Issue published April 1, 2026 Previous issue
- Volume 136, Issue 7
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On the cover: Microtubule bundling in alveolar stem cell differentiation
Konishi et al. report a unique thick microtubule bundle organization that is required to generate expansive and thin cell morphology during alveolar type 2 cell differentiation into alveolar type 1 cells. The cover image shows cultured lung pneumocyte type 1 cells with staining for acetylated tubulin (green) and nuclei (magenta). Image credit: Aleksandra Tata.
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Review Series
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Abstract
Recent advances in genomic technologies have greatly enhanced our understanding of neurodegeneration. Techniques like whole-genome sequencing, long-read sequencing, and large-scale population studies have expanded the range of identified genetic risk factors, uncovering new disease mechanisms and biological pathways that could serve as therapeutic targets. However, translating these genetic insights into clinical practice remains difficult because of challenges in interpreting variants and the limited functional validation of new discoveries. This Review highlights the key genomic technologies advancing diagnosis and research in neurodegeneration. We focus on improvements in variant classification, detection of structural variants and repeat expansions, and combining transcriptomic, proteomic, and functional data to better determine variant pathogenicity. The ongoing integration of genomics, molecular neurobiology, and data science offers great potential for more accurate, biologically informed diagnosis and treatment of neurodegenerative disorders.
Authors
Maurizio Grassano, Alice B. Schindler, Bryan J. Traynor, Sonja W. Scholz
×Abstract
Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.
Authors
Stefano De Tito, Sharon A. Tooze
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Commentaries
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Abstract
Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to target synaptic loss will require human studies that clarify their clinical relevance of these changes. In the current issue, Zakiniaeiz et al. demonstrate that AUD and alcohol consumption are associated with lower synaptic vesicle glycoprotein 2a (SV2A) expression, indexed by regional [11C]UCB-J PET. This is, to our knowledge, the first in vivo evidence of relationships between synaptic density and alcohol use, and, as such, it represents an important step toward understanding how AUD influences brain structure and function. Here, we describe two longstanding clinical issues in the AUD population — relapse and dementia risk — and how the results of the present study may guide future investigations of these issues.
Authors
Sarah K. Royse, Rajesh Narendran
×Abstract
Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.
Authors
Lorenz C. Hofbauer, Martina Rauner
×Abstract
Crohn’s disease can occur anywhere along the small and/or large intestines, but most commonly occurs in the terminal ileum or ascending colon. Factors governing this region-specific inflammation are poorly understood. In this issue of the JCI, Spencer et al. used a TNF-driven mouse model of small intestinal Crohn’s disease to identify a specific bacterial pathobiont, Chlamydia muridarum, as a necessary and sufficient driver of region-restricted inflammation. C. muridarum triggered increased goblet cell expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the mouse proximal colon, analogous to the human ascending colon. IDO1 metabolism of tryptophan stimulated increased levels of kyneurine, and suppression of this IDO1/kyneurine axis alleviated C. muridarum–provoked inflammation in the proximal colon but not the terminal ileum. Analysis of scRNA-seq datasets from patients with Crohn’s disease with ascending colon involvement also supported increased IDO1 expression in a subpopulation of crypt surface epithelial cells. The study highlights a process by which bacterial pathobionts promote region-specific intestinal inflammation.
Authors
Declan F. McCole
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Research Letters
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Abstract
Authors
Bingyu Yan, Jinwoo Lee, Suhas Srinivasan, Pedro Ambriz, Quanming Shi, Diana R. Dou, Srijana Davuluri, Swarna Nandyala, Adrianne Woods, Gwendolyn Leatherman, Yanding Zhao, Roman E. Reggiardo, Manasi Sawant, Hawa Racine Thiam, Ami A. Shah, David F. Fiorentino, Lorinda S. Chung, Howard Y. Chang
×Abstract
Authors
Fadil M. Hannan, Mark Stevenson, Taha Elajnaf, Hussam Rostom, Kate E. Lines, Michelle Stewart, Sara Wells, Lee Moir, Thomas J. Gardella, Rajesh V. Thakker
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Research Articles
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Abstract
Cytokines mediating epithelial and immune cell interactions modulate mucosal healing—a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing and flow cytometry suggested FAS as the predominant colonic epithelial receptor for TNFSF13, which was confirmed by co-immunoprecipitation and binding assays. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in immunoglobulin-producing plasma cells compared to control colonoid cocultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.
