted, with caregivers reporting profound feelings of grief and entrapment. Additionally, there was a similar caregiver burden between multiple sulfatase deficiency and metachromatic leukodystrophy.Our results will help inform psychosocial outcome measures for rare disease families and patient-centered endpoints in impending multiple sulfatase deficiency clinical trials.