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Snakebite envenoming by Crotalus snakes is a relevant public health problem in Brazil. From 2015 to 2024, 26,021 cases were reported in DataSUS, with 78,329 antivenom vials administered. However, only 27,257 vials had the specific antivenom type recorded, indicating 51,072 undocumented vials. In addition, the database records the administration of antivenoms that are not typically indicated for crotalic envenoming. Because these data originate from a secondary surveillance system, such discrepancies may reflect documentation gaps, data entry errors, or potential inconsistencies in antivenom selection. These findings highlight important limitations in national reporting systems and reinforce the need to strengthen clinical training, surveillance quality, and antivenom stewardship policies in Brazil.
Despite extensive development of anticancer agents, there remains a critical need for therapeutics with novel mechanisms of action. This study reports the potent anticancer activity and mechanistic analysis of highly water-soluble dopa-melanin (DM) prepared through a unique synthetic process. DM exhibits distinctive structural and chemical properties that contribute to its exceptional aqueous solubility (≥ 50 mg/mL) and may underlie its enhanced biological activity. DM reduced cell viability in multiple cancer cell lines. Using HeLa cells as a representative model, DM suppressed cell migration and three-dimensional growth. Fractionation revealed that activity was associated with polymers larger than 30 kDa, suggesting a critical role for high-molecular-weight species. Mechanistic studies showed that DM induced S/G2/M arrest followed by cell death with minimal apoptotic body formation. DM rapidly decreased cyclin D1 and D3 protein and mRNA levels. A pan-caspase inhibitor significantly suppressed DM's inhibitory effect on cell viability but did not prevent cyclin D degradation. Cyclin D degradation was mediated through calcium-dependent calpain activation triggered by endoplasmic reticulum Ca2+ release via IP3 receptors, and inhibition of this pathway attenuated DM's activity. In a mouse syngeneic tumor model, oral administration of DM significantly inhibited tumor growth without apparent toxicity. These results demonstrate that both caspase-dependent apoptosis and a caspase-independent cyclin D degradation pathway contribute to DM-induced cell death. Its high solubility, oral efficacy, and unique mechanism of action make DM a promising candidate for therapeutic development.
Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer mortality in South Africa. Understanding locally relevant and modifiable risk factors is crucial for prevention. This study clarifies the syndemic role of lifestyle and environmental factors, such as alcohol, tobacco, socioeconomic indicators (rurality and education), and fuel use, in ESCC. We analyzed 939 histologically confirmed ESCC cases and 3,089 cancer controls from the Johannesburg Cancer Study. Multivariable logistic regression estimated adjusted odds ratios (aORs), with interaction terms for alcohol, tobacco, and sex. Population attributable fractions were calculated using both study-control and national prevalence estimates. Very high alcohol intake (≥840 g ethanol/wk) showed a modest independent association with ESCC (aOR, 1.56 [95% CI, 1.14 to 2.12]). Smoking was a strong risk factor, with aOR = 2.82 (95% CI, 2.20 to 3.62) for ex-smokers and 6.71 (95% CI, 5.15 to 8.76) for current smokers. Among never-smokers, alcohol showed little dose response. Among smokers, risks were high across all alcohol levels, with no consistent increase at higher intakes. Additional risks included rural origin or residence (aOR approximately equal to 1.22-2.38), lower educational attainment (aOR approximately equal to 1.45-1.69), and use of biomass or other fuels (aOR, 1.50 [95% CI, 1.21 to 1.87]). In this high-burden setting, tobacco remains the principal modifiable driver of ESCC. Alcohol showed only a modest independent effect, limited to very high intake, and did not increase the risk among smokers beyond the high risk from smoking. Socioeconomic and environmental disadvantages cluster with behavioral risks, underscoring a syndemic context. These findings, consistent with prior Johannesburg Cancer Study reports yet offering greater exposure granularity, support targeted prevention strategies focused on smoking cessation, mitigation of hazardous drinking patterns, and reduction of household environmental exposures.
