Alblooshi K, Sharaf R, Shenbagam S
… +30 more, Sinha S, Jain R, Yaslam S, Alfalasi R, Abdulbaki A, Alyassi A, Alyafei H, Ramaswamy S, Jaber I, Sato M, Chekroun I, Rabea F, Khadija S, El Naofal M, Sheikh Hassani M, Taylor A, Farag M, Jamalalail B, Sarhan A, AlHajjaj S, Almadhoun F, Elsawy D, Alkhnbashi OS, Khansaheb H, Al Suwaidi H, Aldafrawy O, Albasti A, AlAwadhi M, Alsheikh-Ali A, Abou Tayoun A
Here we describe the feasibility and first implementation of a mandatory, citywide premarital genomic screening program comprising the sequencing of 782 genes, implicated in autosomal recessive disorders, in prospective...Here we describe the feasibility and first implementation of a mandatory, citywide premarital genomic screening program comprising the sequencing of 782 genes, implicated in autosomal recessive disorders, in prospective couples enrolled through 18 primary healthcare centers throughout Dubai city. Since program inception, 1,000 couples have undergone testing, and 79 (8%, 95% confidence interval: 6.4-9.7) were identified as carriers of disease-causing variants in the same gene and, therefore, at risk of having affected children. This rate was significantly higher than that reported in the Australian Mackenzie's Mission study (3.9%; P < 0.0001). Although risk for hemoglobinopathies was most common, 59% of at-risk couples carried variants in 33 other genes. Of the 158 carriers, four (2.5%, 95% confidence interval: 1.0-6.3) were incidentally found to be homozygous for a pathogenic variant, indicating that they would be affected. Of the 79 at-risk couples, 63 (80%) elected to proceed with marriage while considering government-funded reproductive interventions, whereas 16 (20%) chose not to proceed. These findings underscore the feasibility and clinical utility of premarital genomic screening as part of a national strategy to reduce the burden of rare diseases.
The incidence of colorectal cancer (CRC) is rising rapidly in people younger than 50 years. Although this increase parallels shifts in lifestyle and environmental factors-collectively termed the exposome-whether these ar...The incidence of colorectal cancer (CRC) is rising rapidly in people younger than 50 years. Although this increase parallels shifts in lifestyle and environmental factors-collectively termed the exposome-whether these are indeed linked to the development of early-onset CRC (EOCRC) remains uninvestigated. Due to limited exposome data in most cancer cohorts, we constructed weighted methylation risk scores as proxies for exposome exposure to pinpoint specific risk factors associated with EOCRC compared to late-onset CRC (LOCRC) patients diagnosed at ≥70 years. Our analysis confirmed previously identified risk factors, including educational attainment, diet and smoking habits. Moreover, we identified exposure to the herbicide picloram as a new risk factor (adjusted P = 4.4 × 10) in the discovery cohort (31 EOCRC versus 100 LOCRC), which was replicated in a meta-analysis comprising nine CRC cohorts (P = 3.1 × 10; adjusted P = 1.5 × 10; 83 EOCRC versus 272 LOCRC). Subsequently, we analyzed population-based data from 94 US counties over 21 years and validated the association between picloram use and EOCRC incidence (P = 4.52 × 10), which remained significant after adjusting for socioeconomic factors and other pesticide use. These findings highlight the critical role of the exposome in EOCRC risk, underscoring the urgency for targeted personal and policy-level interventions.
