tbuckley/cabot-search huggingface dataset:
Gadoxetic Acid-Enhanced Magnetic Resonance Imaging Features Can Predict Immune-Excluded Phenotype of Hepatocellular Carcinoma
Authors: Eisuke Ueshima, Keitaro Sofue, Takahiro Kodama, Shuhei Yamamoto, Masato Komatsu, Shohei Komatsu, Nobuaki Ishihara, Akihiro Umeno, Takeru Yamaguchi, Masatoshi Hori, Takumi Fukumoto, Tetsuo Takehara, Takamichi Murakami
Journal: Liver Cancer (2024)

Introduction: Immunotherapy is the first-line treatment for intermediate-advanced stage hepatocellular carcinoma (HCC), although its outcomes vary. This study aimed to identify imaging biomarkers of immunotherapy susceptibility linked to gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and immune phenotypes, particularly immune-excluded phenotypes, with a tumor immune barrier. Methods: We performed immunohistochemical staining with a CD8+ antibody, and samples were classified into immune-inflamed, -intermediate, -excluded, and -ignored phenotypes. We assessed EOB-MRI findings obtained from 104 patients who underwent hepatectomy for HCC and evaluated the relationship between MRI findings and immune phenotype. Spatial transcriptome analysis of tumor tissues in each immune phenotype was performed to characterize the MRI findings. For validation, we analyzed the treatment effect on 60 nodules in another cohort of 27 patients who received combined immunotherapy using anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies. Results: HCCs with rim arterial phase hyperenhancement (APHE) (odds ratio [OR] 17.3 P=0.009), peritumoral enhancement on the arterial phase (OR 8.6, P&lt;0.004), and intermediate intensity on the hepatobiliary phase (HBP) measured with a visual 3-point scale (OR 28.2, P=0.002) were associated with immune-excluded phenotype, where tumors tended to be larger and of the single nodular type with extranodular growth and confluent multinodular rather than the simple nodular type. Spatial transcriptome analysis revealed a spatial relationship among cytotoxic T lymphocytes, VEGF signals, and cancer-associated fibroblasts at the tumor-invasive margins in this phenotype. From the validation study, nodules with any one of these three imaging findings had a significantly prolonged time to-nodular progression (P=0.007, median not reached vs. 226 days). Conclusion: HCCs with rim APHE, peritumoral enhancement on arterial phase, and intermediate intensity on HBP with visual 3-point scale could be non-invasive biomarkers to predict the immune-excluded phenotype with tumor immune barrier. These HCCs were most likely to respond to the combined immunotherapy.
Comprehensive analysis of radiologic cancer-free (rCF) status through various treatment approaches in advanced-stage hepatocellular carcinoma
Authors: Keisuke Koroki, Sadahisa Ogasawara, Ryo Izai, Takuya Yonemoto, Teppei Akatsuka, Chihiro Miwa, Sae Yumita, Masanori Inoue, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Takayuki Kondo, Shingo Nakamoto, Shinichiro Nakada, Nozomu Sakai, Masayuki Yokoyama, Masayuki Ohtsuka, Naoya Kato
Journal: Liver Cancer (2024)

Introduction In the realm of oncology, the pinnacle of therapeutic success is achieving a state where the patient is entirely free of cancer, i.e. ‘cancer-free’. This benchmark should not only apply to early-stage malignancies but should also be the standard aim for advanced-stage diseases, including hepatocellular carcinoma (HCC). However, there is a glaring gap in the research landscape concerning the understanding of what cancer-free status truly means for advanced-stage HCC. Our study sheds light on the profound implications of reaching a cancer-free by radiological assessments in patients with advanced-stage HCC. Methods We established a database tracking the full clinical course of all patients with HCC (from 2003–2022). We identified the initial instances of macrovascular invasion or extrahepatic spread. We defined radiologic cancer-free (rCF) as cases in which no recurrence was observed for at least 2 months following curative treatment or complete response to systemic therapies. The frequency of achieving rCF status was investigated, categorised by patients’ background. Results We identified 795 patients with advanced-stage HCC. The rCF rate was 8.7%. Patients who achieved rCF status had significantly better prognoses compared to those who did not (p &lt; 0.001). In the decision tree analysis, the number of tumors ≥8 was the strongest factor making it difficult to achieve rCF status. Analysis of stage progression patterns revealed varying background characteristics at the time of advanced-stage diagnosis, with discrepancies in rCF rates. Conclusions Despite the low rate of achieving rCF status, the prognostic impact was significant. Patients with certain tumor characteristics had a higher likelihood of achieving rCF status. The distribution of tumor conditions varies based on the pattern of progression, which affects the likelihood of achieving a rCF status.
Concerns Regarding Sample Size and Credibility of Progression-Free Survival Results—Reply
Authors: Song Dong, Hong-Hong Yan, Yi-Long Wu
Journal: JAMA Oncology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast JAMA+ AI Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Advancing Global Pharmacoequity in Oncology
Authors: Parsa Erfani, Ruth L. Okediji, Vivienne Mulema, Edward R. Scheffer Cliff, Kwanele Asante-Shongwe, Brittany L. Bychkovksy, Temidayo Fadelu
Journal: JAMA Oncology (2024)