The large-scale production of microbial bioplastics remains limited by high production costs, reliance on refined substrates, and inefficient utilization of agro-industrial residues. Although sugarcane bagasse has been explored as a carbon source for polyhydroxyalkanoate production, studies have predominantly focused on poly (3-hydroxybutyrate) (PHB), with limited reports on copolymer synthesis from pentose-rich lignocellulosic streams. In this study, a newly isolated Bacillus sp. HLI02 was employed for the biosynthesis of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), using pentosan-rich sugarcane bagasse hydrolysate as an inexpensive and sustainable carbon source. Fermentation parameters were systematically optimized at different pH and temperature, and the strain demonstrated efficient conversion of xylose-rich hydrolysate into PHBV without the requirement for external nutrient supplementation. Under optimized conditions (pH 7.0, 37 °C, and C/N ratio of 40), a maximum PHBV yield of 2 g/L, corresponding to 59.5% of cell dry weight, was achieved. Structural and compositional analyses using Fourier transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy confirmed successful PHBV copolymer formation with well-defined structural characteristics. Thermal analysis revealed a decomposition temperature of 166 °C, indicating good thermal stability. The produced PHBV further exhibited favourable biocompatibility and biodegradability, supporting its potential applicability in sustainable packaging and related sectors. This work demonstrates the effective conversion of hemicellulosic sugarcane bagasse hydrolysate into PHBV using a newly isolated Bacillus strain, highlighting an underexplored route for copolymer production from agro-waste-derived C5 sugars. By integrating low-cost feedstock utilization with process optimization and comprehensive polymer characterization, this study contributes to the development of economically viable and sustainable bio-based polymer production strategies.
Vonifimod is a novel sphingosine-1-phosphate receptor (S1PR) modulator with selectivity for S1PR1 and S1PR4 that is under development for the treatment of autoimmune disease. No reports on vonifimod metabolism exist except for the formation of active vonifimod-phosphate in rats. The in vitro metabolic pathways and drug interaction potentials of vonifimod were characterized by identifying the metabolites of vonifimod in human hepatocytes via liquid chromatography-high-resolution mass spectrometry and determining the inhibitory effects of vonifimod on major cytochrome P450 (CYP) and UDPGA-glucuronosyltransferase (UGT) enzyme activities in human liver microsomes. The incubation of vonifimod with human hepatocytes resulted in the formation of nine metabolites, including hydroxy-vonifimod (M1 and M2), inactive carboxylic acids (M3 - M6), active vonifimod-phosphate (M7), and M3 glucuronides (M3-G1 and M3-G2). ω-Hydroxylation of vonifimod to M2 at the methyl terminus of the decyl chain was catalyzed mainly by CYP4F2 enzymes, which were further oxidized to four carboxylic acid metabolites (M3 - M6). UGT1A7, UGT1A8, UGT1A9, and UGT1A10 catalyzed the formation of M3-G2 from M3. Vonifimod revealed the negligible and weak inhibition of major CYP and UGT enzyme activities at 50 µM in human liver microsomes, suggesting that vonifimod has low potential for drug-drug interactions. These findings suggest hepatic metabolism to be the primary elimination pathway for vonifimod.
Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals widely used in the production of industrial and consumer products. Due to their environmental persistence and health effects, PFAS have become a primary focus of global public health concern. This scoping review summarizes the literature on interventions aimed at reducing concentrations of 12 PFAS in soil and edible portions of fruit and vegetables. A comprehensive search of PubMed and Centre for Agricultural and Bioscience International (CABI) was conducted on April 9 and April 17, 2024, without date or language restrictions. Eligible references included experimental studies targeting PFAS reduction in water, agricultural soil, fruits or vegetables. Thirty-two references, with an eligible outcome measured in soil, fruits or vegetables, were included for data charting. Findings suggest that minimal replication exists across studies due to variability in intervention implementation, outcome measurement, and plant growing conditions. A limited number of studies evaluated soil and/or plants as outcomes of interest with only twenty-five references providing extractable data, with most focusing on soil-based outcomes (n = 18) and fewer on plant-based outcomes (n = 7). This heterogeneity highlights a critical need for standardized methodologies to enable meaningful synthesis across literature.