Harray AJ, Lucas AD, Herrmann SE
… +21 more, Vlaskovsky PS, Elagali A, Seewoo BJ, Chan DC, Chiarugi D, Kulkarni R, Trevenen M, Wang X, Mueller J, Thomas KV, Papendorf H, Miller C, Gaudieri S, Smith T, Salman S, Murray K, Symeonides C, Dunlop SA, Watts GF, PERTH Trial Consortium, Lucas M
The everyday use of plastic products exposes us to plastic-associated chemicals (PACs), which have been associated with risks to human health. We present the results of the Plastic Exposure Reduction Transforms Health Tr...The everyday use of plastic products exposes us to plastic-associated chemicals (PACs), which have been associated with risks to human health. We present the results of the Plastic Exposure Reduction Transforms Health Trial, with an observational cohort of 211 Australian participants and a 7-day pilot randomized controlled trial in 60 participants. Intervention groups received combinations of plastic-free kitchenware, low-plastic personal-care products and food sourced from more than 100 producers that minimized all plastic touchpoints from paddock to plate, while the control group received no intervention. The primary trial outcome was a reduction in urinary plastics-associated chemicals levels. In the cohort study, highly processed, plastic-packaged and canned foods were important modifiable factors for urinary PAC metabolite levels. Additionally, we observed negative associations between cardiometabolic biomarkers and higher urinary di(2-ethylhexyl) phthalate metabolites. Our randomized controlled dietary intervention maintained participants' daily energy intake while decreasing plastic exposure (P < 0.001) and urinary levels of mono-n-butyl phthalate, monobenzyl phthalate and bisphenol A by 37.5% (95% confidence interval (CI): -55.6, -12.0; P = 0.007), 53.5% (95% CI: -72.7, -20.6; P = 0.005) and 59.7% (95% CI: -82.5, -6.87; P = 0.033), respectively. Intervention groups provided with foods that had minimal to no contact with plastic had the broadest effect on PAC excretion, and replacing low-plastic personal-care products alone led to an independent decrease in urinary mono-n-butyl phthalate, compared to no intervention. Despite constant plastic exposures, limiting food plastics touchpoints decreases select PACs in 7 days. Australian and New Zealand Clinical Trials Registry: ACTRN12622001252707 .
Mshamu S, Mukaka M, Sanga C
… +17 more, Kambanga S, Rutaihwa AD, Bøjstrup TC, Meta J, Mmbando A, Pell C, Adhikari B, Olotu AI, Kapologwe N, White NJ, Dondorp AM, Day NPJ, Imwong M, Deen J, Lindsay SW, Knudsen JB, von Seidlein L
Malaria, diarrhea and acute respiratory infections (ARIs) are the major causes of mortality in young children in sub-Saharan Africa. Here we provide support for the hypothesis that children can be protected from these di...Malaria, diarrhea and acute respiratory infections (ARIs) are the major causes of mortality in young children in sub-Saharan Africa. Here we provide support for the hypothesis that children can be protected from these diseases by improvements in house design. We designed a novel double-story house, called a Star Home, to provide an insect-proof, cleaner, cooler and smoke-free environment, with a reliable supply of water and sanitation. We conducted a cluster-randomized controlled trial where households with children under 13 years of age were randomly allocated (1:4.7) to living in 110 Star Homes or in 513 traditional mud and thatched-roofed houses. The primary outcome of childhood malaria incidence was met: after 3 years, children living in Star Homes had 44% less malaria (incidence rate ratio (IRR): 0.56 (95% confidence interval (CI): 0.43-0.72), P < 0.0001) compared to children living in traditional homes. Children in Star Homes had 30% less diarrhea (IRR: 0.70 (95% CI: 0.53-0.91), P = 0.0070) and 18% less ARIs (IRR: 0.82 (95% CI: 0.73-0.93), P = 0.0010) than children living in traditional homes. Children under 5 years of age living in Star Homes were also taller for their age than those living in traditional homes. Our house design is intended to inspire those working in the building sector and with local communities to develop innovative designs for healthier homes. Major improvements in rural house design have the potential to make a substantial public health impact across hot, humid regions of Africa. ClinicalTrials.gov: NCT04529434 .
Melero I, Tanos T, Calvo Aller E
… +19 more, Qvortrup C, van Dongen M, Baraibar I, Beom SH, Thistlethwaite F, Riesco MDC, Garcia MM, Woodcock V, Kim TW, Umana P, McIntyre C, Chen L, Heichinger C, Hinton H, Saylan T, Davydov II, Guarin E, Boehnke A, Moreno V
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-loc...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 CD8Ki67 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 .
