tbuckley/cabot-search huggingface dataset:
Forecasting the Economic Burden of Cardiovascular Disease and Stroke in the United States Through 2050: A Presidential Advisory From the American Heart Association
Authors: Dhruv S. Kazi, Mitchell S.V. Elkind, Anne Deutsch, William N. Dowd, Paul Heidenreich, Olga Khavjou, Daniel Mark, Michael E. Mussolino, Bruce Ovbiagele, Sonali S. Patel, Remy Poudel, Ben Weittenhiller, Tiffany M. Powell-Wiley, Karen E. Joynt Maddox
Journal: Circulation (2024)

BACKGROUND: Quantifying the economic burden of cardiovascular disease and stroke over the coming decades may inform policy, health system, and community-level interventions for prevention and treatment. METHODS: We used nationally representative health, economic, and demographic data to project health care costs attributable to key cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia) and conditions (coronary heart disease, stroke, heart failure, atrial fibrillation) through 2050. The human capital approach was used to estimate productivity losses from morbidity and premature mortality due to cardiovascular conditions. RESULTS: One in 3 US adults received care for a cardiovascular risk factor or condition in 2020. Annual inflation-adjusted (2022 US dollars) health care costs of cardiovascular risk factors are projected to triple between 2020 and 2050, from $400 billion to $1344 billion. For cardiovascular conditions, annual health care costs are projected to almost quadruple, from $393 billion to $1490 billion, and productivity losses are projected to increase by 54%, from $234 billion to $361 billion. Stroke is projected to account for the largest absolute increase in costs. Large relative increases among the Asian American population (497%) and Hispanic American population (489%) reflect the projected increases in the size of these populations. CONCLUSIONS: The economic burden of cardiovascular risk factors and overt cardiovascular disease in the United States is projected to increase substantially in the coming decades. Development and deployment of cost-effective programs and policies to promote cardiovascular health are urgently needed to rein in costs and to equitably enhance population health.
Correspondence to “Salivary Immunoinflammatory Proteins Identify Children with Eosinophilic Esophagitis”
Authors: Martina Votto, Caterina Strisciuglio, Cristiana Indolfi, Gian Luigi Marseglia, Michele Miraglia Del Giudice, Amelia Licari
Journal: Allergy (2024)

Data sharing does not apply to this article as no new data were produced or analyzed.
Phase II, multicenter study of plasminogen activator inhibitor-1 inhibitor (TM5614) plus nivolumab for treating anti-PD-1 antibody-refractory malignant melanoma: TM5614-MM trial
Authors: Taku Fujimura, Koji Yoshino, Hiroshi Kato, Satoshi Fukushima, Shoichiro Ishizuki, Atsushi Otsuka, Shigeto Matsushita, Ryo Amagai, Yusuke Muto, Emi Yamazaki, Yumi Kambayashi, Takashi Yahata, Toshio Miyata, Yasuhiro Fujisawa, Yoshihide Asano
Journal: British Journal of Dermatology (2024)

Anti-programmed cell death 1 antibodies (anti-PD-1 Abs) are widely used for advanced melanoma, but the efficacy of an anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Abs treatment, particularly in melanoma patients who are refractory to anti-PD-1 Abs. The aim was to evaluate anti-PD-1 Abs treatment in combination with TM5614 (plasminogen activator inhibitor-1: PAI-1 inhibitor) in patients with unresectable melanoma.
The human gut microbiome and aging
Authors: Evan Bradley, John Haran
Journal: Gut Microbes (2024)