Limited availability and affordability of cancer drugs contribute to staggering disparities in cancer survival between high-income and low- and middle-income countries (LMICs). As infrastructure for cancer care rapidly develops, there is an urgent need to reduce prices and improve access to cancer medicines in LMICs to advance pharmacoequity globally.
Regulatory Fate of Cancer Indications in the European Union After Accelerated Approval in the US
Authors: Tonny Studsgaard Petersen, Kristian Karstoft, Freja Karuna Hemmingsen Sørup, Marie Lund, Allan Cramer
Journal: JAMA Oncology (2024)

This cohort study investigates the regulatory fate in the European Union for drugs that received accelerated approval for cancer indications in the US.
Toripalimab For Extensive-Stage Small Cell Lung Cancer
Authors: Ayse Ece Cali Daylan, Daniel Morgensztern, Saiama N. Waqar
Journal: JAMA Oncology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast JAMA+ AI Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
We need a gender just transition for health systems and climate action
Authors: Arthur Ng’etich, Nachilala Nkombo, Hashim Hounkpatin, Remco Van de Pas, Johanna Riha
Journal: BMJ (2024)

Meaningful progress to mitigate the climate crisis and improve health systems will only be possible with a commitment to equity, justice, and inclusion, say <b>Arthur Ng'etich and colleagues</b>
Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy
Authors: Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li
Journal: Journal of Clinical Investigation (2024)

T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti–programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.
The lung is a megakaryocyte outpost that can defend against thrombocytopenic attack
Authors: Anthony K. Yeung, George J. Murphy
Journal: Journal of Clinical Investigation (2024)

Lung megakaryocytes (Mks) are a unique subset of Mks that are distinct from their bone marrow counterparts. Recent evidence suggests that lung Mks favor an immune phenotype, but have unclear contributions to the total platelet mass. In this issue of the JCI, Livada et al. used an array of complementary in vivo labeling and tracing models in mice to investigate a longstanding question of where lung Mks are derived. By combining these models with stressed conditions, the authors assessed the contribution of lung Mks to total platelet counts in a homeostatic and thrombocytopenic state. Mks were minor contributors to the circulating pool of platelets during homeostasis but increased output during thrombocytopenia. These findings add critical understanding to the development of lung Mks and demonstrate the dynamic potential of these specialized cells to respond to thrombocytopenia.
Rg3-lipo biomimetic delivery of paclitaxel enhances targeting of tumors and myeloid-derived suppressor cells
Authors: Yuru Shen, Bin Zhong, Wanwei Zheng, Dan Wang, Lin Chen, Huan Song, Xuanxuan Pan, Shaocong Mo, Bryan Jin, Haoshu Cui, Huaxing Zhan, Feifei Luo, Jie Liu
Journal: Journal of Clinical Investigation (2024)

Liposomal drug delivery systems have revolutionized traditional cytotoxic drugs. However, the relative instability and toxicity of the existing liposomal drug delivery systems compromised their efficacy. Herein, we present Rg3-lipo, an innovative drug delivery system using a glycosyl moiety–enriched ginsenoside (Rg3). This system is distinguished by its glycosyl moieties exposed on the liposomal surface. These moieties imitate human cell membranes to stabilize and evade phagocytic clearance. The Rg3-lipo system loaded with paclitaxel (PTX-Rg3-lipo) demonstrated favorable bioavailability and safety in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys. With its glycosyl moieties recognizing tumor cells via the glucose transporter Glut1, PTX-Rg3-lipo inhibited gastric, breast, and esophageal cancers in human cancer cell lines, tumor-bearing mice, and patient-derived xenograft models. These glycosyl moieties selectively targeted myeloid-derived suppressor cells (MDSCs) through the glucose transporter Glut3 to attenuate their immunosuppressive effect. The mechanism study revealed that Rg3-lipo suppressed glycolysis and downregulated the transcription factors c-Maf and Mafb overcoming the MDSC-mediated immunosuppressive microenvironment and enhancing PTX-Rg3-lipo's antitumor effect. Taken together, we supply substantial evidence for its advantageous bioavailability and safety in multiple animal models, including nonhuman primates, and Rg3-lipo's dual targeting of cancer cells and MDSCs. Further investigation regarding Rg3-lipo's druggability will be conducted in clinical trials.
HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via non-canonical phosphorylation
Authors: Zhongqiu Pang, Hui Zhang, Shaoqin Zheng, Xueling Yang, Chang Liu, Qing Han, Yi Chen, Zexu Li, Xi Zhang, Liu Cao, Qiang Wang, Yanli Cao, Xun Sun, Pu Zhao, Xuexin Li, Qianqian Zheng, Ren Sheng
Journal: Hepatology (2024)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though mild in early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers, and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine.
Parkin paves the path to antitumor immunity: Expanding Parkin’s role as a tumor suppressor
Authors: Hyungsoo Kim, Ze’ev A. Ronai
Journal: Journal of Clinical Investigation (2024)