This study reports 32 metagenome-assembled genomes (MAGs) reconstructed from arsenic (As)-impacted paddy soils of West Bengal, India, and microcosms from these soil samples. These MAGs, represented by 10 bacterial and 2 archaeal phyla, provided critical insights into the metabolic and biogeochemical potential of microbiomes in a highly As-impacted agroecosystem.
The synthesis of mirror life, an organism composed entirely of the mirror-image counterparts of naturally occurring biomolecules, may be a topic for science fiction today but is suggested to be a reality in the future. Scientists called for strict preemptive regulation for the synthesis of mirror life due to concerns regarding biosecurity risks, such as the potential threat of mirror life to humans and non-human ecosystems. This perspective reports on the discussions held at two recent symposia in Japan, at the Japanese Society for Cell Synthesis Research (JSCSR) meeting and at the Biophysical Society of Japan (BSJ) annual meeting. Participants, including synthetic biologists, social scientists and artists, discussed the feasibility of the synthesis of mirror-image artificial self-replicating cells and the balance between the risks and benefits of this emerging technology. The discussions indicate that, while safety management is essential, a rational, evidence-based framework developed through open dialogue with society is crucial for the responsible advancement of mirror life research.
Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase highly expressed in the brain, and mutations in its gene cause CDKL5 deficiency disorder (CDD). Although reports on CDKL5 substrate proteins are increasing, the phosphorylation-dependent regulation of CDKL5 function remains poorly understood. Therefore, in this study, we investigated the phosphorylation states of CDKL5 and explored the kinases and phosphatases involved in its regulation. The C-terminal region of exogenous CDKL5 was highly phosphorylated in Neuro2a neuroblastoma cells; endogenous CDKL5 in P19 embryonic carcinoma (P19EC) cells was also highly phosphorylated, mainly in the cytoplasm. CDKL5 underwent gradual dephosphorylation during aggregate formation in P19EC cells, and this process was suppressed by retinoic acid (RA), an inducer of neuronal differentiation. Okadaic acid treatment indicated that protein phosphatase 2A (PP2A) partially mediates CDKL5 dephosphorylation during aggregate formation. Kinase inhibitor screening and kinase assay in vitro demonstrated that multiple protein kinase C (PKC) isoforms contribute to CDKL5 phosphorylation. These findings suggest that CDKL5 phosphorylation is dynamically regulated by a balance between PKC and PP2A activities, and that RA signaling modulates this process during neuronal differentiation. Such phosphorylation mechanisms of CDKL5 may underlie the pathogenesis of CDD and help identify potential therapeutic targets.
ORCHARD (NCT03944772) was a phase II, biomarker-directed platform study designed to characterize resistance mechanisms and evaluate novel therapy combinations after progressive disease (PD) on first-line osimertinib. We report results of the module assessing durvalumab plus chemotherapy. Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with PD on first-line osimertinib whose tumors did not harbor a prespecified alteration by next-generation sequencing of a post-osimertinib biopsy, or for whom a biomarker-matched treatment was not available, were eligible. Patients received 4 to 6 cycles of durvalumab 1500 mg plus carboplatin target area under the curve 5 and pemetrexed 500 mg/m2. After platinum-based chemotherapy, patients without PD could continue to receive durvalumab plus pemetrexed maintenance. Primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator assessment. Overall, 25 patients received more than or equal to 1 dose of durvalumab plus chemotherapy; all had discontinued treatment at the primary analysis data cutoff. Confirmed ORR was 16% (80% confidence interval [CI]: 7-30); response was maintained for more than 6 months in the four patients with confirmed response. Furthermore, 22 patients (88%) had PD and median progression-free survival was 4.8 months (95% CI: 2.6-7.6). Ten patients (40%) had died, and median overall survival was 23.4 months (95% CI: 8.8-not calculable). Nine patients (36%) had grade 3 or higher adverse events, most often neutrophil count decreased (20%). Durvalumab plus chemotherapy demonstrated limited clinical benefit for EGFR-mutated NSCLC after PD on first-line osimertinib. Although the combination was well tolerated, the overall risk-benefit profile did not warrant further evaluation.
