Small-molecule drug discovery targeting the orphan G protein-coupled receptor GPR84 as potential therapeutics.

Pyoderma gangrenosum (PG) is a rare, painful neutrophilic dermatosis with a profound impact on patient quality of life. Its management is hindered by a lack of approved therapies, limited clinical trials, and low-quality evidence. The rarity of the disease and funding constraints have impeded research progress and the development of standardized outcome measures. Patient data registries offer a promising solution to these challenges, providing essential infrastructure to improve evidence generation and clinical care. To develop a consensus-based minimum data set for an international treatment effectiveness registry for pyoderma gangrenosum, informed by real-world clinical data. An initial list of candidate domain items was generated based on a systematic literature review following a previously published protocol. An international, multi-stakeholder panel of 45 participants-including patients with PG, clinicians, researchers, methodologists, and industry representatives-was convened from 97 invited experts. Through three rounds of modified Delphi surveys and a virtual consensus meeting, items were ranked using predefined criteria: "consensus in" (≥70% scoring 7-9 and ≤15% scoring 1-3), "consensus out" (≥70% scoring 1-3 and ≤15% scoring 7-9), and "no consensus." A final verification survey confirmed inclusion if <30% of participants voted "no." All 45 stakeholders completed all three Delphi rounds (0% dropout). Thirty-four (76%) participated in the consensus meeting, and 42 (93%) completed the final verification survey. Of 143 initial items across 24 domains, 118 items across 26 domains achieved consensus for inclusion in the minimum data set. This international consensus establishes a standardized framework for collecting real-world data on PG. The resulting registry will serve as a critical resource for evaluating treatment effectiveness, understanding disease progression, and improving patient outcomes. It will also support future clinical trials, guideline development, quality improvement initiatives, and global patient recruitment efforts.

Cardiology in Algeria needs clinical trials: time to step up the game.

The efficacy of combination therapy versus monotherapy in patients with glioblastoma with abnormal epidermal growth factor receptor (EGFR) genes, a systematic review and network meta-analysis.

The G protein-coupled receptor (GPCR) known as protease-activated receptor-1 (PAR-1) is triggered by thrombin and plays a multifaceted role in the onset and progression of Alzheimer's disease (AD). AD is an irreversible neurodegenerative disease characterized by amyloid-β (Aβ) accumulation, neuroinflammation, tau hyperphosphorylation, and synaptic dysfunction. Thrombin activates PAR-1, which plays multiple roles in the brain. It exacerbates neuroinflammation and Aβ pathology but also protects synaptic plasticity. In a preclinical model, PAR-1 inhibition rescues cognitive deficits and decreases Aβ accumulation, suggesting therapeutic potential. However, PAR-1 activation promotes Tau hyperphosphorylation and neurofibrillary tangle formation, contributing to synaptic loss and cognitive decline. PAR-1 increases the permeability of the blood‒brain barrier (BBB), facilitating the entry of toxic substances into the brain and increasing neurodegeneration. Although strong preclinical evidence exists, no clinical trials have yet directly targeted PAR-1 in AD. This review summarizes current understanding of the PAR-1 mechanism in AD and highlights its roles in Aβ deposition, neuroinflammation, and tau pathology. It also discusses the challenges and opportunities for translating PAR-1 modulation into clinical therapies, including repurposing existing PAR-1 inhibitors. By addressing the dual role of PAR-1 function, researchers may develop novel multitarget strategies to combat the multifactorial pathophysiology of AD.