Authors
Xianghui Ma, Shaneice K. Nettleford, Yuhua Tian, Noor Dawany, Ayano Kondo, Yalan Li, Kelly Maurer, Tatiana A. Karakasheva, Rawan Shraim, Patrick A. Williams, Louis R. Parham, Lauren A. Simon, Charles H. Danan, Maire A. Conrad, David A. Piccoli, Marcella Devoto, Neil Romberg, Kathleen E. Sullivan, Klaus H. Kaestner, Judith R. Kelsen, Kathryn E. Hamilton
×Abstract
Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We examined whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome for these patients. Ectopic expression of FGFR1N546K induced constitutive downstream signaling and IL-3–independent growth in Ba/F3 cells, indicating oncogene-addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life, with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1-mutant, high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K-mutant neuroblastoma cells and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant, patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K-mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma associated with failure of current standard chemotherapy and suggest potential clinical benefit of FGFR-directed therapies in patients with high-risk mutant FGFR1.
Authors
Lisa Werr, Jana Boland, Josephine Petersen, Fiorella Iglesias, Stefanie Höppner, Christoph Bartenhagen, Carolina Rosswog, Anna-Maria Hellmann, Yvonne Kahlert, Nadine Hemstedt, Nadliv Ibruli, Marcel A. Dammert, Boris Decarolis, Jan-Michael Werner, Florian Malchers, Kathrin Schramm, Olaf Witt, Klaus H. Beiske, Anne Gro Wesenberg Rognlien, Maria Winther Gunnes, Karin P. Langenberg, Jan Molenaar, Marie Bernkopf, Sabine Taschner-Mandl, Debbie Hughes, Sally L. George, Louis Chesler, Johannes H. Schulte, Giuseppe Barone, Mario Capasso, Lea F. Surrey, Rochelle Bagatell, Julien Masliah-Planchon, Gudrun Schleiermacher, Holger Grüll, Frank Westermann, Anne M. Schultheis, Reinhard Büttner, Anton G. Henssen, Angelika Eggert, Martin Peifer, Neerav N. Shukla, Thorsten Simon, Barbara Hero, H. Christian Reinhardt, Roman K. Thomas, Matthias Fischer
×Abstract
Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, NaV1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.
Authors
Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler
×Abstract
Sleep disturbances are among the most prevalent clinical features of FOXP1 syndrome, yet their nature and underlying mechanisms remain unclear. Here, we report that individuals with FOXP1 syndrome suffer from insomnia with sleep maintenance problems and early waking. Consistently, common variants in FOXP genes were associated with insomnia symptoms and short sleep. These sleep disturbances were recapitulated in Drosophila FoxP mutants, which exhibit severely fragmented and reduced sleep. FoxP loss also led to circadian arrhythmicity and impaired the plasticity of neuropeptide pigment dispersing factor–secreting (PDF-secreting) neurons in a non-cell-autonomous manner. FoxP was required during development for adult sleep integrity, particularly in peptidergic neurons. Transcriptomic analyses revealed a dysregulation of genes involved in peptidergic signaling, including hugin. FoxP was expressed in hugin+ neurons (afferent to PDF-secreting neurons) during development, and its knockdown in these cells was sufficient to induce sleep fragmentation. Our findings establish an evolutionarily conserved role for FOXP proteins in the peptidergic regulation of sleep.
Authors
Mireia Coll-Tané, Ilse Eidhof, Jie Han, Nicholas Raun, Lara V. van Renssen, Simon E. Fisher, Matthew S. Kayser, Tjitske Kleefstra, Sigrid Pillen, Caitlin M. Hudac, Jordi Mayneris-Perxachs, Marieke Klein, Saskia Koene, Anna Castells-Nobau, Annette Schenck
×Abstract
Cells exhibit diverse sizes and shapes, tailored for functional needs of tissues. Lung alveoli are lined by large, extremely thin epithelial alveolar type 1 cells (AT1s). Their characteristic morphology is essential for lung function and must be restored after injury. The mechanisms underlying small, cuboidal alveolar type 2 cell (AT2) differentiation into thin AT1s remain elusive. Here, we demonstrated that AT2s undergo a stepwise morphological transformation characterized by the development of a unique thick microtubule (MT) bundle organization, critical for AT1 morphology. Using AT2 cultures and in vivo genetic loss-of-function models, we found that MT bundling occurred in a transitional cell state during AT2 differentiation and was regulated by the TP53/TAU (encoded by the microtubule-associated protein tau [MAPT] gene) signaling axis. Notably, TAU underwent a linear clustering process, forming beads-on-a-string-like pattern that preceded thick MT bundle formation. Genetic gain or loss of function of TAU in mouse or human models prevented the formation of thick MT bundles, highlighting the critical role of precise TAU levels in generating ultrathin AT1s. This defect was associated with increased tissue fibrosis following bleomycin-induced injury in vivo. GWAS analysis revealed risk variants in the MAPT locus in lung diseases. Moreover, TP53 controlled TAU expression and its loss phenocopied TAU deficiency. This work revealed an unexpected role for TAU in organizing MT bundles during AT2 differentiation.
