tbuckley/cabot-search huggingface dataset:
Complex immune microenvironment of chordoma: a road map for future treatment
Authors: Hua-Qing Niu, Bo-Yv Zheng, Ming-Xiang Zou, Bo-Wen Zheng
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Chordoma, a rare bone tumor, presents limited treatment options and patients typically exhibit poor survival outcomes. While immunotherapy has shown promising results in treating various tumors, research on the immune microenvironment of chordomas is still in its early stages. Therefore, understanding how the immune microenvironment of chordomas influences the outcomes of immunotherapy is crucial. Methods We employed single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, CellChat, gene set variation analysis, as well as calculation of immune features to further dissect the complex immune microenvironment of chordoma. Results Previous research by van Oost et al argued that compared with other sarcomas, chordomas typically exhibit an immunologically “hot” microenvironment, a conclusion with which we concur based on their research findings. Additionally, the authors suggest that T cell-mediated immunotherapy is feasible for the majority of chordomas. However, we are inclined to categorize them as an immune-excluded phenotype according to the latest classification methods, rather than persisting with the concepts of “cold” and “hot”. Unlike them, we explored immune infiltration scores (IS), T lymphocyte scoring (TLS), and human leucocyte antigen class I (HLA-I) using Bulk RNA-seq data from 126 chordoma patients and found that higher IS, TLS, and higher HLA-I expression were associated with poorer patient prognosis. Additionally, CellChat analysis of scRNA-seq results from six chordoma patients revealed no direct interaction between T cells and tumor cells. Conclusions These findings suggested that the efficacy of T cell-based immunotherapy may be limited or even ineffective for patients with chordoma.
Decoding the chromatin accessibility in Andrographis paniculata genome, a case study of genome-wide investigation of the cis-regulatory elements in medicinal plants
Authors: Mingkun Huang, Yufang Hu, Ling Zhang, Hua Yang, Chen Feng, Chunhong Jiang, Ning Xie, Difa Liu, Shilin Chen, Jihua Wang, Wei Sun
Journal: Acta Pharmaceutica Sinica B (2024)
Single-arm study of camrelizumab plus apatinib for patients with advanced mucosal melanoma
Authors: Lianjun Zhao, Yu Ren, Guiying Zhang, Kelin Zheng, Jiayu Wang, Huizi Sha, Mengke Zhao, Rong Huang, Donglin Kang, Xinyu Su, Yirong Wu, Wangling Zhang, Ruihe Lai, Lin Li, Rui Mei, Yitao Wang, You Tian, Fufeng Wang, Baorui Liu, Zhengyun Zou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Previous studies have suggested the potential synergistic antitumor activity when combining immune checkpoint inhibitors with anti-angiogenic agents in various solid tumors. We aimed to assess the efficacy and safety of camrelizumab (a humanized programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) for patients with advanced mucosal melanoma (MM), and explore-related biomarkers. We conducted a single-center, open-label, single-arm, phase II study. Patients with unresectable or recurrent/metastatic MM received camrelizumab and apatinib. The primary endpoint was the confirmed objective response rate (ORR). Between April 2019 and June 2022, 32 patients were enrolled, with 50.0% previously received systemic therapy. Among 28 patients with evaluable response, the confirmed ORR was 42.9%, the disease control rate was 82.1%, and the median progression-free survival (PFS) was 8.05 months. The confirmed ORR was 42.9% (6/14) in both treatment-naïve and previously treated patients. Notably, treatment-naïve patients had a median PFS of 11.89 months, and those with prior treatment had a median PFS of 6.47 months. Grade 3 treatment-related adverse events were transaminase elevation, rash, hyperbilirubinemia, proteinuria, hypertension, thrombocytopenia, hand-foot syndrome and diarrhea. No treatment-related deaths were observed. Higher tumor mutation burden (TMB), increased T-cell receptor (TCR) diversity, and altered receptor tyrosine kinase (RTK)/RAS pathway correlated with better tumor response. Camrelizumab plus apatinib provided promising antitumor activity with acceptable toxicity in patients with advanced MM. TMB, TCR diversity and RTK/RAS pathway genes were identified as potential predictive biomarkers and warrant further validation. Chinese Clinical Trial Registry, ChiCTR1900023277.
Integrated analysis of tertiary lymphoid structures and immune infiltration in ccRCC microenvironment revealed their clinical significances: a multicenter cohort study
Authors: Yu-Qi Wang, Wen-Jin Chen, Wang Zhou, Ke-Qin Dong, Li Zuo, Da Xu, Jia-Xin Chen, Wei-Jie Chen, Wen-Yan Li, Zi-Chang Liu, Zheng-Yu Jiang, Yi-Fan Tang, Yu-Xuan Qin, Lin-Hui Wang, Xiu-Wu Pan, Xin-Gang Cui
Journal: Journal for ImmunoTherapy of Cancer (2024)

Tertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC). TLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance. The study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm2) and maturation of TLSs predicted good overall survival (OS) (p<0.01) in ccRCC patients. However, high infiltration (>151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p<0.001). The presence of TLSs was correlated with improved progression-free survival (p=0.002) and responsiveness to therapy (p<0.001). Interestingly, the combination of age and TLSs abundance had an impact on OS (p<0.001). Higher senescence scores were detected in individuals with immature TLSs (p=0.003). The study revealed the contradictory features of intratumoral TLSs and TILs in the ccRCC microenvironment and their impact on clinical prognosis, suggesting that abundant and mature intratumoral TLSs were associated with decreased risks of postoperative ccRCC relapse and death as well as favorable therapeutic response. Distinct spatial distributions of immune infiltration could reflect effective antitumor or protumor immunity in ccRCC.
The Link Between Alzheimer’s Disease and Stroke: A Detrimental Synergism
Authors: Tapan Behl, Ishnoor Kaur, Aayush Sehgal, Prasanna Shama Khandige, Mohd Imran, Monica Gulati, Md. Khalid Anwer, Gehan M. Elossaily, Nemat Ali, Pranay Wal, Amin Gasmi
Journal: Ageing Research Reviews (2024)
Improving equitable access for effective antibacterials: an ecosystem approach
Authors: Jennifer Cohn, Manica Balasegaram, Hema Srinivasan, Leena Menghaney, Mirfin Mpundu, Brenda Waning, Yewande Alimi
Journal: Clinical Microbiology and Infection (2024)

Background Antibiotics are indispensable to modern healthcare, yet their equitable access remains a pressing global challenge. Factors contributing to inequities include insufficient evidence for optimal clinical use, limited registration, pricing for Reserve antibiotics, and supply chain challenges. These issues disproportionately affect low- and middle-income countries (LMICs), exacerbating antimicrobial resistance (AMR) burdens. Objectives This paper explores the multifaceted dimensions of inequitable antibiotic access and proposes a comprehensive framework to address the crisis. Sources Published articles, grey literature analysis, and the authors' own expertise contributed to this article. Content While much attention has been paid to push and pull incentives for antibiotic development, these interventions are inadequate to reach sustainable and equitable access to antibiotics. Improving equitable antibiotic access requires an ecosystem approach, involving multiple stakeholders and including public-private partnerships. The paper advocates for initiatives spanning research and development (R&D), regulatory pathways, procurement strategies, and financing mechanisms and suggests concrete interventions in each of these areas. The specific interventions and mix of public and private actors may vary according to antibiotic, market, and health system context, but must be designed to meet public health needs while also supporting a market that will sustain quality-assured production and delivery of antibiotics. Implications Addressing the challenge of equitable antibiotic access requires coordinated efforts across sectors and regions. By embracing an ecosystem approach centred on public health priorities, stakeholders can pave the way for a sustainable supply of antibiotics, and equitable access, safeguarding the future of global healthcare amidst the growing threat of AMR.
Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine
Authors: Saru Basnet, Mirte Van der Heijden, Dafne C A Quixabeira, Elise Jirovec, Susanna A M Grönberg-Vähä-Koskela, James H A Clubb, Anna Kanerva, Santeri Pakola, Lyna Haybout, Victor Arias, Otto Hemminki, Tatiana Kudling, Sadia Zafar, Victor Cervera-Carrascon, Joao M Santos, Akseli Hemminki
Journal: Molecular Therapy (2024)

T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322 treatment stimulated T cell cytotoxicity through the increased presence of granzyme B, perforin, and interferon-gamma. Additional immune profiling indicated TILT-322 increased gamma delta T cell activation and impacted other cell types such as natural killer cells and natural killer-like T cells that are traditionally involved in cancer immunotherapy. TILT-322 treatment also decreased the proportion of exhausted CD8
Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration
Authors: Jeffrey S. Heier, Michael N. Cohen, Daniel L. Chao, Anthony Pepio, Yoko Shiraga, George Capuano, Adam Rogers, Jessica Ackert, H. Nida Sen, Karl Csaky
Journal: Ophthalmology (2024)