Menozzi E, Ren Y, Geiger M
… +32 more, Macnaughtan J, Avenali M, Toffoli M, Gilles M, Calabrese R, Mitrotti P, Gallo L, Famechon A, Del Pozo SL, Mezabrovschi R, Koletsi S, Loefflad N, Yalkic S, Limbachiya N, Clasen F, Yildirim S, Shoaie S, Blottière H, Morabito C, David A, Quinquis B, Pons N, Le Chatelier E, Valzania F, Cavallieri F, Fioravanti V, Toschi G, Blandini F, Almeida M, Ehrlich SD, Meslier V, Schapira AHV
Parkinson's disease (PD) is a major cause of disability. GBA1 variants are the most common genetic risk factor for PD and increase the risk up to 30-fold. Why only approximately 20% of GBA1 variant carriers develop PD re...Parkinson's disease (PD) is a major cause of disability. GBA1 variants are the most common genetic risk factor for PD and increase the risk up to 30-fold. Why only approximately 20% of GBA1 variant carriers develop PD remains unknown. Here, by combining clinical and fecal metagenomics data from 271 patients with PD, from 43 carriers of GBA1 variants not manifesting PD symptoms (GBA-NMC) and from 150 healthy controls, and using an innovative microbiome analysis, combining differential abundance of species and coherence of differential abundance variation between the groups as assessed by Cliff's delta (δ), we show that the composition of a large component of the gut microbiome (approximately 25%) in GBA-NMC is intermediate between healthy controls and patients with PD. This component is strongly correlated with disease progression in patients and prodromal symptoms suggestive of future development of PD in both GBA-NMC and healthy individuals. We found microbiome alterations similar to those described here in three independent cohorts from the United States, Korea and Turkey, totaling 638 patients with PD and 319 healthy controls, and we conclude that gut microbiome alterations can identify both genetically and non-genetically at-risk individuals in the general population who may be progressing toward PD, thus serving as an early marker of disease development in the premanifest phase.
Nadeem O, Cordas Dos Santos DM, Nikiforow S
… +39 more, Bosch-Vilaseca A, O'Donnell E, Redd R, DeBraganca KC, Sperling AS, Liu Y, McEntire C, Arters F, O'Donnell C, Kineavy B, Marto M, Bergeron A, Swenson E, McHugh K, Caron A, Berry Q, Wei H, Durlacher E, Grimm E, Corrado F, Bidikian N, Montes de Oca R, Lengil T, De Wiest D, Gervais C, Panaro K, Smith EL, Anderson K, Jacobson C, Munshi NC, Richardson P, Madduri D, Schecter JM, Tendler C, Wildgust MA, Trippa L, Mateos MV, Ritz J, Ghobrial IM
High-risk smoldering multiple myeloma (HR-SMM) carries an increased risk of progression to multiple myeloma, making it an ideal setting to test whether chimeric antigen receptor (CAR) T cell therapy can achieve curative...High-risk smoldering multiple myeloma (HR-SMM) carries an increased risk of progression to multiple myeloma, making it an ideal setting to test whether chimeric antigen receptor (CAR) T cell therapy can achieve curative outcomes. Here in this phase 2 study, patients with HR-SMM received ciltacabtagene autoleucel (cilta-cel) at 0.3-0.5 × 10 or >0.5 × 10 viable CAR T cells per kilogram without induction or bridging therapy. Patients with >40% marrow involvement were excluded. Primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events; secondary endpoints included response and minimal residual disease (MRD) negativity. As of 11 February 2026, 20 patients had been treated. The trial met the prespecified endpoints. No DLTs occurred. Adverse events included transient cytopenias (90% grade 3/4) and cytokine release syndrome (100% grade 1/2). Non-immune effector cell-associated neurotoxicity syndrome neurologic toxicities (NINTs) occurred in seven patients, with four comprising cranial nerve palsies that completely resolved. Three patients had persistent grade 1 symptoms. At a median follow-up of 15.3 months, all patients achieved MRD negativity 10 by 2 months and have remained MRD negative. Sixteen patients with follow-up >6 months achieved a complete response; no progression or deaths were observed. Cilta-cel produced rapid, deep, sustained MRD-negative responses in HR-SMM without induction therapy. Toxicities were consistent with the safety profile of cilta-cel. ClinicalTrials.gov: NCT05767359 .