Angioimmunoblastic T-cell lymphoma (AITL) is a rare peripheral T-cell lymphoma characterized by diverse and aggressive clinical manifestations that frequently mimic autoimmune disorders. Cutaneous presentations are common and may lead to diagnostic delay. A 67-year-old woman first presented with non-blanchable skin rash, with normal platelet count and negative autoimmune markers. The rash improved with corticosteroids but recurred two months later, accompanied by fever, night sweats, limb edema, diarrhea, and cervical lymphadenopathy. Skin biopsy reported vasculitis and panniculitis, as direct immunofluorescence was compatible with IgA vasculitis. Subsequent laboratory tests revealed atypical lymphocytes, Coombs-positive anemia, thrombocytopenia, and detected Epstein-Barr virus DNA. Computed tomography showed new splenomegaly and periaortic lymphadenopathy. Lymph node biopsy confirmed AITL. Although CHOP chemotherapy was planned after staging, the patient rapidly deteriorated and died of septic shock. Serial peripheral blood flow cytometry at admission, post-splenectomy, and follow-up showed dynamic immunophenotypic changes: reductions in exhaustion and senescence markers as well as activated regulatory T cells after splenectomy; and later upregulation of exhaustion markers on naïve T cells. This case illustrates the misleading presentation as immunoglobulin A (IgA) vasculitis and rapid progression of AITL. While vasculitis is accompanied by cytopenia, lymphadenopathy, or aggressive clinical course, early lymph node biopsy is essential for timely diagnosis.
This study investigated the association between aerobic exercise preconditioning and macrophage migration inhibitory factor (MIF) expression, as well as myelination in sciatic nerve in experimental autoimmune neuritis (EAN) rats. Female Lewis rats underwent 4-week swimming protocols including High-intensity daily (HI-Daily), Moderate-intensity daily (MOD-Daily), and Moderate-intensity alternate-day (MOD-AltDay) regimens prior to EAN induction, with control groups of EAN without exercise and Sham operation. Assessment of disease severity, nerve conduction velocity, and sciatic nerve pathology revealed that the moderate-intensity alternate-day exercise regimen significantly delayed disease onset, lowered peak clinical scores, and improved neurological function. Molecular analyses demonstrated that this protective effect was mediated through divergent regulation of MIF: systemic MIF was substantially suppressed (27205.94 ± 4291.76 pg/mL vs EAN 71075.61 ± 10166.41 pg/mL; p<0.001) with concomitant reduction in macrophage infiltration, while local MIF expression within the sciatic nerve was significantly elevated (p<0.01), correlating with enhanced remyelination as evidenced by increased myelin sheath area (LFB: 67.42 ± 3.26% vs EAN 40.64 ± 9.63%, p<0.01) and elevated myelin basic protein expression (0.92 ± 0.14 AU vs EAN 0.59 ± 0.02 AU, p<0.05). Crucially, both high-intensity daily and moderate-intensity daily exercise protocols failed to confer comparable benefits. These findings indicate that the protective effect of MOD-AltDay exercise preconditioning on EAN is associated with tissue-specific regulation of MIF, and this change correlates with reduced systemic inflammation and enhanced local remyelination. Pharmacological/genetic studies are needed to confirm mechanisms and evaluate this exercise regimen as a non-pharmacological intervention for autoimmune neuropathy.
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Heart failure is a leading cause of morbidity and mortality, highlighting the need for improved therapeutic strategies. Critical to the success of therapies is efficient and targeted delivery systems. Extracellular vesicle-based delivery systems have emerged as promising candidates due to their biocompatibility and low immunogenicity. While extracellular vesicles from a wide variety of cells have been used, they have demonstrated divergent effects on the heart. The present review first summarizes the current sources of extracellular vesicles employed in heart failure therapy and their contrasting outcomes. The review then examines the view that these contrasting outcomes arise from limited cell specificity, inefficient delivery, and suboptimal cargo loading. Finally, the review discusses how these problems are being dealt with by recent advances, including genetic modification, chemical functionalization, and enhanced loading strategies. Together, these approaches highlight the potential of extracellular vesicle-based systems as precision therapeutics in cardiovascular medicine.