The composition of the human gut microbiome has been observed to change over the course of an individual's life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.
Dual targeting of αv and α5β1 integrins in triple-negative breast cancer (TNBC).
Authors: Fei Song, Kevin Do, Daniel E.C. Fein, Narges Jahanseir, Raghav Joshi, Paul Mathew
Journal: Journal of Clinical Oncology (2024)

e15073 Background: Integrin αv has been implicated in a stem-phenotype of breast cancer (1) and is cross-regulated by fibronectin-binding integrin α5β1 in tumor cells (2). We hypothesized that these integrins are expressed in TNBC cells and dual targeting of αv and α5β1 integrins by a bispecific antibody (BsAbαv/α5β1) will be superior to monospecific integrin antibodies (MsAbs) alone or in combination. Methods: A representative panel of basal-subtype TNBC lines was assembled: MDA-MB-231 (P53 mutated, KRAS mutated), MDA-MB-468 (P53 mutated, PTEN deleted, EGFR amplified) and BT-20 (P53 and PIK3CA mutated, EGFR amplified). Integrin expression was determined by flow cytometry and Western blot in cell lines and by IHC in the residual cancer burden (RCB) of TNBC specimens following neoadjuvant chemotherapy (positive: &gt;2+ membranous, &gt;10% cells). The impact of MsAbs targeting αv and α5β1 integrins alone or in combination versus the BsAbαv/α5β1 was assessed in adhesion, migration, and clonogenic survival. The impact of integrin blockade on nuclear localization of basal markers including FAK, YAP, EGFR and beta-catenin, was assessed. Results: Robust integrin αv expression was present in all TNBC lines with variable α5β1 expression. Marked reduction in α5 and in αv expression following BsAbαv/α5β1 was uniquely demonstrated by Western blot and/or flow cytometry compared to MsAbs, likely due to endosomal trafficking and lysosomal degradation of target integrins as reported previously (Joshi, MCR. 2020). Combined α5 and αv neutralization with MsAbs was superior to individual single agents in blocking adhesion and migration across all TNBC lines studied. However, the BsAbα5β1/αv was superior to combinatorial MsAbs in MDA-MB-468 and BT-20 lines in chemotaxis assays. A significant (&gt;50%) reduction in clonogenic cell survival was noted with the BsAbα5β1/αv compared to MsAbs. BsAbαv/α5β1 blocked nuclear localization of FAK, EGFR, activated beta-catenin, and YAP in MDA-MB-231 uniquely compared to MsAbs alone or in combination. RCB tumor cells were strongly positive for membranous αv [7/9, (78%)]. Diffuse expression of integrin α5 (67%) in alpha smooth-muscle actin-expressing fibroblasts with dual staining for integrin αv was found. Marked CD68+ macrophage and CD3+ infiltration was seen in tumor and stroma of all RCB tumors. Conclusions: Combinatorial α5 and αv integrin targeting with BsAbα5/αvβ1 defines a novel therapeutic strategy with a distinct mechanism of action for further investigation in TNBC. Enrichment of integrins αv and α5 in the inflamed RCB of TNBC tumors and stroma respectively point to a potential role of these integrins in epithelial-stromal interactions and therapeutic resistance. 1. Desgrosellier, Dev Cell. 2014. 2. Joshi, MCR. 2020.
Correlating survival outcomes in patients with advanced prostate cancer with novel hyperpolarized <sup>13</sup>C MRI metabolic imaging biomarkers.
Authors: Hsin-Yu Chen, Ivan de Kouchkovsky, Robert A. Bok, Michael A. Ohliger, Zhen J. Wang, Daniel Gebrezgiabhier, Tanner Nickles, Lucas E. Carvajal, Jeremy W. Gordon, Peder E.Z. Larson, John Kurhanewicz, Rahul Raj Aggarwal, Daniel B. Vigneron
Journal: Journal of Clinical Oncology (2024)