KRAS p.G12C (c.34G > T) inhibitors have been reported to have varying survival outcomes in CRC patients across studies. Hence, our review aimed to provide a comprehensive understanding of the efficacy and safety of these agents among the CRC population. Major databases, including but not limited to PubMed and Ovid, were searched for original clinical trials assessing the efficacy or safety of KRAS p.G12C (c.34G > T) inhibitors in CRC patients through May 2025. Studies with non-G12C KRAS-mutated populations were excluded. Data on patient demographics and various variables, including but not limited to OS, PFS, and TRAE incidence, were extracted from included studies. Our systematic review analyzed 18 trials and 1011 patients. Adagrasib monotherapy yielded a median PFS of 4.4-5.6 months, an OS of 10-19.8 months, and an ORR of 19-23%, while its combination with cetuximab reported a PFS of 6.9 months, an OS of 13.4-15.9 months and an ORR of 34-46%. Sotorasib monotherapy (960 mg) reported a PFS of 4 months, an OS of 10.6 months, and an ORR of 9.7. When combined with panitumumab, 960 mg sotorasib demonstrated better results with a PFS of 5.6-5.7 months, OS of 15.2 months and an ORR of 12.5-30%. Similarly, divarasib monotherapy led to a PFS of 5.6-6.9 months and an ORR of 20%, while its combination with cetuximab resulted in a PFS of 8.1 months and an ORR of 62.5%. Combination therapy of olomorasib and MK-1084, which are new-generation KRAS p.G12C (c.34G > T) inhibitors, with cetuximab also demonstrated highly promising efficacy with ORR of 38-44% and 50%, respectively. Olomorasib with cetuximab also showed a PFS of 6.6-7.5 months. Nausea, vomiting, diarrhea, rash, and increased AST/ALT were the most common TRAEs. Initial results of KRAS-G12C inhibitors appear highly promising when they are combined with anti-EGFR therapy compared to historical therapeutic agents indicated for patients with chemotherapy-refractory CRC. Encouraging benefits warrant frontline trials with these novel therapeutics.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy exhibiting both hepatocytic and cholangiocytic differentiation. Since the 2019 World Health Organization (WHO) reclassification, growing molecular and clinical evidence has reshaped our understanding of this entity. However, patients with cHCC-CCA have been systematically excluded from landmark clinical trials in both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), leaving clinicians without prospective evidence to guide treatment selection. This review comprehensively evaluates the current evidence on systemic therapy for advanced cHCC-CCA, encompassing cytotoxic chemotherapy, immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and molecularly targeted agents. Retrospective data indicate that gemcitabine plus platinum-based chemotherapy achieves the most consistent efficacy among conventional regimens, with median overall survival (OS) of 10-16 months. ICIs demonstrate objective response rates of 20-33% with durable responses in a subset of patients, supported by the finding that approximately 57% of cHCC-CCA tumors harbor an immune-high phenotype. Nearly 25% of tumors carry potentially actionable genomic alterations, including fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and human epidermal growth factor receptor 2 (HER2) amplification. The molecular heterogeneity of cHCC-CCA-with tumors classifiable as HCC-like or CCA-like in approximately 75% of cases-provides a rational framework for personalized treatment selection. We propose an emerging molecular classification-based treatment algorithm and identify critical gaps requiring dedicated prospective investigation. For clinical settings where comprehensive genomic profiling is not feasible, we discuss a pragmatic surrogate-based approach using imaging characteristics and serum tumor markers to guide initial treatment selection. We also address post-progression treatment considerations, including phenotype-based regimen switching and the role of re-biopsy.

Arthritis, an acute inflammatory disease affecting single or multiple joints, causes irreversible damage to cartilage and bone, leading to substantial pain and economic burden. Current treatments lack specificity. Curcumin, with its anti-inflammatory and antioxidant properties, shows promise in arthritis treatment, yet its poor water solubility and low bioavailability hinder clinical use. This study investigates the efficacy of a nanocarrier-based curcumin delivery system for non-infectious arthritis. Four types of nanocarriers-liposomes, biomolecule-based nanoparticles, nanoemulsions, and improved nanocarriers-are reviewed for their ability to target curcumin delivery. These nanocarriers improve curcumin's therapeutic effects by enhancing pharmacokinetics, prolonging circulation, and protecting against degradation. Demonstrating potential in various non-infectious arthritis types, including ankylosing spondylitis, rheumatoid arthritis, juvenile idiopathic arthritis, and gout, this study underscores the efficacy of nanocarrier-based curcumin delivery systems in reducing inflammation, modulating immune responses, and alleviating disease symptoms. Future research should focus on optimizing nanocarrier design for increased bioavailability and conducting more clinical trials to validate safety and effectiveness in humans.

