The study of rare pediatric disorders is fundamentally limited by small patient numbers, making it challenging to draw meaningful biological conclusions. To address this, we developed a framework integrating clinical ontologies with proteomic profiling, enabling the systematic analysis of rare conditions in aggregate. We applied this approach to urine and plasma samples from 1140 children and adolescents

Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in five pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped

Gonadotropin injections used to stimulate oocyte production during assisted reproductive technology (ART) procedures are associated with the risk of an abnormal response in predisposed patients suffering polycystic ovary syndrome (PCOS). Liver X receptors (LXR) pathway has been identified as key regulators during this process. This study explores the integration of the hormonal signals, cellular networks

The L-Leu amino acid transporter SLC7A5 has become an important target in inflammation and cancer. However, its role in acute graft-versus-host disease (aGVHD) and graft versus tumor (GVT) remains unexplored. We demonstrate that SLC7A5 deletion affected T cell activation, expansion and survival, and reduced IFNγ and granzyme B expression, thus controlling aGVHD, but without effect on tumor growth.

Toxoplasma gondii, a neurotropic protozoan, causes toxoplasmosis, a prevalent zoonotic and food-borne infection, posing significant risks to immunocompromised individuals and congenital cases. The chronic phase, characterized by dormant, cyst-forming bradyzoites, is central to disease progression but is poorly understood due to the lack of serological tests to detect bradyzoite-specific antigens. This

Mutations in PIK3R1 have recently been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85α which acts as the regulatory subunit of the lipid kinase PI3Kα. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway. Currently, there are no approved treatments specifically dedicated to patients with PIK3R1 mutations, and medical care

Triple transfection of HEK293 cells is the most widely used method for producing recombinant adeno-associated virus (rAAV), a leading gene delivery vector for human gene therapy. Despite its tremendous success, this approach generates several vector-related impurities that could potentially compromise the safety and potency of rAAV. In this study, we introduce a method for high-purity AAV vector production

Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D

Glioblastoma remains incurable and recurs in all patients. Here we design and characterize a novel induced-recurrence model in which mice xenografted with primary patient-derived glioma initiating/stem cells (GIC) are treated with a therapeutic regimen closely recapitulating patient standard of care, followed by monitoring until tumours recur (induced recurrence patient-derived xenografts, IR-PDX)

Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling

Primary cilia are solitary organelles formed by a microtubule-based skeleton protruding in a single copy on the surface of most cells. Alterations in their function cause a plethora of human conditions collectively called the ciliopathies. The kidney is frequently and severely affected in the ciliopathies, presenting with a spectrum of phenotypes. Cyst formation is a common trait of all renal ciliopathies

Fibrosis is a key feature of a broad spectrum of cystic kidney diseases, especially autosomal recessive kidney disorders such as nephronophthisis (NPHP). However, its contribution to kidney function decline and the underlying molecular mechanism(s) remains unclear. Here, we show that kidney-specific deletion of Fbxw7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase, results in a juvenile-adult

Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across

Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution

Genomics has transformed the diagnostic landscape of pediatric malignancies by identifying and integrating actionable features that refine diagnosis, classification, and treatment. Yet, translating precision oncology data into effective therapies for hard-to-cure childhood, adolescent, and young adult malignancies remains a significant challenge. We present the case for combining proteomics with patient-derived

Saccharin has been part of the human diet for over 100 years, and there is a comprehensive body of evidence demonstrating that it can influence the gut microbiome, ultimately impacting human health. However, the precise mechanisms through which saccharin can impact bacteria have remained elusive. In this work, we demonstrate that saccharin inhibits cell division, leading to cell filamentation with

Circulating neutrophils are responsible for poor neurological outcomes and have been implicated in respiratory morbidity after acute ischemic stroke (AIS). However, the molecular mechanisms regulating neutrophil responses and their pathological relevance in post-stroke complications remain unclear. In this study, we investigated the involvement of hematopoietic progenitor kinase 1 (HPK1) in neutrophil

Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different

Metastatic melanoma can be treated with anti-PD-1 monotherapy or in combination with anti-CTLA-4 or anti-Lag3. However, combination therapy is associated with a high risk of toxicity. Recently, we reported that high plasma soluble CD27 (sCD27) levels reflect the intratumoral interaction of CD70-CD27 and dysfunctional T cells in the tumor microenvironment of renal cell carcinoma. In this study, we first

The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin

The intratumoral immune milieu is crucial for the success of anti-cancer immunotherapy. We show here that stromal modulation by the tubulin-binding anti-cancer drugs combretastatin A4 (CA-4) and eribulin improved tumor perfusion and anti-tumor immunity. This was achieved by reverting highly proliferative, angiogenic pericytes into a quiescent, contractile state which durably normalized the vascular

Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. Here, we identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic intervention through a high-throughput chemical screening of 2160 compounds. Moreover, we detailed how both genetic

ADP-ribosyl transferases (ARTs) are a family of enzymes which catalyze the addition of a chain (PARylation) or a single moiety (MARylation) of ADP-ribose to their substrates. PARP7 is a mono-ADP-ribosyl transferase (mono-ART) which has recently gained attention due to its emerging role as a negative regulator of the type I interferon (IFN-I) and nuclear receptor signaling, and due to its aberrant expression

Molecular changes underlying the persistent health effects after SARS-CoV-2 infection remain poorly understood. To discern the gene regulatory landscape in the upper respiratory tract of COVID-19 patients, we performed enzymatic DNA methylome and single-cell RNA sequencing in nasal cells of COVID-19 patients (n = 19, scRNA-seq n = 14) and controls (n = 14, scRNA-seq n = 10). In addition, we resampled

Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality, with maternal stress-related disorders, such as depression and anxiety, linked to idiopathic PTB (iPTB). At the maternal-fetal interface, decidualized stromal cells (DSCs) exclusively express the progesterone receptor (PR) and play pivotal roles in maintaining pregnancy and initiating labor. DSCs also express FKBP51, a protein

We aimed to restore MHC-I expression on the surface of solid tumors including breast cancer and melanoma cells to regain sensitivity to immunotherapy and suppress metastatic progression. We screened a natural compound library and identified macbecin II as a reagent that upregulates MHC-I expression and induces antigen-dependent cell death in pre-invasive and invasive breast cancer models. Furthermore

Viral infections pose a significant global burden. Host susceptibility to pathogens is determined by many factors including genetic variation that can lead to immunodeficient or dysregulated antiviral immune responses. Pax5 heterozygosity (Pax5-/+), resulting in reduced PAX5 levels in mice, mimics germline or somatic PAX5 dysregulation contributing to diseases such as childhood B-cell precursor acute

Host-microbiome communication is frequently perturbed in gut pathologies due to microbiome dysbiosis, leading to altered production of bacterial metabolites. Among these, 7α-dehydroxylated bile acids are notably diminished in inflammatory bowel disease patients. Herein, we investigated whether restoration of 7α-dehydroxylated bile acids levels by Clostridium scindens, a human-derived 7α-dehydroxylating

Tumors often recapitulate programs to acquire invasive and dissemination abilities, during which pro-metastatic proteins are distinctively stabilized in cancer cells to drive further progression. Whether failed protein degradation affects the metastatic programs of cancer remains unknown. Here, we show that the human cancer cell-specific knockout (KO) of LAMP-2A, a limiting protein for chaperone-mediated

Mycobacterial infections pose a significant global health concern, requiring precise identification for effective treatment. However, diagnosing them is challenging due to inaccurate identifications and prolonged times. In this study, we aimed to develop a novel peptidome-based method using mycobacterial growth indicator tube (MGIT) cultures for faster and more accurate identification. We created the

As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction and neurological deficits, accompanied by a reduction

After the Covid-19 pandemic, pertussis has made a spectacular comeback in Europe and many other parts of the world, while during the pandemic it had essentially disappeared because of the social distancing requirements. However, even before the Covid-19 pandemic, the disease was on the rise in many countries, especially those that have replaced whole-cell pertussis vaccines by acellular pertussis vaccines