Authors
Satoshi Konishi, Khaliun Enkhbayar, Shuyu Liu, Naoya Miyashita, Yoshihiko Kobayashi, Vera Hutchison, Ashna Sai, Pankaj Agarwal, Jonathan Witonsky, Nathan D. Jackson, Max A. Seibold, Jichao Chen, Aleksandra Tata, Purushothama Rao Tata
×Abstract
BACKGROUND Susceptibility to HIV-1 infection varies between individuals, but the biological determinants of acquisition risk remain poorly defined.METHODS We conducted a case-control study nested within a high-risk cohort in Kenya. We compared the plasma extracellular RNA collected before HIV-1 acquisition with that from matched uninfected individuals acting as controls to identify immunological processes linked to infection risk.RESULTS Individuals who later acquired HIV-1 exhibited upregulation of immune processes that facilitate viral infection, including T cell suppression and type II IFN and Th2 immune responses. In contrast, processes associated with antiviral defence and tissue repair, such as neutrophil and NK cell responses, type I IFN responses, wound healing, and angiogenesis, were downregulated.CONCLUSION These findings highlight dampened antiviral immunity prior to exposure as a correlate of increased risk for subsequent HIV-1 acquisition.FUNDING This work was supported by a Wellcome Trust Award (209289/Z/17/Z) and the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) through the Developing Excellence in Leadership, Training and Science in Africa (DELTAS Africa) programme (Del-22-007), which is supported by the Science for Africa Foundation; Wellcome Trust; the UK Foreign, Commonwealth & Development Office; the European Union; and the Ragon Institute of Mass General, MIT, and Harvard. The Bill & Melinda Gates Foundation, Gilead Sciences Inc., and Aidsfonds provided additional support. The US President’s Emergency Plan for AIDS Relief (PEPFAR) supported the cohort study through the US Agency for International Development (USAID).
Authors
Mwikali Kioko, Shaban Mwangi, Lynn Fwambah, Amin S. Hassan, Jason T. Blackard, Philip Bejon, Eduard Sanders, Thumbi Ndung’u, Eunice W. Nduati, Abdirahman I. Abdi
×Abstract
Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or “senotype,” is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast with clearance of p16+ senescent mesenchymal cells, targeted clearance of p16+ myeloid cells in aged mice had only minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.
Authors
Madison L. Doolittle, Mitchell N. Froemming, Jennifer L. Rowsey, Ming Ruan, Leena Sapra, Joshua N. Farr, David G. Monroe, Sundeep Khosla
×Abstract
Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and patients with obesity often develop cardiac hypertrophy and diastolic dysfunction, termed obesity cardiomyopathy. Proinflammatory cytokines, including IL-6, have been implicated in the pathogenesis of the cardiac dysfunction associated with obesity cardiomyopathy. Elevation of FFAs induced by high-fat diet (HFD) consumption induced diastolic dysfunction in the heart as early as after 1 month. HFD consumption directly stimulated IL-6 production in cardiomyocytes before local inflammation developed and induced diastolic dysfunction even in the presence of macrophage depletion with clodronate in the heart. PPARα played an essential role in mediating Il6 transcription in response to HFD consumption by forming a heterodimer with p50/RelA and binding to the NF-κB element in cardiomyocytes. Local production of IL-6 in cardiomyocytes, in turn, mediated the development of diastolic cardiac dysfunction. HFD-induced diastolic dysfunction was attenuated by cardiac-specific deletion of either Pparα or Il6, as well as by interference with the PPARα–NF-κB heterodimer formation by a molecular decoy. These results suggest elevated FFA levels directly upregulate Il6 through the PPARα–NF-κB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.
Authors
Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima
×Abstract
Mycobacterium tuberculosis remains a global health crisis, ranking among the deadliest infectious diseases worldwide. In response to the WHO’s call for therapeutic vaccines to complement antibiotic regimens and reduce tuberculosis (TB) treatment duration, we developed an intranasal DNA vaccine fusing the M. tuberculosis stringent response gene relMtb with the gene encoding the DC-targeting chemokine Mip3a (also known as CCL20). Administered alongside the first-line regimen, this vaccine accelerated a stable cure in immunocompetent murine TB models, reducing lung inflammation and eliciting robust and sustained RelMtb-stimulated T cell responses systemically and locally. The Mip3a/relMtb vaccine enhanced DC recruitment, activation, and spatial coordination with T cells, suggesting improved innate-adaptive immune synergy. Notably, it augmented the efficacy of a novel drug-resistant TB regimen as well. Critically, the vaccine induced analogous antigen-stimulated T cell immunity in nonhuman primates, the gold standard for preclinical TB vaccine evaluation, with responses detected in blood and bronchoalveolar lavage mirroring those observed in the murine models. These findings underscore the potential of this strategy to advance therapeutic TB vaccine development targeting M. tuberculosis persisters while providing a framework to define correlates of vaccine-mediated protection.