Uncertainty persists regarding the estimated effects of vitamin C supplementation on blood pressure, including the strength of the evidence supporting these estimates and the magnitude of the observed effects relative to the minimal important difference. We aimed to provide an overview of the effects of vitamin C supplementation on blood pressure among adults through an umbrella review of randomized controlled trials (RCTs). PubMed, Scopus, and Web of Science, and the Cochrane Library were searched from the earliest date available to 25 December 2024. We identified eligible meta-analyses and included all primary trials, adding any RCTs not included in the largest review. For each trial, we extracted the mean change in blood pressure and its SD for both groups to calculate the mean difference as the effect size. The certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We identified six meta-analyses involving a total of 17 RCTs reporting systolic blood pressure (SBP) and diastolic blood pressure (DBP) as outcomes. The findings suggest that vitamin C supplementation may reduce SBP by approximately 3.7 mmHg. Although DBP did not decrease overall, a clinically important reduction was observed in patients with diabetes (-2.27 mmHg). These results indicate that vitamin C supplementation may have a meaningful beneficial effect on blood pressure. Nevertheless, the low certainty of evidence highlights the necessity for larger, long-term randomized trials to definitively confirm its efficacy.

Denosumab biosimilars were developed to provide cost-effective alternatives to the reference monoclonal antibody for postmenopausal osteoporosis (PMO). This review assessed their efficacy, safety, and immunogenicity in the treatment of PMO. A systematic search of PubMed/Medline, Ovid-Embase, and Web of Science (to April 2025) identified randomized controlled trials comparing denosumab biosimilars with either the originator (Prolia®) or placebo. Data on bone mineral density (BMD), bone turnover markers, adverse events, and immunogenicity were synthesized descriptively. In addition, the National Institutes of Health (NIH) Quality Assessment Tool was employed to evaluate the risk of bias across all eligible studies. Eleven RCTs met the inclusion criteria. Biosimilars showed therapeutic equivalence to the reference product, with comparable BMD gains at the lumbar spine, total hip, and femoral neck, and similar reductions in CTX and P1NP. In placebo-controlled trials, biosimilars significantly increased BMD and reduced bone turnover by more than 70%. Safety and immunogenicity profiles were comparable to the originator, with no new safety signals or neutralizing antibodies. Denosumab biosimilars demonstrate efficacy and safety equivalent to Prolia®, offering an accessible, cost-efficient option for PMO management. Long-term data are needed to confirm sustained antifracture benefits.

Stiff person syndrome (SPS) is an autoimmune disorder with muscle stiffness and spasms, for which current therapies provide incomplete relief. Botulinum neurotoxin (BoNT) has been explored as an adjunctive symptomatic treatment. The aim of this review was to critically evaluate the clinical evidence for BoNT therapy in SPS. Using Medline, Scopus and Google Scholar, we identified nine reports that were published up to 1 January 2026. English articles and articles with information on study type, type/dose of BoNT and treatment results were included. One study was double-blind and placebo-controlled, one was retrospective and seven were single-case reports, comprising 46 patients. Open-label trials used botulinumtoxin-A (Botox, Dysport or Xeomin), while the blind study applied abobotulinumA (Dysport). All but one study (a case report) demonstrated motor improvement and a reduction in painful spasms associated with patient satisfaction. Reported doses ranged from 300 to 800 units for onabotulinumtoxinA and incobotulinumtoxinA and from 700 to 1000 units for abobotulinumtoxinA. The literature highlights the need for randomized clinical trials in larger cohorts, with careful selection of dose, injection sites, and adjunct physiotherapy, as well as an evaluation of early BoNT therapy in SPS. The novelty of this review lies in its critical synthesis of reported data and inclusion of most recent reports.