ObjectiveTo evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD).DesignPhase 1, open-label, single-center, first-in-human clinical study.SubjectsAdult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included.MethodsPatients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months.Main Outcome MeasuresSafety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate.ResultsBaseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24.ConclusionsAll 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.
Corrigendum to “HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma” [Biomaterials 284 (2022) 121512]
Authors: Minjiang Chen, Gaofeng Shu, Xiuling Lv, Xiaoling Xu, Chenying Lu, Enqi Qiao, Shiji Fang, Lin Shen, Nannan Zhang, Jun Wang, Chunmiao Chen, Jingjing Song, Zhuang Liu, Yongzhong Du, Jiansong Ji
Journal: Biomaterials (2024)
Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect
Authors: Conghua Lu, Ziyuan Gao, Di Wu, Jie Zheng, Chen Hu, Daijuan Huang, Chao He, Yihui Liu, Caiyu Lin, Tao Peng, Yuanyao Dou, Yimin Zhang, Fenfen Sun, Weiling Jiang, Guoqing Yin, Rui Han, Yong He
Journal: Journal for ImmunoTherapy of Cancer (2024)

The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC.
Protein O-fucosyltransferase 1 promotes PD-L1 stability to drive immune evasion and directs liver cancer to immunotherapy
Authors: Qianyu Li, Wenyun Guo, Yifei Qian, Songling Li, Linfeng Li, Zijun Zhu, Fan Wang, Yu Tong, Qiang Xia, Yanfeng Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

The immunosuppressive tumor microenvironment (TME) plays an essential role in cancer progression and immunotherapy response. Despite the considerable advancements in cancer immunotherapy, the limited response to immune checkpoint blockade (ICB) therapies in patients with hepatocellular carcinoma (HCC) remains a major challenge for its clinical implications. Here, we investigated the molecular basis of the protein O-fucosyltransferase 1 (POFUT1) that drives HCC immune evasion and explored a potential therapeutic strategy for enhancing ICB efficacy. De novo MYC/Trp53-/- liver tumor and the xenograft tumor models were used to evaluate the function of POFUT1 in immune evasion. Biochemical assays were performed to elucidate the underlying mechanism of POFUT1-mediated immune evasion. We identified POFUT1 as a crucial promoter of immune evasion in liver cancer. Notably, POFUT1 promoted HCC progression and inhibited T-cell infiltration in the xenograft tumor and de novo MYC/Trp53-/- mouse liver tumor models. Mechanistically, we demonstrated that POFUT1 stabilized programmed death ligand 1 (PD-L1) protein by preventing tripartite motif containing 21-mediated PD-L1 ubiquitination and degradation independently of its protein-O-fucosyltransferase activity. In addition, we further demonstrated that PD-L1 was required for the tumor-promoting and immune evasion effects of POFUT1 in HCC. Importantly, inhibition of POFUT1 could synergize with anti-programmed death receptor 1 therapy by remodeling TME in the xenograft tumor mouse model. Clinically, POFUT1 high expression displayed a lower response rate and worse clinical outcome to ICB therapies. Our findings demonstrate that POFUT1 functions as a novel regulator of tumor immune evasion and inhibition of POFUT1 may be a potential therapeutic strategy to enhance the efficacy of immune therapy in HCC.
Correlation of K<sup>trans</sup>derived from dynamic contrast-enhanced MRI with treatment response and survival in locally advanced NSCLC patients undergoing induction immunochemotherapy and concurrent chemoradiotherapy
Authors: DaQuan Wang, SongRan Liu, Jia Fu, PengXin Zhang, ShiYang Zheng, Bo Qiu, Hui Liu, YongQuan Ye, JinYu Guo, Yin Zhou, HaiHang Jiang, ShaoHan Yin, HaoQiang He, ChuanMiao Xie, Hui Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Purpose This study aimed to investigate the prognostic significance of pretreatment dynamic contrast-enhanced (DCE)-MRI parameters concerning tumor response following induction immunochemotherapy and survival outcomes in patients with locally advanced non-small cell lung cancer (NSCLC) who underwent immunotherapy-based multimodal treatments. Material and methods Unresectable stage III NSCLC patients treated by induction immunochemotherapy, concurrent chemoradiotherapy (CCRT) with or without consolidative immunotherapy from two prospective clinical trials were screened. Using the two-compartment Extend Tofts model, the parameters including K trans , K ep , V e , and V p were calculated from DCE-MRI data. The apparent diffusion coefficient was calculated from diffusion-weighted-MRI data. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to assess the predictive performance of MRI parameters. The Cox regression model was used for univariate and multivariate analysis. Results 111 unresectable stage III NSCLC patients were enrolled. Patients received two cycles of induction immunochemotherapy and CCRT, with or without consolidative immunotherapy. With the median follow-up of 22.3 months, the median progression-free survival (PFS) and overall survival (OS) were 16.3 and 23.8 months. The multivariate analysis suggested that Eastern Cooperative Oncology Group score, TNM stage and the response to induction immunochemotherapy were significantly related to both PFS and OS. After induction immunochemotherapy, 67 patients (59.8%) achieved complete response or partial response and 44 patients (40.2%) had stable disease or progressive disease. The K trans of primary lung tumor before induction immunochemotherapy yielded the best performance in predicting the treatment response, with an AUC of 0.800. Patients were categorized into two groups: high-K trans group (n=67, K trans ＞164.3×10 −3 /min) and low-K trans group (n=44, K trans ≤164.3×10 −3 /min) based on the ROC analysis. The high-K trans group had a significantly higher objective response rate than the low-K trans group (85.1% (57/67) vs 22.7% (10/44), p&lt;0.001). The high-K trans group also presented better PFS (median: 21.1 vs 11.3 months, p=0.002) and OS (median: 34.3 vs 15.6 months, p=0.035) than the low-K trans group. Conclusions Pretreatment K trans value emerged as a significant predictor of the early response to induction immunochemotherapy and survival outcomes in unresectable stage III NSCLC patients who underwent immunotherapy-based multimodal treatments. Elevated K trans values correlated positively with enhanced treatment response, leading to extended PFS and OS durations.
Trends and cross-country inequalities in the global burden of osteoarthritis, 1990–2019: A population-based study
Authors: Fan Cao, Zhiwei Xu, Xiao-Xiao Li, Zi-Yue Fu, Rong-Ying Han, Jun-Lin Zhang, Peng Wang, Shengping Hou, Hai-Feng Pan
Journal: Ageing Research Reviews (2024)
Real‐world biologics response and super‐response in the International Severe Asthma Registry cohort
Authors: Eve Denton, Mark Hew, Matthew J. Peters, John W. Upham, Lakmini Bulathsinhala, Trung N. Tran, Neil Martin, Celine Bergeron, Mona Al‐Ahmad, Alan Altraja, Désirée Larenas‐Linnemann, Ruth Murray, Carlos Andrés Celis‐Preciado, Riyad Al‐Lehebi, Manon Belhassen, Mohit Bhutani, Sinthia Z. Bosnic‐Anticevich, Arnaud Bourdin, Guy G. Brusselle, John Busby, Giorgio Walter Canonica, Enrico Heffler, Kenneth R. Chapman, Jérémy Charriot, George C. Christoff, Li Ping Chung, Borja G. Cosio, Andréanne Côté, Richard W. Costello, Breda Cushen, James Fingleton, João A. Fonseca, Peter G. Gibson, Liam G. Heaney, Erick Wan‐Chun Huang, Takashi Iwanaga, David J. Jackson, Mariko Siyue Koh, Lauri Lehtimäki, Jorge Máspero, Bassam Mahboub, Andrew N. Menzies‐Gow, Patrick D. Mitchell, Nikolaos G. Papadopoulos, Andriana I. Papaioannou, Luis Perez‐de‐Llano, Diahn‐Warng Perng, Paul E. Pfeffer, Todor A. Popov, Celeste M. Porsbjerg, Chin Kook Rhee, Nicolas Roche, Mohsen Sadatsafavi, Sundeep Salvi, Johannes Martin Schmid, Chau‐Chyun Sheu, Concetta Sirena, Carlos A. Torres‐Duque, Laila Salameh, Pujan H. Patel, Charlotte Suppli Ulrik, Eileen Wang, Michael E. Wechsler, David B. Price
Journal: Allergy (2024)

Abstract Background Biologic asthma therapies reduce exacerbations and long‐term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real‐world population of adults with severe asthma. Methods Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow‐up were grouped into those who did, or did not, initiate biologics (anti‐IgE, anti‐IL5/IL5R, anti‐IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV 1 ) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super‐response criteria were: FEV 1 increase by ≥500 mL, new well‐controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. Results 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non‐initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV 1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super‐responses. Responses/super‐responses were more frequent in biologic initiators than in non‐initiators; nevertheless, ~40–50% of initiators did not meet response criteria. Conclusions Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non‐initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super‐responses in all outcome domains, 40–50% did not meet the response criteria.
Exosomal miRNA-26b-5p from PRP suppresses NETs by targeting MMP-8 to promote diabetic wound healing
Authors: Shunli Rui, Linrui Dai, Xiaoshi Zhang, Min He, Fan Xu, Wei Wu, David G Armstrong, Yuehua You, Xiaoqiu Xiao, Yu Ma, Yan Chen, Wuquan Deng
Journal: Journal of Controlled Release (2024)