Authors
Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Farah Shamma, Harley T. Harris, Fengyixin Chen, Rowan E. Bates, Heemee Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zheng, Jiaqi Zhang, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, J David Peske, Richard B. Markham, Petros C. Karakousis
×Abstract
Vision begins in the outer segment compartment of photoreceptor cells, which is constantly renewed through the addition of membrane material at its base and ingestion of mature membranes at its tip by the retinal pigment epithelium (RPE). The close apposition of outer segments to the RPE is believed to be critical for maintaining this renewal process. Yet, in several retinal diseases, expansion of the subretinal space separating photoreceptors from the RPE does not immediately impact photoreceptor functionality. Here, we analyzed outer segment function and renewal in the Adam9-knockout mouse characterized by a major expansion of the subretinal space. Surprisingly, photoreceptor-RPE separation affected neither the sensitivity of photoreceptor light responses nor the normal rate of outer segment renewal in this mouse prior to the onset of photoreceptor degeneration. The latter is achieved through the formation of elongated RPE pseudopods extending across the enlarged subretinal space to ingest outer segment tips. This work suggests that pseudopod formation may underlie the persistence of photoreceptor function in human diseases accompanied by photoreceptor-RPE separation, such as vitelliform macular dystrophy or age-related macular degeneration associated with subretinal drusenoid deposits.
Authors
Tylor R. Lewis, Carson M. Castillo, Sebastien Phan, Camilla R. Shores, Kylie K. Hayase, Keun-Young Kim, Mark H. Ellisman, Oleg Alekseev, Marie E. Burns, Vadim Y. Arshavsky
×PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARPi may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restored NK cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlated with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells bound to ANXA6 and activated the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocked FPR1/AKT signaling and diminished the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolonged survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.
Authors
Zheng Chao, Le Li, Xiaodong Hao, Hao Peng, Yanan Wang, Chunyu Zhang, Xiangdong Guo, Peikun Liu, Sheng Ma, Junbiao Zhang, Guanyu Qu, Yuzheng Peng, Zhengping Wei, Jing Luo, Bo Liu, Peixiang Lan, Zhihua Wang
×Abstract
New androgen receptor (AR) pathway inhibitors (ARPIs) in clinical development, including AR degraders and CYP11A inhibitors, largely target ligand-dependent AR activation and have reported antitumor activity in metastatic castration-resistant prostate cancer (mCRPC) resistant to established ARPIs, predominately against tumors with AR mutations. We hypothesized that AR-mutated mCRPC exhibits lower AR splice variant 7 (AR-V7) expression and remains full-length–AR (FL-AR) driven, explaining, in part, the antitumor activity of these AR ligand–binding domain (LBD) targeting drugs. The data herein demonstrate that mCRPC tissue biopsies with detectable AR mutations express significantly lower levels of AR-V7 protein and associate with better overall survival and enhanced sensitivity to ARPIs. This is independent of differences in the total number of global splicing events but may be related to differences in splicing factor expression between AR-mutated and nonmutated mCRPC. In conclusion, AR-mutated mCRPC frequently exhibits low AR-V7 expression, arguably explaining the enhanced sensitivity to ARPIs observed in these cancers. Consequently, AR mutation status may serve as a biomarker to predict response to AR-directed therapies.