Chronic respiratory diseases (CRDs) affect over 545 million individuals globally, with COPD alone causing approximately 3.2 million deaths annually. Flavonoids have shown promise in reducing lung inflammation and disease risk; however, their clinical application is hindered by poor solubility and low bioavailability. Nanocarrier-based pulmonary delivery systems offer a solution by enabling targeted, controlled release and improved solubility. This review explores the preclinical and clinical potential of flavonoid-loaded nanocarriers in mitigating CRDs by regulating inflammation and cellular senescence, while offering sustained release and enhanced biocompatibility. A comprehensive analysis of flavonoid mechanisms in modulating inflammatory pathways (e.g. NF-κB, Nrf2/Keap1) and enzymes (COX, 5-LOX, iNOS) was conducted using data from electronic databases (PubMed, ScienceDirect, Web of Science, TRIP, Springer). MeSH terms included 'Flavonoids,' 'Preclinical Studies,' 'Clinical Trials,' and 'Lung Health.' Taxonomy, epidemiology, and chemical data were verified using World Flora Online, WHO factsheets, and ChemSpider. Flavonoid-loaded nanocarriers demonstrated significant anti-inflammatory and antioxidant effects. PLGA-based systems reduced TNF-α and IL-6 levels by up to 80%. Lipid-based carriers (SLNs, NLCs) enhanced bioavailability 2-5 fold, while liposomes improved cell viability (40-50%) and reduced oxidative stress (>60%). Inhalable nanoformulations, such as quercetin achieved 3-fold higher lung concentration and 50% longer retention compared with oral formulations. Flavonoid-loaded nanocarriers, especially liposomes, show enhanced pulmonary targeting, bioavailability, and therapeutic efficacy in CRDs. Their ability to suppress inflammation and cellular aging highlights their potential as a promising nanomedicine strategy for improving lung health.

Surgical treatment of high anal fistulas is challenging and associated with a relatively high rate of complications and failure. Stem cell therapy has shown promising results for fistulas associated with Crohn's disease but remains less studied in cryptoglandular fistulas. This clinical trial is being performed to evaluate the outcome of treating complex cryptoglandular perianal fistulas (PAFs) using minimal surgical debridement combined with either non-cultured (autologous) or cultured (allogeneic) adipose-derived regenerative cells (ADRCs). The primary outcome is the clinical healing rate after 12months. Secondary outcomes include functional outcomes regarding quality of life and anal continence (measured by the 36-Item Short Form Health Survey [SF-36] and the Wexner Fecal Incontinence Score), risk factors for fistula recurrence, radiological healing assessed by magnetic resonance imaging, and comparison of autologous versus allogeneic ADRCs with respect to cell characterization, immune responses, and efficacy. This is a double-blinded, randomized interventional non-inferiority, phase I-II clinical trial using two approved investigational medicinal products. The study will be conducted at the surgical department, Odense University Hospital OUH, in Odense, Denmark. Inclusion criterion is an adult patient (≥ 18years) with complex PAF (high transsphincteric or suprasphincteric), involving more than 30% of the anal sphincter. Key exclusion criteria are ongoing suppuration, simple anal fistula, ano- or rectovaginal fistula, inflammatory bowel disease, body mass index (BMI) of < 18.5kg/m2, known allergy to penicillin or streptomycin, pregnancy, and verified syphilis, human immunodeficiency virus (HIV), or hepatitis on screening test. The primary investigator (PI) is responsible for participants' recruitment. Eligible patients will undergo 1-day surgery, including debridement of the fistula tract and closure of the internal orifice, liposuction from the anterior abdominal wall, injection of 30-40mL of autologous microfat around the fistula tract, and injection of 30 million stem cells (either autologous ADRCs or allogeneic ADRC001) according to randomization (1:1 allocation ratio). Patients who receive treatment will attend follow-up visits at 3, 6, and 12months postoperatively. Serious adverse events will be reported including large abscess formation, wound dehiscence causing fecal incontinence, sepsis, major bleeding, and serious allergic reactions. The trial has been approved by the European Medicines Agency EMA and is monitored by the Good Clinical Practice (GCP) Unit at OUH. A total of 75 patients will be included. Recruitment began in October 2024, with a planned duration of 3years. The trial intervention is designed as a minimally invasive treatment with the potential to shorten and ease recovery, enable a quicker return to daily activities and work, and avoid sphincter damage, thereby preserving function. The trial is expected to provide evidence on whether allogeneic ADRCs combined with microfat are a viable alternative to autologous ADRCs with microfat for the treatment of PAF. Clinical Trials Information System (CTIS) EU CT 2022-502659-73-01. Registered on 18 November 2023. org NCT06303752. Registered on 25 February 2024.

