{"title":"A genome-wide association study identified PRKCB as a causal gene and therapeutic target for Mycobacterium avium complex disease.","authors":"Ruijuan Zheng, Zhiqiang Li, Weijun Fang, Hai Lou, Feng Liu, Qin Sun, Xiang Shi, Hua Liu, Qing Chen, Xiaona Shen, Lan Yao, Liru Guan, Jianxia Chen, Yingzhou Xie, Yifan Yang, Hua Yang, Ling Wang, Lianhua Qin, Xiaochen Huang, Jie Wang, Zhonghua Liu, Haipeng Liu, Baoxue Ge, Jinfu Xu, Wei Sha","doi":"10.1016/j.xcrm.2024.101923","DOIUrl":"10.1016/j.xcrm.2024.101923","url":null,"abstract":"<p><p>Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic progressive lung disease that is increasing in incidence. Host genetic factors are associated with NTM-PD susceptibility. However, the heritability of NTM-PD is not well understood. Here, we perform a two-stage genome-wide association study (GWAS) and discover a susceptibility locus at 16p21 associated with NTM-PD, especially with pulmonary Mycobacterium avium complex (MAC) disease. As the lead variant, rs194800 C allele augments protein kinase C beta (PRKCB) gene expression and associates with severer NTM-PD. The functional studies show that PRKCB exacerbates M. avium infection and promotes intracellular survival of M. avium in macrophages by inhibiting phagosomal acidification. Mechanistically, PRKCB interacts with subunit G of the vacuolar-H<sup>+</sup>-ATPase (V-ATPase) and vacuolar protein sorting-associated protein 16 homolog (VPS16), blocking the fusion between lysosomes and mycobacterial phagosomes. PRKCB inhibitor has therapeutic potential against M. avium infection. These findings provide insights into the genetic etiology of NTM-PD and highlight PRKCB as an attractive target for host-directed therapy of MAC disease.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101923"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Wang, Rachel Aaron, Nadine Attal, Luana Colloca
{"title":"An update on non-pharmacological interventions for pain relief.","authors":"Yang Wang, Rachel Aaron, Nadine Attal, Luana Colloca","doi":"10.1016/j.xcrm.2025.101940","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101940","url":null,"abstract":"<p><p>Chronic pain affects a substantial portion of the population, yet current treatments often fail to provide adequate relief. Non-pharmacological interventions, which target behaviors and brain processes underlying the experience of pain, hold promises in offering relief for people with chronic pain. This review consolidates the current knowledge concerning the efficacy of non-pharmacological interventions for chronic pain. We focus on psychological interventions (e.g., cognitive behavioral therapy-based interventions and emotion-based therapies) that use mental techniques and physical practices (e.g., exercise, massage, acupuncture, and yoga) that use body techniques to reduce pain. The efficacy of neuromodulation is also discussed. Given that placebo and expectation effects may enhance benefits for non-pharmacological interventions, we also discuss placebo interventions and expectation management practices. Finally, we describe digital therapeutics as an emerging approach for managing chronic pain. We argue that non-pharmacological interventions are critical adjunctive or stand-alone interventions for chronic pain conditions.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101940"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiangyan Jiang, Tao Wang, Bin Zhao, Haonan Sun, Yuman Dong, Yong Ma, Zhigang Li, Yuxia Wu, Keshen Wang, Xiaoying Guan, Bo Long, Long Qin, Wengui Shi, Lei Shi, Qichen He, Wenbo Liu, Mingdou Li, Lixia Xiao, Chengliang Zhou, Hui Sun, Jing Yang, Junhong Guan, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao
{"title":"KRAS<sup>G12D</sup>-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.","authors":"Xiangyan Jiang, Tao Wang, Bin Zhao, Haonan Sun, Yuman Dong, Yong Ma, Zhigang Li, Yuxia Wu, Keshen Wang, Xiaoying Guan, Bo Long, Long Qin, Wengui Shi, Lei Shi, Qichen He, Wenbo Liu, Mingdou Li, Lixia Xiao, Chengliang Zhou, Hui Sun, Jing Yang, Junhong Guan, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao","doi":"10.1016/j.xcrm.2025.101966","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101966","url":null,"abstract":"<p><p>The KRAS<sup>G12D</sup> inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRAS<sup>G12D</sup> remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS<sup>G12D</sup> drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRAS<sup>G12D</sup>-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRAS<sup>G12D</sup>-mutated PDAC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101966"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-10DOI: 10.1016/j.xcrm.2025.101967