Authors
Alec Paschalis, Ines Figueiredo, Denisa Bogdan, Arian Lundberg, Rita Santos, Bora Gurel, Tarek Taha, Ossian Longoria, Ana Ferreira, Claudia Bertan, Nicholas Brittain, Ryan Nelson, Laura Walker, Antje Neeb, Jonathan Welti, Wei Yuan, Costas Mitsopoulos, Stephen R. Plymate, Michael C. Haffner, Adam G. Sowalsky, Suzanne Carreira, Adam Sharp, Luke Gaughan, Johann de Bono
×Splicing factor TRA2B enhances synthesis of androgen receptor variant AR-V7 in prostate cancer cells
Abstract
Treatment of locally advanced and metastatic prostate cancer (PC) with androgen receptor–targeting (AR-targeting) therapies has limited durability, with disease eventually progressing to castrate-resistant PC (CRPC). Constitutively active AR splice variants (AR-Vs), such as AR-V7, play a key role in driving treatment resistance and disease progression. Importantly, the failure to attenuate AR-V function represents a major unmet clinical need, and as such, defining how AR-Vs are generated is likely to yield new therapeutic targets. Our knowledge of factors that mediate splicing of AR-V–encoding mRNAs remains limited. Here, we have employed an RNA-targeting CasRx approach to identify selective protein interactors of AR-V7 mRNA in PC. TRA2B and its ortholog, TRA2A, were identified as splicing regulators of AR transcripts that facilitate AR-V synthesis at the expense of full-length AR isoforms. TRA2B expression correlated with AR-V7 transcript in CRPC and attenuation of TRA2-mediated splicing diminished PC cell growth. Exploiting TRA2B function may therefore provide new therapeutic opportunities in advanced disease.
Authors
Nicholas Brittain, Alec Paschalis, Ryan Nelson, Beth Adamson, Laura Walker, Ruaridh Duncan, Graham R. Smith, Suzanne McGill, Richard J.S. Burchmore, Denisa Bogdan, Juan M. Jiménez-Vacas, Jonathan Welti, Wei Yuan, Craig N. Robson, Pasquale Rescigno, Sara Luzzi, Adam Sharp, Johann de Bono, Luke Gaughan
×Abstract
BACKGROUND Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS.METHODS We performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 64).RESULTS After VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data.CONCLUSION MBS/VSG prompts kidney molecular adaptations, providing potential targets for nonsurgical interventions against obesity- and diabetes-associated kidney disease.FUNDING University of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.
Authors
Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad
×Abstract
BACKGROUND Cervical cancer (CC) remains the fourth leading cause of cancer-related deaths in women globally, with poor prognosis for metastatic and recurrent cases. Although genomic alterations have been extensively characterized, global proteogenomic landscape of the disease is largely under explored.METHODS Here, we present the first genome-wide proteogenomic characterization of CC, analyzing 139 tumor-normal tissue pairs using whole-genome sequencing, transcriptomics, proteomics, and phosphoproteomics.RESULTS We identified 4 distinct molecular subtypes with unique clinical outcomes: epithelial-mesenchymal transition (EMT, C1), proliferation (C2), immune response (C3), and epithelial differentiation (C4). A 4-protein classifier (CDH13, TP53BP1, NNMT, HSPB1) was developed with strong prognostic and predictive value, particularly for immunotherapy response in subtype C3. Phosphoproteomic profiling uncovered subtype-specific kinase activity, identifying actionable therapeutic targets.CONCLUSION Our findings further revealed previously uncharacterized somatic copy number alterations, extrachromosomal DNA landscape, and human-HPV fusion peptides, with implications for genetic heterogeneity and therapeutic targets. This study enhances the understanding of cervical cancer through deeper proteogenomic insights and facilitates the development of personalized therapeutic strategies to improve patient outcomes.FUNDING Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0544102);The National Natural Science Foundation of China (82172584); Key Technology R&D Program of Hubei (2024BCB057 and 2025BCB053); National Natural Science Foundation of China (82373260); the “4+X” clinical trial programs of Women’s Hospital, School of Medicine, Zhejiang University (LY2022004); and the programs of Zhejiang Traditional Chinese Medicine Innovation Team (CZ2024009); and Guangxi Natural Science Foundation (2024GXNSFBA010045).
Authors
Xun Tian, Mansheng Li, Zhi Wang, Tian Fang, Yi Liu, Jin Fang, Lejing Wang, Zhichao Jiang, Xingyu Zhao, Chen Cao, Zhiqiang Yu, Meiying Yang, Songfeng Wu, Yifan Wu, Rui Tian, Hui Wang, Yunping Zhu, Zheng Hu
×Abstract
Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 (AQP4) water channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron microscopy–based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid droplet burden, and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patient’s spinal cord revealed disease-associated microglia surrounding motor neurons in nondestructive lesions. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.