Older adults with acute coronary syndrome (ACS) face high risks of recurrent ischemia, mortality, and bleeding complications from antiplatelet therapy. The safety and efficacy of ticagrelor versus clopidogrel in this vulnerable population remain uncertain due to their underrepresentation in clinical trials. We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, and the Cochrane Library were searched from inception to October 2025 for randomized controlled trials and cohort studies comparing ticagrelor versus clopidogrel in ACS patients aged ≥70 years. Outcomes included myocardial infarction (MI), stroke, major bleeding, all-cause death, cardiovascular (CV) death, and the composite of CV death/MI/stroke. Hazard ratios (HRs) or risk ratios with 95% confidence intervals (CIs) were pooled using random-effects models. Heterogeneity was assessed via I2 statistics. Five studies (2 randomized controlled trials and 3 cohort studies) with 22,806 participants were included. Ticagrelor significantly reduced the risk of MI (HR 0.84, 95% CI 0.75-0.95, P = 0.004) and the composite endpoint of CV death, MI, or stroke (HR 0.85, 95% CI 0.74-0.98, P < 0.05). No significant differences were found between ticagrelor and clopidogrel in stroke incidence, major bleeding, or all-cause mortality. Heterogeneity was substantial for certain outcomes, particularly bleeding and mortality. In patients aged ≥70 years with ACS, ticagrelor was associated with reduced MI and composite ischemic events compared with clopidogrel, while no statistically significant differences in bleeding events or mortality were observed. However, substantial heterogeneity and reliance on observational data for some outcomes warrant cautious clinical interpretation.

HIV/sexually transmitted infection (STI) prevention interventions are only modestly successful among youth, particularly for young people of colour and sexual and gender minority (SGM) youth. Even among disparate intervention modalities delivered with high fidelity, differences between intervention types have been minimal. One consistent theme has emerged: the role of the youth:provider relationship in predicting intervention response. In line with calls for examination of relational factors, the next essential step is a harmonised analysis to evaluate connections between the youth:provider relationship and co-occurrence of alcohol and cannabis use, in youth HIV/STI prevention intervention response. Our team has completed six sizeable HIV/STI behavioural prevention studies, generating n=1136 independent youth (baseline Mage=17, range=13-24; 43% female; 21% SGM; 54% Hispanic; 9% African American; 7% Native American/Alaska Native) who received prevention programming and were followed at 1-, 3-, 6-, and/or 12 months. We will harmonise these studies and build a longitudinal mixed-effects machine learning model, with youth:provider relationship as a predictor of intervention response. Participant factors, provider factors and their interaction will be included in the model. Given high rates of alcohol and cannabis comorbidity, we will also examine syndemic outcomes (co-occurring HIV/STI risk behaviours, alcohol use and cannabis use). These data are crucial to informing next step HIV/STI and syndemic intervention programming with this age group. This secondary analysis study is exempt from human subjects regulations under category 4(iii) as determined by the Institutional Review Board at UConn Health. Results will be disseminated via presentations at annual scientific conferences, submissions to peer-reviewed journals, to mental health and substance use providers, as well as community programmes for youth at high risk for HIV/STI and substance use.