Recurrent isocitrate dehydrogenase (IDH) wild-type glioblastoma has no established standard-of-care treatment. Preclinical models have demonstrated that hypoxia-inducible factor-2 alpha (HIF-2α) contributes to stabilizing the hypoxic environment in glioblastoma. It was thus hypothesized that the first-in-class HIF-2α inhibitor, belzutifan, may improve outcomes in patients with recurrent IDH wild-type glioblastoma. The glioblastoma cohort of the phase 1 LITESPARK-001 trial enrolled participants who had received radiotherapy and temozolomide. Although targeting HIF-2α may have a role in advancing treatment options for patients with glioblastoma, single-agent belzutifan did not have antitumor activity in this cohort.
The sarco(endo)plasmic reticulum calcium (Ca2+)-ATPase 2 (SERCA2) is a crucial regulator of cardiac muscle function that is sensitive to changes in the cellular environment, such as increased oxidative stress. This can be observed in heat stress experiments, where the thermal inactivation of SERCA is linked to an increased production of reactive oxygen species. Previous studies have shown that regulatory proteins, including phospholamban (PLN) and heat shock protein 70 (Hsp70), can physically bind to SERCA2, preserving its function in the face of heat stress. Furthermore, we have demonstrated that the inhibition of glycogen synthase kinase 3β (GSK3β) can alter the protein levels of PLN and HSP70 in cardiac tissues obtained from male mice; however, its potential downstream effects on the thermal inactivation of SERCA have not yet been investigated. In this study, we examined the potential effects of GSK3β inhibition through six weeks of low-dose lithium chloride supplementation (LiCl, 10 mg/kg body mass/day via drinking water) on the thermal inactivation of left ventricle SERCA2 obtained from male C57BL/6J mice. Our results show that LiCl supplementation increased inhibitory serine 9 phosphorylation on GSK3β while also significantly raising SERCA2 content and the SERCA2:PLN ratio. There were no changes to Hsp70 with LiCl supplementation. Although LiCl decreased baseline maximal SERCA activity, the decline in activity in response to heat stress was less compared to control. In conclusion, GSK3β inhibition with LiCl is associated with protection of SERCA from thermal inactivation in the heart, and future studies should explore the underlying cellular mechanisms.
Treatment options are limited for patients with primary biliary cholangitis (PBC) and cirrhosis. Seladelpar, a first-in-class delpar (selective PPAR-δ agonist), had generally similar efficacy and safety among patients with versus without compensated cirrhosis in the phase 3 RESPONSE study. Here we provide additional data on seladelpar in patients with compensated cirrhosis from the phase 3 program. In RESPONSE, patients with PBC and an inadequate response or intolerance to UDCA were randomized 2:1 to seladelpar 10 mg or placebo for 1 year. Upon completion, patients rolled over into the open-label (seladelpar 10 mg) phase 3 ASSURE study, which also enrolled patients from earlier seladelpar legacy PBC studies. Here, we assessed the composite endpoint [alkaline phosphatase (ALP) <1.67×upper limit of normal (ULN), ALP decrease ≥15%, and total bilirubin ≤ULN], other laboratory changes, and safety in all patients with cirrhosis from RESPONSE and an interim analysis of the ongoing ASSURE study through January 2024. Twenty-seven patients with compensated cirrhosis enrolled in RESPONSE (18 seladelpar, 9 placebo). At month 12, 38.9% and 22.2% of patients in the seladelpar and placebo groups, respectively, met the composite endpoint; mean percent change from baseline in ALP was -37.1% and -10.1%, respectively. Upon rollover to ASSURE (13 seladelpar, 6 placebo), ALP declines were maintained for up to 18 months. An additional 35 patients with compensated cirrhosis in ASSURE from legacy studies had similar reductions in ALP with up to 2 years of treatment. Bilirubin remained overall stable. No treatment-related serious adverse events occurred. Variceal bleeding and/or ascites developed in 3 patients after ≥9 months. Seladelpar decreased markers of cholestasis and was overall safe and well-tolerated in patients with PBC and compensated cirrhosis.