Authors
Fangfang Qi, Vanda A. Lennon, Shunyi Zhao, Yong Guo, Husheng Ding, Caiyun Liu, Whitney M. Bartley, Tingjun Chen, Claudia F. Lucchinetti, Long-Jun Wu
×Abstract
Mild traumatic brain injury (mTBI) from a closed-head injury (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI (mCHI) is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA-seq analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation, and astrocyte reactivity persisted up to 21 days in a model for mTBI, with significant reduction of this pattern in Asc–/– mice. Importantly, mild cognitive impairment induced after mCHI was largely abrogated in Asc–/– mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mCHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
Authors
Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka
×Abstract
BACKGROUND Chronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear.METHODS Thirty-two people with AUD (n = 17 women; n = 15 men) and 29 control participants (n = 17 women; n = 12 men)completed 1 PET brain imaging scan with the radiotracer [11C]UCB-J, which binds to SV2A, a marker of synaptic density. The levels of synaptic density were quantified by estimating the nondisplaceable binding potential (BPND) across 4 regions of interest: frontal cortex, striatum, hippocampus, and cerebellum.RESULTS People with AUD were, on average (±SD), 43 ± 13 years of age, and most met the criteria for having mild or moderate AUD. The control participants were 37 ± 12 years of age. People with AUD had, on average, a 11% lower [11C]UCB-J BPND than did controls in the frontal cortex [F(1,62) = 13.074, P < 0.001], striatum [F(1,60) = 10.283, P = 0.002], and hippocampus [F(1,60) = 5.964, P = 0.018], trending in the same direction in the cerebellum [F(1,50) = 3.438, P = 0.070]. Among people with AUD, lower [11C]UCB-J BPND was significantly related to more drinks per drinking day, in the frontal cortex (P = 0.022) and striatum (P = 0.026). People with AUD performed worse on executive function than did controls (P = 0.020), but this was not related to [11C]UCB-J BPND.CONCLUSION Synaptic density deficits were evident, even in people with mild-to-moderate AUD, with larger deficits observed in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD.FUNDING NIH (U54AA027989, P01AA02747307, K01AA029706, and K24AA031345); UCB Pharma SA.
Authors
Yasmin Zakiniaeiz, Nakul R. Raval, Will Riordan, Nabeel Nabulsi, Yiyun Huang, Brian Pittman, David Matuskey, Gustavo A. Angarita, Robin Bonomi, Sherry A. McKee, Ansel T. Hillmer, Kelly P. Cosgrove
×Abstract
The gastrointestinal tract varies in structure and function by region, yet the drivers of region-specific inflammatory disease remain elusive. Here, a TNF-overexpressing murine model (TnfΔARE/+) of Crohn’s disease (CD) was used to investigate how pathobionts interact with host immune susceptibilities to drive region-specific disease. We identified the pathobiont Chlamydia muridarum, an intracellular bacterium and murine counterpart to the human sexually transmitted C. trachomatis, as a necessary and sufficient trigger for disease manifestation in the proximal/ascending colon, a common site of CD. In genetically susceptible hosts, pathobiont-triggered proximal colonic inflammation is driven by goblet cell responses, including tryptophan metabolism via indoleamine 2,3-dioxygenase 1 (IDO1). Our findings translate to human disease, where we demonstrate upregulation of epithelia-derived IDO1 in actively inflamed ascending colon specimens, but not actively inflamed terminal ileum specimens, of patients with CD. Our findings mechanistically reveal how genetic and microbial factors drive the manifestation of disease in a region-specific manner and provide a unique model to study CD specific to the ascending colon.
Authors
Paige N. Spencer, Monica E. Brown, Erin P. Smith, Jiawei Wang, William Kim, Luisella Spiga, Naila Tasneem, Alan J. Simmons, Taewoo Kim, Yilin Yang, Yanwen Xu, Lin Zheng, James Ro, Harsimran Kaur, Seung Woo Kang, Matthew D. Helou, Mason A. Lee, Deronisha Arceneaux, Katherine D. Mueller, Ozge S. Kuddar, Mariah H. Harned, Jing Li, Amrita Banerjee, Nicholas O. Markham, Keith T. Wilson, Lori A. Coburn, Jeremy A. Goettel, Qi Liu, M. Kay Washington, Raphael H. Valdivia, Wenhan Zhu, Ken S. Lau
×Abstract
BACKGROUND Plasma heparan sulfate, a glycosaminoglycan released during endothelial glycocalyx degradation, predicts sepsis mortality. Chondroitin sulfate is a circulating glycosaminoglycan not specific to glycocalyx degradation; its relevance to sepsis is unknown.METHODS We studied the associations of plasma chondroitin sulfate with (a) mortality in patients with sepsis-associated hypotension and (b) the relative effectiveness of a randomly assigned liberal versus restrictive intravenous fluid resuscitation strategy. We selected 574 patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial using an outcome-enriched sampling strategy. We used liquid chromatography–mass spectrometry to quantify plasma chondroitin sulfate. In comparison, we measured hyaluronic acid as a glycocalyx degradation marker and IL-6 as an inflammatory biomarker. We conducted Cox proportional hazards regression analyses to examine associations of baseline biomarker concentrations with mortality and resuscitation strategy effectiveness. We used inverse probability of selection weights and generalized raking to account for the nonrepresentative sampling design.RESULTS Plasma chondroitin sulfate, hyaluronic acid, and IL-6 were associated with mortality within 90 days. As baseline chondroitin sulfate increased, subsequent randomization to a restrictive strategy was increasingly beneficial (P = 0.022): treatment effect hazard ratio (restrictive versus liberal) for mortality was estimated as 1.49 (95% CI, 0.98–2.27), 1.30 (95% CI, 1.00–1.69), 1.09 (95% CI, 0.82–1.44), 0.88 (95% CI, 0.66–1.16), and 0.71 (95% CI, 0.52–0.97) for 10th, 25th, 50th, 75th, and 90th percentiles of baseline chondroitin sulfate.CONCLUSION Plasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal versus restrictive intravenous fluid resuscitation strategy.TRIAL REGISTRATION ClinicalTrials.gov NCT03434028.FUNDING NIH grants R01HL149422 and R01HL094786.