Transforming Patient Recruitment in Clinical Trials: Communication Training to Manage Uncertainties about Risks and Benefits

Digitizing rehabilitation outcomes and assessing data quality in clinical trials: implementing validated scales in REDCap for a stroke RCT.

Caffeine, predominantly consumed through coffee and tea, has received growing attention for its potential cardioprotective actions. Evidence suggests a non-linear association between habitual intake and cardiovascular risk, with moderate consumption offering the most favorable profile. Given that caffeine is often ingested within complex beverage matrices, distinguishing the effects of pure caffeine from those of coffee components and preparation methods is essential for accurate interpretation. This study synthesizes findings from epidemiological research, Mendelian randomization analyses, mechanistic experiments, and clinical trials to evaluate caffeine's cardiovascular impact. We assess key outcomes such as coronary artery disease, heart failure, stroke, hypertension, and arrhythmias. Mechanistic pathways are explored, including adenosine receptor antagonism, modulation of autonomic tone, influences on endothelial function and arterial stiffness, anti-inflammatory and antioxidant effects, and indirect metabolic actions on glucose and lipid regulation. Additional analyses examine how genetics, comorbid conditions, and concomitant medications may modify individual responses. Integrated evidence from observational studies demonstrates a non-linear, J-shaped association between coffee and caffeine intake and cardiovascular outcomes, with moderate consumption associated with the lowest observed risk; however, Mendelian randomization analyses generally do not support a clear causal protective effect of caffeine. Pure caffeine and coffee-derived effects diverge in several respects: unfiltered coffee may elevate lipid levels due to diterpenes, whereas filtered coffee generally has neutral lipid effects. Habitual use is shown to attenuate the acute pressor response through tolerance development. Variability in cardiovascular responses is influenced by genetic polymorphisms, baseline blood pressure phenotype, concurrent illnesses, and interacting medications. Overall, moderate caffeine intake generally appears safe for cardiovascular health. The cardioprotective links seen in epidemiological studies may be affected by coffee components, how it is prepared, and residual behavioral confounding, while solid evidence for a direct protective effect of caffeine is still limited. Remaining uncertainties highlight the need for future trials that isolate caffeine's dose-response from coffee matrices, incorporate genotype-based stratification, evaluate baseline hemodynamic phenotypes, and use standardized clinical endpoints. Such work is essential to clarify causal pathways and optimize the clinical relevance of caffeine-related recommendations.

Detox diets have become widely popular as strategies for weight loss and metabolic improvement, especially through social media. However, scientific evidence regarding their effects remains limited. The aim of this review was to analyze the metabolic impact and anthropometric changes associated with following detox diets in adults, focusing on variables such as body weight, body composition, and selected metabolic parameters. A systematic review of the literature was conducted following PRISMA methodology. A search was carried out in scientific databases, applying predefined inclusion and exclusion criteria. Twelve articles published between 2014 and 2024 were included, comprising interventional clinical trials, observational studies, and review articles. The results showed that detox diets are associated with short-term reductions in body weight, mainly as a consequence of energy restriction, and attributed more to reductions in body fluids and fat-free mass than to adipose tissue. Although reductions in body mass index and waist circumference were observed, there were no consistent changes across studies. Regarding metabolic parameters, some studies reported transient improvements in glucose and lipid profile, which did not persist after discontinuing the diet. This indicates that detox diets produce temporary metabolic and anthropometric effects, without demonstrating sustained health benefits, highlighting the need to promote balanced nutritional interventions grounded in scientific evidence.

It is well established that the majority of anti-cancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later stage clinical trials. The simple explanations are that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice (GLP) toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. While this is certainly hyperbole, it is true that drug efficacy often appears significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models in common use for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.