BACKGROUND Metastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODS Our prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTS Patients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSION These data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDING National Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.
Nima Sharifi, Robert Diaz, Hui-Ming Lin, Evan Roberts, Lisa G. Horvath, Andrew Martin, Martin R. Stockler, Sonia Yip, Vinod V. Subhash, Neil Portman, Ian D. Davis, Christopher J. Sweeney
BACKGROUND. Neoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes are poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 TCRs specific for KRASG12V restricted to HLA-A3 superfamily of class I alleles. METHODS. A phase I clinical vaccine trial targeting KRASMUT was conducted. TCRs targeting KRASG12V restricted to HLA-A*03:01 or HLA-A*11:01 were isolated from vaccinated patients or healthy individuals. A comprehensive analysis of TCR antigen specificity, affinity, cross-reactivity, and CD8 coreceptor dependence was performed. TCR lytic activity was evaluated, and target antigen density was determined by quantitative immunopeptidomics. RESULTS. Vaccination against KRASMUT resulted in the priming of CD8+ and CD4+ T cell responses. KRASG12V -specific natural (not affinity-enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernable reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude cross-reactivity to non-cognate peptides derived from the human proteome. Both HLA-A*03:01 and HLA-A*11:01 restricted TCR-redirected CD8+ T cells exhibited potent lytic activity against KRASG12V cancers, while only HLA-A*11:01 restricted TCR-T CD4+ T cells exhibited anti-tumor effector functions consistent with partial co-receptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of of peptide/HLA (4.4 to 242) complexes per cell. CONCLUSION. This study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT03592888. FUNDING. AACR SU2C / Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH (R01 CA204261, P01 CA217805, P30 CA016520).
Adham S. Bear, Rebecca B. Nadler, Mark H. O'Hara, Kelsey L. Stanton, Chong Xu, Robert J. Saporito, Andrew J. Rech, Miren L. Baroja, Tatiana Blanchard, Maxwell H. Elliott, Michael J. Ford, Richard C. Jones, Shivang Patel, Andrea L. Brennan, Zachary O'Neil, Daniel J. Powell Jr., Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno
BACKGROUND Frailty significantly affects morbidity and mortality rates in the older population (age >65 years). Age-related degenerative diseases are influenced by the intestinal microbiota. However, limited research exists on alterations in the intestinal microbiota in frail older individuals, and the effectiveness of prebiotic intervention for treating frailty remains uncertain.OBJECTIVE We sought to examine the biological characteristics of the intestinal microbiome in frail older individuals and assess changes in both frailty status and gut microbiota following intervention with a prebiotic blend consisting of inulin and oligofructose.METHODS The study consisted of 3 components: an observational analysis with a sample size of 1,693, a cross-sectional analysis (n = 300), and a multicenter double-blind, randomized, placebo-controlled trial (n = 200). Body composition, commonly used scales, biochemical markers, intestinal microbiota, and metabolites were examined in 3 groups of older individuals (nonfrail, prefrail, and frail). Subsequently, changes in these indicators were reevaluated after a 3-month intervention using the prebiotic mixture for the prefrail and frail groups.RESULTS The intervention utilizing a combination of prebiotics significantly improved frailty and renal function among the older population, leading to notable increases in protein levels, body fat percentage, walking speed, and grip strength. Additionally, it stimulated an elevation in gut probiotic count and induced alterations in microbial metabolite expression levels as well as corresponding metabolic pathways.CONCLUSIONS The findings suggest a potential link between changes in the gut microbiota and frailty in older adults. Prebiotics have the potential to modify the gut microbiota and metabolome, resulting in improved frailty status and prevention of its occurrence.TRIAL REGISTRATION ClinicalTrials.gov NCT03995342.
Jie Yang, Liming Hou, Anhui Wang, Lei Shang, Xin Jia, Rong Xu, Xiaoming Wang
BACKGROUND. Bariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1 to 3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin. METHODS. To identify mediators of disordered metabolism in PBH, we analyzed plasma metabolome in fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-RYGB (n = 10), and non-surgical controls (n = 8). RESULTS. In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30% to 80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20% to 50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2- to 10-fold in PBH in fasting state. Postprandially, plasma serotonin was uniquely increased by 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin. CONCLUSION. Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target. FUNDING. NIH grant R01 DK121995, NIH grant P30 DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP grant 2018/22111-2.