Authors
Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D’Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt
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Abstract
Loss-of-function mutations in DNAJC6, encoding the co-chaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson’s disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons, we hypothesized that DNAJC6 dysfunction may not be limited to juvenile-onset disorders but could also be associated with adult-onset brain diseases. Here, we show that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues and transcriptomic datasets from patients with late-onset sporadic PD. Consistently, human pluripotent stem cell–derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by midbrain-specific factors NURR1/FOXA2 and reduced protein stability regulated by LRRK2. Beyond neurons, DNAJC6 was robustly expressed in astrocytes and similarly downregulated in sporadic PD contexts. Astrocytic DNAJC6 deficiency impaired phagocytic, autolysosomal, and mitochondrial functions while promoting a pro-inflammatory phenotype, thereby exacerbating neurodegenerative pathology. Importantly, epigenetic restoration of DNAJC6 in neurons and astrocytes using a CRISPRa-AAV9 system in the substantia nigra of an α-synuclein–induced PD mouse model alleviated behavioral deficits and neuropathology. These findings provide evidence that DNAJC6 dysregulation is associated with pathogenic processes in sporadic PD and suggest that targeting neuronal and astrocytic DNAJC6 could represent a potential disease-modifying strategy.
Authors
Wahyu Handoko Wibowo Darsono, Yeongran Hwang, Erica Valencia, Leonardo Tejo Gunawan, Seung Jae Hyeon, Hoon Ryu, Thor D. Stein, Mi-Yoon Chang, Noviana Wulansari, Sang-Hun Lee
Abstract
BACKGROUND. Current diagnosis and surveillance of bladder cancer relies on cystoscopy which is invasive and user dependent. The urine mRNA panel, uRNAp, measures expression of 3 genes for identification of bladder cancer. Here we report validation of uRNAp for patients undergoing initial work-up for suspected bladder cancer and surveillance for bladder cancer. METHODS. Urine specimens were prospectively collected prior to cystoscopy at two health care systems from patients without (detection cohort) or with (surveillance cohort) a history of bladder cancer. RNA was isolated from urine sediment for RT-qPCR to determine ROBO1, CRH, and IGF2 expression and calculate the uRNAp bladder cancer probability score. RESULTS. In the detection cohort, 547 samples were collected from 529 patients. There were 123 new diagnoses of bladder cancer in the detection cohort and uRNAp demonstrated 98% sensitivity and 51% specificity for identification of bladder cancer. In the surveillance cohort, 1543 samples were collected from 447 patients with 286 recurrences. uRNAp demonstrated 94% overall sensitivity with 43% specificity and 99% sensitivity for high-grade recurrence. The receiver operating characteristic area under the curve was 0.92 in the detection and 0.81 in the surveillance cohort. uRNAp scores significantly increased with tumor size and grade. CONCLUSIONS. Prospective validation of uRNAp demonstrated a strong potential clinical utility as a non-invasive adjunct to cystoscopy for management of bladder cancer. uRNAp may be a useful triage tool to defer or expedite cystoscopy for patients undergoing detection or surveillance of bladder cancer. FUNDING. Department of Veterans Affairs BLR&D Merit Review I01 BX004962 to JCL.