Stephane Champiat, Elena Garralda, Vladimir Galvao, Philippe A Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Peter Grell, Aung Naing, Patricia LoRusso, Romana Mikyskova, Nada Podzimkova, Milan Reinis, Kaissa Ouali, Andreu Schoenenberger, Joachim Kiemle-Kallee, Sascha Tillmanns, Richard Sachse, Ulrich Moebius, Radek Spisek, David Bechard, Lenka Palova Jelinkova, Irena Adkins, Aurelien Marabelle
{"title":"Nanrilkefusp alfa (SOT101), an IL-15 receptor βγ superagonist, as a single agent or with anti-PD-1 in patients with advanced cancers.","authors":"Stephane Champiat, Elena Garralda, Vladimir Galvao, Philippe A Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Peter Grell, Aung Naing, Patricia LoRusso, Romana Mikyskova, Nada Podzimkova, Milan Reinis, Kaissa Ouali, Andreu Schoenenberger, Joachim Kiemle-Kallee, Sascha Tillmanns, Richard Sachse, Ulrich Moebius, Radek Spisek, David Bechard, Lenka Palova Jelinkova, Irena Adkins, Aurelien Marabelle","doi":"10.1016/j.xcrm.2025.101967","DOIUrl":"10.1016/j.xcrm.2025.101967","url":null,"abstract":"<p><p>Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8<sup>+</sup> T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8<sup>+</sup> T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101967"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-16DOI: 10.1016/j.xcrm.2024.101913
Liming Gui, Kaiwen Chen, Jingjing Yan, Ping Chen, Wei-Qiang Gao, Bin Ma
{"title":"Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity.","authors":"Liming Gui, Kaiwen Chen, Jingjing Yan, Ping Chen, Wei-Qiang Gao, Bin Ma","doi":"10.1016/j.xcrm.2024.101913","DOIUrl":"10.1016/j.xcrm.2024.101913","url":null,"abstract":"<p><p>The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101913"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-07DOI: 10.1016/j.xcrm.2025.101938
Francesco Campo, Alessia Neroni, Cataldo Pignatelli, Silvia Pellegrini, Ilaria Marzinotto, Libera Valla, Fabio Manenti, Martina Policardi, Vito Lampasona, Lorenzo Piemonti, Antonio Citro
{"title":"Bioengineering of a human iPSC-derived vascularized endocrine pancreas for type 1 diabetes.","authors":"Francesco Campo, Alessia Neroni, Cataldo Pignatelli, Silvia Pellegrini, Ilaria Marzinotto, Libera Valla, Fabio Manenti, Martina Policardi, Vito Lampasona, Lorenzo Piemonti, Antonio Citro","doi":"10.1016/j.xcrm.2025.101938","DOIUrl":"10.1016/j.xcrm.2025.101938","url":null,"abstract":"<p><p>Intrahepatic islet transplantation in patients with type 1 diabetes is limited by donor availability and lack of engraftment. Alternative β cell sources and transplantation sites are needed. We demonstrate the feasibility to repurpose a decellularized lung as an endocrine pancreas for β cell replacement. We bioengineer an induced pluripotent stem cell (iPSC)-based version, fabricating a human iPSC-based vascularized endocrine pancreas (iVEP) using iPSC-derived β cells (iPSC-derived islets [SC-islets]) and endothelial cells (iECs). SC-islets and iECs are aggregated into vascularized iβ spheroids (ViβeSs), and over 7 days of culture, spheroids integrate into the bioengineered vasculature, generating a functional, perfusable human endocrine organ. In vitro, the vascularized extracellular matrix (ECM) sustained SC-islet engraftment and survival with a significantly preserved β cell mass and a physiologic insulin release. In vivo, iVEP restores normoglycemia in diabetic NSG mice. We report a human iVEP providing a controlled in vitro insulin-secreting phenotype and in vivo function.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101938"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"How close are we to a cAMP- and cGMP-theory-based pharmacological therapy for fragile X syndrome?","authors":"Barbara Bardoni, Carole Gwizdek, Thomas Maurin","doi":"10.1016/j.xcrm.2025.101972","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101972","url":null,"abstract":"<p><p>Recent advances in targeting cAMP and cGMP pathways offer hope for treating fragile X syndrome, a leading cause of inherited intellectual disability. PDE4 and PDE2 inhibitors have shown promise in animal models, improving memory, social behavior, and cognitive function. Clinical trials are underway, raising optimism for future therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101972"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-10DOI: 10.1016/j.xcrm.2025.101941
Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Sukjin Yang, Kuldeep S Attri, Songyeon Ahn, Divya Murthy, Tagari Samanta, Debasmita Dutta, Meron Ghidey, Somik Chatterjee, Seung Yeop Han, Diego A Pedroza, Abha Tiwari, Joyce V Lee, Caitlin Davis, Shuting Li, Vasanta Putluri, Chad J Creighton, Nagireddy Putluri, Lacey E Dobrolecki, Michael T Lewis, Jeffrey M Rosen, José N Onuchic, Andrei Goga, Benny Abraham Kaipparettu
{"title":"Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway.","authors":"Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Sukjin Yang, Kuldeep S Attri, Songyeon Ahn, Divya Murthy, Tagari Samanta, Debasmita Dutta, Meron Ghidey, Somik Chatterjee, Seung Yeop Han, Diego A Pedroza, Abha Tiwari, Joyce V Lee, Caitlin Davis, Shuting Li, Vasanta Putluri, Chad J Creighton, Nagireddy Putluri, Lacey E Dobrolecki, Michael T Lewis, Jeffrey M Rosen, José N Onuchic, Andrei Goga, Benny Abraham Kaipparettu","doi":"10.1016/j.xcrm.2025.101941","DOIUrl":"10.1016/j.xcrm.2025.101941","url":null,"abstract":"<p><p>The biguanide metformin attenuates mitochondrial oxidation and is proposed as an anti-cancer therapy. However, recent clinical studies suggest increased proliferation and fatty acid β-oxidation (FAO) in a subgroup of patients with breast cancer (BC) after metformin therapy. Considering that FAO can activate Src kinase in aggressive triple-negative BC (TNBC), we postulate that low-dose biguanide-driven AMPK-ACC-FAO signaling may activate the Src pathway in TNBC. The low bioavailability of metformin in TNBC xenografts mimics metformin's in vitro low-dose effect. Pharmacological or genetic inhibition of FAO significantly enhances the anti-tumor properties of biguanides. Lower doses of biguanides induce and higher doses suppress Src signaling. Dasatinib and metformin synergistically inhibit TNBC patient-derived xenograft growth, but not in high-fat diet-fed mice. This combination also suppresses TNBC metastatic progression. A combination of biguanides with Src inhibitors provides synergy to target metastatic TNBC suffering with limited treatment options.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101941"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessandro Micarelli, Simona Mrakic-Sposta, Alessandra Vezzoli, Sandro Malacrida, Sara Caputo, Beatrice Micarelli, Ilaria Misici, Valentina Carbini, Ilaria Iennaco, Ivan Granito, Valter D Longo, Marco Alessandrini
{"title":"Chemosensory and cardiometabolic improvements after a fasting-mimicking diet: A randomized cross-over clinical trial.","authors":"Alessandro Micarelli, Simona Mrakic-Sposta, Alessandra Vezzoli, Sandro Malacrida, Sara Caputo, Beatrice Micarelli, Ilaria Misici, Valentina Carbini, Ilaria Iennaco, Ivan Granito, Valter D Longo, Marco Alessandrini","doi":"10.1016/j.xcrm.2025.101971","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.101971","url":null,"abstract":"<p><p>Obesity is associated with a decrease in chemosensory perception acuity and increased disease risk, pointing to the need for feasible interventions that affect smell, taste, and cardiometabolic markers. Here, subjects with overweight/obesity are treated with six monthly cycles of a fasting-mimicking diet (FMD) lasting 5 days followed by a normal diet for the rest of the month to determine their effects on chemosensory function and cardiometabolic risk factors. Both arms of the 102 randomized cross-over trial participants indicate FMD-dependent improvements in a wide range of taste and smell chemosensory functions. The portion of hyposmic subjects is reduced from 38.1% at baseline to 6.4% at the end of 6 FMD cycles. FMD cycles also reduce cardiometabolic and inflammatory markers and drug use in diabetic patients. This trial provides evidence for the effect of periodic FMD cycles in improving chemosensory function while reducing cardiometabolic risk factors without requiring long-term lifestyle changes. The trial is registered at ClinicalTrials.gov (NCT04529161).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101971"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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