Rafael Ferraz-Bannitz, Berkcan Ozturk, Cameron J. Cummings, Vissarion Efthymiou, Pilar Casanova Querol, Lindsay Poulos, Hanna J. Wang, Valerie Navarrete, Hamayle Saeed, Christopher M. Mulla, Hui Pan, Jonathan M. Dreyfuss, Donald C. Simonson, Darleen A. Sandoval, Mary-Elizabeth Patti
BACKGROUND. Recent studies conducted in COVID-19 survivors suggest that SARS-CoV-2 infection is associated with an increased risk of dyslipidemia. However, it remains unclear whether this augmented risk is confirmed in the general population and how this phenomenon is impacting the overall burden of cardiometabolic diseases. METHODS. To address these aspects, we conducted a 6-year longitudinal study to examine the broader effects of COVID-19 on dyslipidemia incidence within a real-world population (228,266 subjects) residing in Naples, Southern Italy. The pre-COVID-19 and the COVID-19 groups were balanced for demographic and clinical factors using propensity score matching. RESULTS. Our analysis spans over a period of three years during the pandemic (2020–2022), comparing dyslipidemia incidence with pre-pandemic data (2017–2019), with a follow-up time of at least 1,095 days corresponding to 21,349,215 person-years. During the COVID-19 period we detected an increased risk of developing any dyslipidemia when compared with the pre-COVID-19 triennium (OR = 1.29, 95% CI 1.19–1.39). Importantly, these estimates were adjusted for comorbidities by a multivariate analysis. CONCLUSIONS. Taken together, our data reveal a notable rise in dyslipidemia incidence amid the COVID-19 pandemic, suggesting to establish specialized clinical monitoring protocols for COVID-19 survivors to mitigate the risk of dyslipidemia development.
Valentina Trimarco, Raffaele Izzo, Stanislovas S. Jankauskas, Mario Fordellone, Giuseppe Signoriello, Maria Virginia Manzi, Maria Lembo, Paola Gallo, Giovanni Esposito, Roberto Piccinocchi, Francesco Rozza, Carmine Morisco, Pasquale Mone, Gaetano Piccinocchi, Fahimeh Varzideh, Bruno Trimarco, Gaetano Santulli
BACKGROUND. The HIV Organ Policy Equity (HOPE) Act allows individuals living with HIV to accept organs from donors with HIV. This practice widens the pool of available organs, but also presents important virological questions, including the potential for HIV superinfection of the recipient, viral persistence in the kidney, and loss of virological control. METHODS. We addressed these questions by performing in-depth longitudinal viral sequence analyses on urine, blood, and urine-derived renal epithelial cells from twelve recipients of HIV+ kidney allografts. RESULTS. We amplified donor-derived HIV-1 env sequences in 5 out of 12 recipients post-transplant. These donor-derived env sequences were amplified from recipient urine, urine-derived renal epithelial cells, and plasma between 12 and 96-hours post-transplant and remained detectable up to 16-days post-transplant. Env sequences were also detected in kidney biopsies taken from the allografts before implantation in 6 out of the 12 transplant cases, indicating the presence of donor virus within the organ. One recipient had a viremic episode 3.5 years after transplantation as a result of ART interruption. Only recipient strain viral sequences were detected in blood, suggesting that the donor virus, if still present, was not reactivated during the temporary ART withdrawal. CONCLUSIONS. This study demonstrates that the HIV env sequences in a donor kidney can be amplified from biopsies taken from the allograft before implantation and can be detected transiently in blood and urine samples collected from the organ recipients post-transplantation.