This study evaluated treatment outcomes of opicapone when used as add-on to levodopa in US patients with Parkinson's disease (PD) experiencing OFF episodes in clinical settings. The prospective, open-label, multicenter, observational OPTI-ON study examined patient characteristics, treatment outcomes, and safety/tolerability of Opicapone over 6 months. Clinician-reported outcomes included the Clinician Global Impression of Change (CGI-C), and Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts IA and IV. Patient-reported outcomes included the Patient Global Impression of Change (PGI-C), MDS-UPDRS Parts IB and II, and the novel Patient Global Impression of Severity in ON and OFF states (PGI-S ON and OFF) and Non-motor Fluctuation Assessment (NoMoFa). The completer set included 161 patients (mean age, 66.8 years; PD duration, 7.8 years; fluctuation onset, 3.6 years). 38.0% of patients were 'very much/much improved' on CGI-C; 48.7% and 57.5% showed improvement on MDS-UPDRS Parts IA and IV, respectively; 23.5% of patients rated themselves 'very much/much improved' on PGI-C, and 49.5% and 56.5% reported improvements on MDS-UPDRS Parts IB and II, respectively. On PGI-S ON, the proportions of patients with 'none/very mild' PD symptoms during ON times were maintained, while, on PGI-S OFF, the proportion of patients with 'moderately to extremely severe' PD symptoms during OFF times decreased by 12.7%. NoMoFa Total Score improved in 48.0% of patients. Opicapone was generally well tolerated. In clinical practice, OPC treatment led to improvements in motor and non-motor fluctuations, quality of OFF episodes, and was generally well tolerated.
In the time since the last Clinical Practice Committee review of treatment of women with endometrial cancer in 2021, the field of gynecologic oncology has seen significant changes in endometrial cancer from understanding risk factors, addition of molecular staging, and expanded use of maintenance and targeted therapies. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease continued to rise. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer, including increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress. The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, Document Review Panel, and the Board of Directors prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice Committee and subject matter experts. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.
We evaluated cibisatamab, a carcinoembryonic antigen (CEA)-directed CD3 T cell-engaging bispecific antibody, in combination with FAP-4-1BBL, a fibroblast activation protein (FAP)-targeted 4-1BB ligand providing tumor-localized co-stimulation, in an open-label phase 1b dose-escalation study in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) progressing after two or more prior therapies. Patients received cibisatamab with escalating doses of FAP-4-1BBL weekly or every 3 weeks after obinutuzumab pretreatment to mitigate anti-drug antibody formation. The primary endpoint was safety; secondary endpoints included antitumor activity, pharmacokinetics and biomarker analyses. Among 52 treated patients, the combination showed a manageable safety profile. Dose-limiting toxicities occurred in 2 out of 52 patients (3.8%). Cytokine release syndrome (CRS) occurred in 30 out of 52 patients (57.7%; grade ≥3: 2 out of 52, 3.8%) and was manageable; after a cycle 1 cibisatamab dose reduction to 60 mg, serious CRS occurred in 4 out of 27 patients (14.8%; grade ≥3: 0 out of 27). Gastrointestinal toxicities consistent with CEA-directed T cell engagement were observed. Colitis occurred in 7 out of 52 patients (13.5%), including immune-mediated enterocolitis and one fatal cytomegalovirus colitis. No maximum tolerated dose of FAP-4-1BBL was established. Confirmed partial responses were observed in 7 out of 52 patients (13.5%). Pharmacodynamic analyses demonstrated systemic immune activation, including increased IFNγ, soluble CD25, soluble 4-1BB (CD137) and activated, proliferating CD8+ T cells. Paired tumor biopsies showed increased intratumoral CD8+ and CD8+Ki67+ T cell infiltration. These findings demonstrate the feasibility of combining tumor antigen-directed T cell engagement with localized co-stimulation, with evidence of immune activation and preliminary antitumor activity supporting further clinical development. ClinicalTrials.gov identifier: NCT04826003 .