Parkin, a ring-between-ring-type E3 ubiquitin ligase, first shown to play a critical role in autosomal recessive juvenile Parkinsonism, has recently emerged as a key player in cancer biology. Parkin is now known to serve as a tumor suppressor, and its deregulation frequently promotes tumorigenesis. In this issue of the JCI, Perego et al. expand that role by showing that Parkin expression stimulated an interferon (IFN) response to modulate CD8+ T cell activity. These findings suggest that, in addition to directly inhibiting tumor progression, Parkin enhances antitumor immune responses, highlighting it as a promising therapeutic target for cancer treatment.
Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles
Authors: Maryam Rezaei, Manqi Liang, Zeynep Yalcin, Jacinta H. Martin, Parinaz Kazemi, Eric Bareke, Zhao-Jia Ge, Majid Fardaei, Claudio Benadiva, Reda Hemida, Adnan Hassan, Geoffrey J. Maher, Ebtesam Abdalla, William Buckett, Pierre-Adrien Bolze, Iqbaljit Sandhu, Onur Duman, Suraksha Agrawal, JianHua Qian, Jalal Vallian Broojeni, Lavi Bhati, Pierre Miron, Fabienne Allias, Amal Selim, Rosemary A. Fisher, Michael J. Seckl, Philippe Sauthier, Isabelle Touitou, Seang Lin Tan, Jacek Majewski, Teruko Taketo, Rima Slim
Journal: Journal of Clinical Investigation (2024)

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1–/– female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1–/– mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1–/– oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.
MGA loss-of-function variants cause premature ovarian insufficiency
Authors: Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen
Journal: Journal of Clinical Investigation (2024)

Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/− female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.
Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation
Authors: Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W. Snyder, Dimitris G. Placantonakis, Jeremy N. Rich
Journal: Journal of Clinical Investigation (2024)

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell–intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis
Authors: Xianpeng Liu, Ziyou Ren, Can Tan, Félix L Núñez-Santana, Megan E Kelly, Yuanqing Yan, Haiying Sun, Hiam Abdala-Valencia, Wenbin Yang, Qiang Wu, Takahide Toyoda, Marija Milisav, S Marina Casalino-Matsuda, Emilia Lecuona, Emily Jeong Cerier, Lena J Heung, Mohamed E Abazeed, Harris Perlman, Ruli Gao, Navdeep S Chandel, G R Scott Budinger, Ankit Bharat
Journal: Journal of Clinical Investigation (2024)

A major limitation of immunotherapy is the development of resistance resulting from cancer-mediated inhibition of host lymphocytes. Cancer cells release CCL2 to recruit classical monocytes expressing its receptor CCR2 for the promotion of metastasis and resistance to immunosurveillance. In the circulation, some CCR2-expressing classical monocytes lose CCR2 and differentiate into intravascular nonclassical monocytes that have anticancer properties but are unable to access extravascular tumor sites. We found that in mice and humans, an ontogenetically distinct subset of naturally underrepresented CCR2-expressing nonclassical monocytes was expanded during inflammatory states such as organ transplant and COVID-19 infection. These cells could be induced during health by treatment of classical monocytes with small-molecule activators of NOD2. The presence of CCR2 enabled these inducible nonclassical monocytes to infiltrate both intra- and extravascular metastatic sites of melanoma, lung, breast, and colon cancer in murine models, and they reversed the increased susceptibility of Nod2-/- mutant mice to cancer metastasis. Within the tumor colonies, CCR2+ nonclassical monocytes secreted CCL6 to recruit NK cells that mediated tumor regression, independent of T and B lymphocytes. Hence, pharmacological induction of CCR2+ nonclassical monocytes might be useful for immunotherapy-resistant cancers.
Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1
Authors: Yong Liu, Zhi Yang, Shuanglian Wang, Rui Miao, Chiung-Wen Mary Chang, Jingyu Zhang, Xin Zhang, Mien-Chie Hung, Junwei Hou
Journal: Journal of Clinical Investigation (2024)

Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1–increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.