Tatianna Travieso, Hannah Stadtler, Naseem Alavian, Feng Gao, Mary Klotman, Cameron R. Wolfe, Maria Blasi
BACKGROUND It is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODS Three cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTS Monogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (–3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (–2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONS Monogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATION NA.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
Mark D. Elliott, Natalie Vena, Maddalena Marasa, Enrico Cocchi, Shiraz Bheda, Kelsie Bogyo, Ning Shang, Francesca Zanoni, Miguel Verbitsky, Chen Wang, Victoria Kolupaeva, Gina Jin, Maayan Sofer, Rafael Gras Pena, Pietro A. Canetta, Andrew S. Bomback, Lisa M. Guay-Woodford, Jean Hou, Brenda W. Gillespie, Bruce M. Robinson, Jon B. Klein, Michelle N. Rheault, William E. Smoyer, Larry A. Greenbaum, Larry B. Holzman, Ronald J. Falk, Afshin Parsa, Simone Sanna-Cherchi, Laura H. Mariani, Matthias Kretzler, Krzysztof Kiryluk, Ali G. Gharavi, CureGN Consortium
Background. Most humans have been infected by Cytomegalovirus (CMV) by the time they reach forty years of age. Whereas most of these CMV infections are well controlled by the immune system, congenital infection can lead to serious health effects and death for the fetus and neonate. Most humans have been infected bywith cytomegalovirus (CMV) by the time they reach mid-life without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled, and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus is lower during chronic maternal infection, and varies in association with gestational age at the time of primary maternal infection, further research on humoral immune responses to primary CMV infection during pregnancy is needed. Methods. Here, systems serology tools were applied to characterize antibody responses to CMV infection inamong pregnant and non-pregnant women experiencing either primary or chronic infection. Results. Whereas strikingly different antibody profiles were observed depending on infection status, more limited differences were associated with pregnancy status. Beyond known differences in IgM responses that are used clinically for identification of primary infection, distinctions observed in IgA and FcγR- binding antibodiesy responses and among viral antigen specificities accurately predicted infection status in a cross-sectional cohort. Leveraging machine Machine learning, longitudinal samples were also was used to define an immunological clock of CMV infectionthe transition from primary to chronic states and predict time since primary infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as is typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection. Conclusion. In sum, this work provides new insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics and to support clinical trials of interventions to reduce mother-to-fetus transmission of CMV. Trial registration. Not applicable Funding. CYMAF consortium and National Institutes of Health
Andrew P. Hederman, Christopher J. Remmel, Shilpee Sharma, Harini Natarajan, Joshua A. Weiner, Daniel Wrapp, Catherine Donner, Marie-Luce Delforge, Piera d'Angelo, Milena Furione, Chiara Fornara, Jason S. McLellan, Daniele Lilleri, Arnaud Marchant, Margaret E. Ackerman
Background. Donor cell engraftment is a pre-requisite of successful allogeneic hematopoietic stem cell transplantation. Based on peripheral blood analyses it is characterized by early myeloid recovery and T- and B-cells lymphopenia. However, cellular networks associated with bone marrow engraftment of allogeneic human cells have been poorly described. Methods. Mass cytometry and CITEseq analyses were performed on bone marrow cells, three months post-transplant in patients with acute myelogenous leukemia. Results. Mass cytometry in 26 patients and 20 healthy controls disclosed profound alterations in myeloid and B-cell progenitors, with a shift towards terminal myeloid differentiation and decreased B-cell progenitors. Unsupervised analysis separated recipients into 2 groups, one of them being driven by previous GVHD (R2 patients). We then used single-cell CITEseq to decipher engraftment, which resolved 36 clusters, encompassing all bone marrow cellular components. Hematopoiesis in transplant recipients was sustained by committed myeloid and erythroid progenitors in a setting of monocytes-, NK cells- and T-cells mediated inflammation. Gene expression disclosed major pathways in transplant recipients, namely, TNFα signaling via NFκ-B, and interferon-γ response. The hallmark of allograft rejection was consistently found in clusters from transplant recipients, especially in R2 recipients. Conclusion. Bone marrow cell engraftment of allogeneic donor cells is characterized by a state of emergency hematopoiesis in the setting of allogeneic response driving inflammation. Trial registration. Not applicable. Funding. This study has been supported by the French National Cancer Institute (Institut National du Cancer): PLBIO19-239 and by an unrestricted research grant by Alexion Pharmaceutical.
Jennifer Bordenave, Dorota Gajda, David Michonneau, Nicolas Vallet, Mathieu F. Chevalier, Emmanuelle Clappier, Pierre Lemaire, Stéphanie Mathis, Marie Robin, Aliénor Xhaard, Flore Sicre de Fontbrune, Aurélien Corneau, Sophie Caillat-Zucman, Regis PEFFAULT de LATOUR, Emmanuel Curis, Gerard Socie
Background Cystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases. Methods Using whole genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies. Results In 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with novel statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK BioBank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations but suggested this category of variation contributes 3-9% to the heritability of CyKD across European ancestries. Conclusion By providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counselling in the clinic. Keywords: genomics, cystic kidney disease, renal, ADPKD, WGS
Omid Sadeghi-Alavijeh, Melanie MY. Chan, Gabriel T. Doctor, Catalin D. Voinescu, Alexander Stuckey, Athanasios Kousathanas, Alexander T. Ho, Horia C. Stanescu, Detlef Bockenhauer, Richard N. Sandford, Adam P. Levine, Daniel P. Gale
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