Authors
Kathleen E. Mach, Zachary Kornberg, Eugene Shkolyar, Jin Long, Timothy J. Lee, Vinh La, Ihna Yoo, Gabriela Rodriguez, Alan E. Thong, Kris B. Prado, Jay B. Shah, John T. Leppert, Eila C. Skinner, Joseph C. Liao
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody–drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinical application in prostate cancer has been limited. Izalontamab brengitecan (Iza-bren; BL-B01D1) is a bispecific ADC targeting EGFR and HER3 that has demonstrated activity in other malignancies. Here, we evaluated its therapeutic potential in prostate cancer. Multi-omics analyses revealed frequent EGFR and HER3 expression in CRPC adenocarcinoma but not in neuroendocrine subtypes. BL-B01D1 exerted potent, target-dependent cytotoxicity in prostate cancer cell lines, xenografts, and patient-derived organoids (PDOs). We highlight a representative mCRPC patient with high EGFR/HER3 expression who achieved a rapid and durable clinical and radiologic response to BL-B01D1, concordant with matched PDO sensitivity. Mechanistic studies identified ABCG2 upregulation as a driver of acquired resistance, with genetic or pharmacologic inhibition restoring BL-B01D1 sensitivity. Importantly, tumor tissue obtained at progression after BL-B01D1 treatment confirmed ABCG2 upregulation, validating a clinically relevant resistance mechanism. These findings support BL-B01D1 as a promising therapeutic strategy in mCRPC and nominate ABCG2 as a rational target for overcoming resistance.
Authors
Bangwei Fang, Xiaomeng Li, Ying Lu, Weiwei Ma, Hualei Gan, Tingwei Zhang, Qi Liu, Beihe Wang, Zixian Wang, Yi Zhu, Hai Zhu, Sa Xiao, Xiaojie Bian, Gonghong Wei, Dingwei Ye, Yao Zhu
Abstract
Background. Functional B cell responses for both prevention and control of hepatitis B virus (HBV) infection remain poorly understood, including in the context of HBV/HIV co-infection. Methods. Here, we employed high-dimensional single cell analysis to assess global and hepatitis B surface antigen (HBsAg)-specific B cells in a longitudinal cohort of incident HBV from the Multicenter Aids Cohort Study (MACS), with a subset of the cohort living with HIV-1. Results. We observed that prior HIV infection has negative consequences for B cell function in early post-acute HBV infection, including increased frequencies of atypical memory (AtM) B cells and regulatory B cells (Bregs), expression of the activation marker CD86 on multiple B cell subsets in chronic HBV (CHB), and restricted expansion of HBsAg-specific B cells. In contrast, in HBV mono-infection, we observed no changes in the global B cell population from prior to infection and robust expansion of HBsAg-specific B cells. These expanded antigen-specific B cells resembled class-switched intermediate and resting memory (IM and RM) B cells, with activation phenotypes that may contribute to ongoing HBV control. Conclusion. HIV infection has a significant impact on B cell responses to subsequent HBV infection that may promote development of CHB in HBV/HIV co-infection. Funding. National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation.
Authors
Katherine Cascino, Thomas Liechti, Eric C. Seaberg, Kathleen E. Stevens, Steven M. Wolinsky, Mallory D. Witt, Robbie B. Mailliard, Mario Roederer, Justin Bailey, Chloe L. Thio, Andrea L. Cox
Abstract
Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkpoint blockade (ICB) efficacy are incompletely defined. Here, we identified tumor-intrinsic tescalcin (TESC) as a previously unrecognized phagocytic checkpoint that contributes to immune evasion and ICB resistance in HCC. Mechanistically, H3K4 methylation drove TESC expression in hepatoma cells, facilitating cytosolic Ca²⁺ buffering and attenuating endoplasmic reticulum (ER) stress-induced calreticulin (CALR) plasma membrane exposure, an essential “eat-me” signal. Consequently, this process abrogates membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells, thereby impairing antigen presentation and subsequent T-cell activation. Clinically, elevated H3K4me3-TESC signaling was a promising prognostic biomarker for poor ICB response of HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Thus, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapy efficacy in HCC.
Authors
Jiong-Liang Wang, Jun-Cheng Wang, Yangxun Pan, Minrui He, Zhikai Zheng, Hao Zou, Tianqing Wu, Yuhan Zhang, Zili Hu, Yizhen Fu, Wei Peng, Zhenyun Yang, Li Xu, Yao-Jun Zhang, Min-Shan Chen, Dandan Hu, Jinbin Chen, Ming Zhao, Dong-Ping Chen, Zhong-Guo Zhou
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Neurodegeneration
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Neurodegenerative diseases are devastating progressive conditions, many which lack effective therapies. This series of reviews, curated by Dr. Craig Blackstone, focuses on common themes across neurodegenerative disease pathophysiology, and explores recent advances in technology that have improved our understanding of these conditions and may lead to the development of new therapeutic approaches.
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