Nicholls SJ, Nelson AJ, Ditmarsch M
… +20 more, Kastelein JJP, Ballantyne CM, Ray KK, Navar AM, Nissen SE, Goldberg AC, Brunham LR, Wuerdeman E, Neild AL, Kling D, Hsieh A, Butters J, Ference BA, Laufs U, Banach M, Mehran R, Catapano AL, Szarek M, Balinskaite V, Davidson MH
Ewing sarcoma (ES) is a bone and soft tissue sarcoma that is absolutely dependent on the EWS::FLI1 transcription factor for cell survival. No compound has been shown to reverse EWS::FLI1 activity in patients, and outcome...Ewing sarcoma (ES) is a bone and soft tissue sarcoma that is absolutely dependent on the EWS::FLI1 transcription factor for cell survival. No compound has been shown to reverse EWS::FLI1 activity in patients, and outcomes for relapsed patients remain poor. Trabectedin above a threshold concentration reverses the activity of EWS::FLI1 and is potentiated by low-dose irinotecan in vivo. This open-label phase 1/2 trial of trabectedin with irinotecan (SARC037) enrolled 37 relapsed/refractory patients with ES. The primary objectives were to determine the safety, tolerability, recommended phase 2 dose (RP2D; phase 1) and objective response rate (ORR; phase 2) of trabectedin administered as a 1-hour infusion in combination with low-dose irinotecan in patients with ES. The secondary objectives were to determine the progression-free survival (PFS), 6-month PFS, duration of response and F-fluorothymidine positron emission tomography (F-FLT PET) avidity of ES tumors. The RP2D was trabectedin 1.0 mg m over 1 hour (day 1) and irinotecan 25 mg m (days 2 and 4) of a 21-day cycle. Toxicities were manageable with grade 3 or higher toxicities (>15%) of myelosuppression and alanine aminotransferase elevations at RP2D. The phase 2 ORR was 33% (39%, including RP2D phase 1 patients), and 6-month PFS was 48%. Transcriptional profiling demonstrated reversal of the EWS::FLI1 transcriptome in tumors from a subset of patients. Additional correlative objectives captured molecular profiling, circulating tumor DNA levels, pharmacokinetics and F-FLT PET avidity. Here we provide the basis for further development of trabectedin/irinotecan for patients with ES by the international cooperative groups. ClinicalTrials.gov: NCT04067115 .
Zamani SA, Wu L, Black EL
… +18 more, Bartram A, Ng AWT, Secrier M, Perelman JD, Ustaoglu A, Ococks E, Jacobson D, Devonshire G, Grehan N, Nützinger B, Freeman A, Miremadi A, O'Donovan M, Frankell AM, Killcoyne S, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Coleman HG, Fitzgerald RC
Cancer generally takes years to evolve, and early diagnosis can prevent life-threatening cancer. Establishing a link between precancerous states and cancer is essential for effective screening and prevention. Esophageal...Cancer generally takes years to evolve, and early diagnosis can prevent life-threatening cancer. Establishing a link between precancerous states and cancer is essential for effective screening and prevention. Esophageal adenocarcinoma (EAC) is an increasingly prevalent, poor-outcome cancer, and its presumed precursor, Barrett's esophagus (BE), characterized by intestinal metaplasia, is evident in only about half of cases. Here to test whether BE is a prerequisite to EAC, we integrated epidemiological and clinical characteristics in a prospective cohort of 3,100 patients with EAC for any evidence of BE (BE-positive and BE-negative) and compared genomic features using a subset of 710 patients with whole-genome sequencing and 87 patients (380 samples) with multiregional whole-exome sequencing. Demographic and genomic features typically associated with BE were observed across BE-positive and BE-negative EAC cases. Notably, molecular features consistent with early BE evolution were detected in both phenotypes. Advanced tumor stage was the only variable that corresponded with increased likelihood of BE-negative EAC, including in some patients with a previous BE diagnosis. Phylogenetic analyses revealed shared evolutionary trajectories, and spatial transcriptomic and proteomic analyses demonstrated intestinal metaplasia-associated lineage markers in both groups. These findings suggest a single pathway to EAC, with implications for early diagnosis and prevention strategies.