X-linked myopathy with excessive autophagy (XMEA), a rare childhood-onset autophagic vacuolar myopathy caused by mutations in VMA21, is characterized by proximal muscle weakness and progressive vacuolation. VMA21 encodes a protein chaperone of the vacuolar hydrogen ion ATPase, the loss of which leads to lysosomal neutralization and impaired function. At present, there is an incomplete understanding

Regulatory T cells (Tregs) play critical roles in inhibiting antitumor immunity, which is dependent on FOXP3-mediated transcriptional activity. However, no Treg-specific therapeutics has been approved for clinical use. We performed a high-throughput screen of FDA-approved drugs for potential inhibitors of FOXP3 transcriptional activity. These efforts identified Lanatoside C (Lac), which potently inhibits

Glioblastomas (GBM) are routinely treated with high doses of ionizing radiation (IR), yet these tumors recur quickly, and the recurrent tumors are highly therapy resistant. Here, we report that IR-induced senescence of tumor cells counterintuitively spurs GBM recurrence, driven by the senescence-associated secretory phenotype (SASP). We find that irradiated GBM cell lines and patient derived xenograft

The adipokine apelin has been directly implicated in various physiological processes during embryogenesis and human cancers. Nevertheless, the importance of the conversion of its precursor proapelin to mature apelin in tumorigenesis remains unknown. In this study, we identify Furin as the cellular proprotein convertase responsible for proapelin cleavage. We explore the therapeutic potential of targeting

In 2020-2021, a "mysterious illness" struck Senegalese fishermen, causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity. Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins. Specifically, we show that the toxin PortimineA

Colorectal cancer (CRC) is a major health problem, with an alarming increase of early-onset CRC (EO-CRC) cases among individuals under 50 years of age. This trend shows the urgent need for understanding the underlying mechanisms leading to EO-CRC development and progression. There is significant evidence that the gut microbiome acts as a key player in CRC by triggering molecular changes in the colon

Changes in gut microbiota composition have been linked to anxiety behavior in rodents. However, the underlying neural circuitry linking microbiota and their metabolites to anxiety behavior remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed to live microbes, increased anxiety-related behavior was observed correlating with a significant increase in the immediate early c-Fos gene in

Esophagitis is a frequent, but at the molecular level poorly characterized condition with diverse underlying etiologies and treatments. Correct diagnosis can be challenging due to partially overlapping histological features. By proteomic profiling of routine diagnostic FFPE biopsy specimens (n = 55) representing controls, Reflux- (GERD), Eosinophilic-(EoE), Crohn's-(CD), Herpes simplex (HSV) and Candida

Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing

The exposome is the measure of all the exposures of an individual in a lifetime and how those exposures relate to health. Exposomics is the emerging field of research to measure and study the totality of the exposome. Exposomics can assist with molecular medicine by furthering our understanding of how the exposome influences cellular and molecular processes such as gene expression, epigenetic modifications

Studying the human immune system in vivo is challenging and often not possible. Therefore, most human immunology studies have been predominantly confined to peripheral blood analyses, which by themselves have inherent limitations, as many immune reactions take place within tissues. For example, potent antibody responses that contribute to fighting infections and provide protection following vaccination

Recent studies argue for a novel concept of the role of chromatin as a carrier of epigenetic memory through cellular and organismal generations, defining and coordinating gene activity states and physiological functions. Environmental insults, such as exposures to unhealthy diets, smoking, toxic compounds, and infections, can epigenetically reprogram germ-line cells and influence offspring phenotypes

The gut microbiome, or the community of microorganisms residing in the gastrointestinal tract, has emerged as an important factor in breast cancer etiology and treatment. Specifically, the impact of gut bacterial populations on breast cancer therapeutic outcomes is an emerging area of research. The microbiota's role in modifying the pharmacokinetics of chemotherapy and endocrine-targeting therapies

In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially

Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells

Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This

Current studies pictured the enteric nervous system and macrophages as modulators of neuroimmune processes in the inflamed gut. Expanding this view, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. In the early postsurgical phase, we detected strong neuronal activation, followed by transcriptional

The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated

Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Although the risk of developing CRC increases with age, approximately 10% of newly diagnosed cases occur in individuals under the age of 50. Significant changes in dietary habits in young adults since industrialization create a favorable microenvironment for colorectal

The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical