Journal of Clinical Investigation

STUDY QUESTIONAre pathogenic variants in Homeodomain-interacting protein kinase (HIPK4) associated with sperm head abnormalities causing male infertility? SUMMARY ANSWERHIPK4 is a novel candidate gene associated with sperm head defects and human male infertility. WHAT IS KNOWN ALREADYNumerous genes causing male infertility due to Multiple Morphological Abnormalities of the sperm flagella (MMAF) have been described but the genetic basis of sperm head defects is less well understood. STUDY DESI...

The long-term impact of SARS-CoV-2 infection on kidney allograft survival remains incompletely understood, particularly regarding the influence of vaccination, acute kidney injury (AKI), and post-infection immunosuppression. We conducted a retrospective analysis of 129 kidney transplant recipients with confirmed SARS-CoV-2 infection between March 2020 and March 2022 with a median follow-up of 50 months. Among 129 recipients, 106 (82%) received vaccination at any time before or after SARS-CoV-2 i...

Kidney transplantation faces a critical paradox: while thousands await organs, approximately 30% of potential deceased donor kidneys are discarded for various reasons, including subjective assessments due to the lack of an objective molecular biomarker of preservation quality. Here, we applied novel "top-down" proteoform imaging mass spectrometry across living donor (LD), deceased donor (brain death or cardiac death), and discarded human kidneys to quantify proteoforms correlating with post-tran...

Allogeneic hematopoietic cell transplantation (allo-HCT) hinges on a delicate trade-off between graft-versus-tumor control and graft-versus-host disease (GvHD), mediated by donor T-cell recognition of antigens presented by recipient human leukocyte antigen (HLA) molecules. We hypothesized that, beyond allele-level matching, sequence divergence at peptide-binding grooves across donor and recipient HLA loci shapes these responses. To this end, we evaluated the effect of HLA evolutionary divergence...

BackgroundIn lung transplantation, de novo immunodominant donor-specific anti-HLA antibodies recognizing HLA-DQ antigens (dn-iDSA-DQ) are predominant and can induce chronic lung allograft dysfunction (CLAD). We previously developed a method to measure the active concentration of dn-iDSA-DQ. We aimed to determine whether this new quantitative biomarker is associated with transplantation outcomes. MethodsThis retrospective multicentre cohort study included 90 lung transplant recipients (LTRs) dev...

BackgroundIron metabolism disorder is highly prevalent before and after heart transplantation (HTx). The impact of pretransplant and posttransplant iron disorder on posttransplant outcomes is unclear. ObjectivePretransplant serum levels of key regulator proteins of iron metabolism (hepcidin, interleukin-6, erythroferrone) were tested for prediction of the composite outcome 1-year posttransplant all-cause mortality (ACM) or [≥]moderate acute cellular rejection (ACR). Furthermore, serum levels...

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with bo...

Relapsed and/or refractory disease remains the leading cause of death in AML, highlighting the need for broadly applicable, high-sensitivity approaches to MRD detection. We developed AML-CAPP-Seq (Cancer Personalized Profiling by Deep Sequencing), a personalized hybrid-capture assay that tracks both canonical AML drivers and patient-specific variants identified by whole-exome sequencing. In 56 patients with longitudinal plasma and matched peripheral blood and bone marrow samples, AML-CAPP-Seq en...

Plant-based dietary strategies may offer a tractable approach to mitigating microbiome disruption and improving outcomes in patients undergoing autologous hematopoietic cell transplantation (auto-HCT) for multiple myeloma, a population in whom intestinal dysbiosis has been linked to infectious complications and inferior survival. We conducted a single-arm study to test the feasibility and biological activity of a high-fiber, plant-based, whole-food meal delivery intervention during the peri-tran...

Antiphospholipid syndrome (APS) and systemic sclerosis (SSc) are immune-mediated multisystem autoimmune diseases with distinct clinical phenotypes but overlapping pathogenic themes, including immune dysregulation, chronic inflammation, and endothelial injury. Using peripheral blood transcriptome datasets from the Gene Expression Omnibus (GSE102215: 9 APS/9 controls; GSE231691: 49 SSc/18 controls), we performed differential expression analysis within each cohort (limma; |log2FC|>1, P<0.05) and id...

Allogeneic hematopoietic cell transplantation is the only curative option for many patients with acute myeloid leukemia (AML). In the current study, we designed and implemented a personalized assay, called v96, incorporating up to 96 mutations in 30 AML patients undergoing transplantation. The assay was performed on DNA derived in cells from the bone marrow as well as in cell-free plasma. All 30 (100%) of patients harbored molecular evidence of residual leukemia during remission that was detecta...

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and life-threatening complication of chimeric antigen receptor (CAR) T-cell therapy, with early detection being critical for timely intervention and improved outcomes. Cytokines such as interleukin-6 (IL-6) are key mediators of the inflammatory cascade underlying ICANS pathogenesis, but prospective clinical evidence for their predictive value is limited. Here we quantify IL-6 levels in a prospective cohort of 40 CAR-T pat...

BackgroundAnthracyclines are central to childhood cancer therapy but predispose patients to cardiotoxicity leading to long-term cardiovascular risk. Endothelial injury and impaired repair contribute to this, yet pediatric data remain limited. ObjectiveTo longitudinally assess endothelial injury and repair in childhood cancer patients treated with anthracyclines by quantifying circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs). MethodsIn a single-centre retrospective c...

BackgroundChronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent and debilitating condition with unclear etiology. Increasing evidence implicates immune dysregulation, yet the molecular mechanisms underlying impaired immune regulation remain poorly defined. This study investigated the role of adaptive immune responses and DNA methylation in CP/CPPS pathogenesis. MethodsVoided bladder 3 (VB3) urine samples from CP/CPPS patients and healthy controls were analyzed for CD4 T cell...

PurposeNovel therapies to prevent lethal castration resistant prostate cancer in response to standard-of-care androgen deprivation therapy (ADT) are required. Unfortunately, most prostate cancers are "immune cold" and fail to respond to checkpoint inhibitors (CPIs). To assess whether ADT induces changes that enable more effective CPI therapy, we examined the tumor immune micro-environment (TiME) following neoadjuvant ADT (nADT). DesignRadical prostatectomy specimens from 43 nADT-treated patient...

BackgroundThe effects of Banff histological diagnoses on kidney transplant outcome have been well characterized. However, repeated observation of such histological injury across multiple biopsies in kidney transplant recipients remains insufficiently explored. MethodsIn an observational cohort (N=1819 transplantations with 5736 post-transplant biopsies, recurrent event survival models quantified transitions between diagnoses of T-cell mediated rejection (TCMR), antibody-mediated rejection (AMR)...

Aggressive variant prostate cancer (AVPC) is a lethal subtype of prostate cancer characterized by its androgen independence, resistance to chemotherapy, and display of neuroendocrine features which can emerge either de novo or via transformation after a prior diagnosis of adenocarcinoma. The poor clinical outcomes in patients with AVPC are associated with its profound molecular heterogeneity. In this study, we analyzed 23 consecutive AVPC cases treated at a dedicated small-cell clinic (2017-2025...

The integration of regenerative medicine into dynamic organ preservation may mitigate ischemia-reperfusion injury in kidney transplantation. This systematic review and meta-analysis evaluated the therapeutic potential of stem cell-based interventions during machine perfusion. Following PRISMA guidelines, PubMed, Embase, and Scopus were searched for experimental studies using stem cells or extracellular vesicles (EVs) during hypothermic or normothermic machine perfusion in animal or discarded hum...

This small pilot feasibility study shows that reverse phase protein array (RPPA) technology is a useful tool for targeted proteomics analysis in human ovarian follicular fluid. RPPA supplements mass spectrometry approaches that are currently used by providing functional signal transduction data that drive cellular biology. Herein, we present the first report of using RPPA in follicular fluid to elucidate protein signaling pathways. The results show potential associations between follicular fluid...

IntroductionBRCA1/2 alterations are increasingly recognized as biologically and clinically relevant features in prostate cancer, yet the prognostic and therapeutic significance of zygosity status remains uncertain. Understanding differences between monoallelic and biallelic inactivation may refine risk stratification and guide therapeutic decision-making. Materials and MethodsA retrospective, desk-based observational analysis was performed using publicly accessible datasets from TCGA-PRAD (prim...