In late 2021, high pathogenicity avian influenza A(H5N1) clade 2.3.4.4b viruses entered North America and reassorted rapidly with local avian influenza viruses. In September 2024, we detected a new reassortant later clas...In late 2021, high pathogenicity avian influenza A(H5N1) clade 2.3.4.4b viruses entered North America and reassorted rapidly with local avian influenza viruses. In September 2024, we detected a new reassortant later classified as genotype D1.1. Using active and passive avian influenza surveillance across Canada and the USA, we tracked the emergence and rapid spread of D1.1 viruses in wild birds during the 2024 fall migration. Phylodynamic analysis showed that D1.1 viruses formed a monophyletic group and displaced earlier A(H5) genotypes across several flyways. Their expansion coincided with detections in other hosts, including 17 human cases, 4 of which were severe or fatal. None of the mammalian-adaptive markers detected in human cases were found in wild bird viruses, and candidate vaccine viruses retained antigenic cross-reactivity with D1.1 strains.
Li C, Richards SM, Quinn G
… +22 more, Abedini A, Zhu M, Verma T, Mohandes S, Pitts R, Barros V, Qiu X, Shin T, Loureiro JJ, Finkel N, Surapaneni A, Coresh J, Grams ME, Karihaloo A, Li H, Verma A, Ritchie M, Rader DJ, Penn Medicine BioBank, Dietrich WF, Jennings LL, Susztak K
Individuals of African ancestry carrying APOL1 (apolipoprotein L1) high-risk genotypes face a markedly increased risk of kidney failure, yet tools to identify those individuals likely to progress to chronic kidney diseas...Individuals of African ancestry carrying APOL1 (apolipoprotein L1) high-risk genotypes face a markedly increased risk of kidney failure, yet tools to identify those individuals likely to progress to chronic kidney disease are lacking. Here we profiled plasma proteomes of 851 Penn Medicine BioBank participants of African ancestry (285 males and 566 females) with APOL1 high-risk genotypes and preserved estimated glomerular filtration rate (eGFR) (≥60 ml min 1.73 m). Using elastic net Cox regression adjusted for age, sex, eGFR and albuminuria, we derived a nine-protein APOL1 Proteomic Risk Score (APRS) that predicts a composite outcome of ≥40% eGFR decline, kidney failure or death. APRS achieved a time-dependent area under the receiver operating characteristic curve (tAUC) of 86.5%, outperforming the Kidney Failure Risk Equation (66.1%) and polygenic risk scores, with 10-year event rates of 62.5% versus 3.3% across risk quintiles. External validation in Atherosclerosis Risk in Communities and UK Biobank cohorts confirmed robust accuracy (tAUC 82-85%) and consistent performance across demographic and clinical subgroups. Plasma levels of APRS component proteins correlated with kidney tissue fibrosis and tubular injury pathways, indicating strong biological plausibility. By enabling early and accurate prediction of disease progression in APOL1 high-risk individuals, APRS bridges the gap between genetic susceptibility and clinical translation. This scalable and biologically informed approach provides a precision medicine framework for early intervention and may accelerate development of APOL1-targeted therapies to reduce kidney disease disparities.