e15059 Background: Hyperpolarized 13 C (HP 13 C) MRI is a novel molecular imaging approach that detects aberrant aerobic metabolism, namely elevated rates of pyruvate-to-lactate conversion (k PL ), in patients with advanced malignancies. Higher k PL has been shown to correlate with higher tumor grade among patients with localized prostate cancer (PC). This research sought to evaluate the correlation between k PL and clinical outcome measures in patients with advanced PC. Methods: Patients with metastatic or locally advanced PC (castration sensitive or resistant) were prospectively enrolled at our institution and underwent HP 13 C MRI of one or more target lesions identified on prior conventional imaging. Voxelwise k PL values were computed in MATLAB using an inputless two site exchange model. k PL,median was defined as the median k PL value per-patient across all target lesions; k PL,kurtosis measured the tailedness of the k PL distribution per-patient. We retrospectively analyzed progression free survival (PFS) and overall survival (OS) in subgroups divided by metabolic activity below versus above cut-point (k PL,median &lt;0.017 s -1 and ≥ 0.017s -1 , respectively). Survival statistics were calculated using the Cox PH model. Results: Sixteen patients (6 with castration-sensitive and 10 with castration-resistant PC) were accrued. With a median follow-up of 22.0 months from the date of MRI, the lower-k PL subgroup had significantly longer median PFS (11.2 vs 0.5 months; p&lt;0.01) and OS (NR vs 18.4 months; p&lt;0.05) compared to the higher-k PL subgroup. By comparison, baseline serum PSA (PFS: p=0.19, OS: p=0.41) and LDH (PFS: p=0.60, OS: p=0.34) did not demonstrate a significant association with clinical outcomes. There was a strong negative correlation between k PL,kurtosis and OS (r = -0.75), and moderate negative correlations between k PL,median and OS (r = -0.45) as well as k PL,max with both PFS (r = -0.48) and OS (r = -0.54). There was no significant k PL,median difference between castration-sensitive and resistant subgroups (0.015±0.011 vs 0.016±0.006 s -1 , p&gt;0.8). Conclusions: HP 13 C MRI-derived non-invasive metabolic biomarker k PL,median significantly correlated with clinical outcome measures in a retrospective analysis of patients with advanced PC, outperforming established serological prognostic markers PSA and LDH. Limitations include our small sample size, retrospective design, and heterogeneous patient population. Nevertheless, these encouraging preliminary results support further investigation of HP 13 C MRI as a prognostic and/or predictive PC biomarker in multi-center prospective imaging trials. [Table: see text]
A phase 1 study of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated (TAA) CD8+T cells in patients with advanced solid tumors.
Authors: Xianjun Yu, Jian Zhang, Jiajian Liu
Journal: Journal of Clinical Oncology (2024)

e15074 Background: PD-1/PD-L1-targeted immunotherapies have become critical in the treatment for many tumors. However, there has been limited progress in low immunogenic cancers such as pancreatic ductal adenocarcinoma (PDAC) or CRC. LB4330 is a novel, bi-functional molecule targeting Claudin18.2 and IL-10 with high affinity anti-CLDN18.2 (14pM). It may activate TAA CD8+ T cells in the tumor microenvironment (TME) and has potential alone or in combination with immunotherapeutic agents, including PD-1/PD-L1 mAbs, for the treatment of advanced solid tumors. A FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001) is ongoing in China. Methods: Eligible patients were ≥ 18 years old with ECOG PS 0-1. Dose cohorts ranged from 0.001 mg/kg to1 mg/kg IV QW: 0.001mg/kg-0.05mg/kg in an accelerated titration design, and 0.2mg/kg-1 mg/kg using traditional 3+3 design. The primary objective is safety, including dose-limiting toxicities (DLTs). The secondary/exploratory objectives include efficacy, pharmacokinetics (PK), and immunogenicity. Results: As of January 5, 2024, 30 patients with advanced solid tumors who have failed standard treatments or who did not have standard treatments available or applicable at this stage were recruited, including 17 PDAC, 6 GC, 3 CRC and 4 other solid tumor patients. All patients enrolled had multiple organ metastases. Treatment emergent AEs (TEAEs) occurred in 90.3% of patients. The most common Treatment related AEs (TRAE) were thrombocytopenia, anemia, fever, rash/itching, and fatigue. 7 patients (23.3%) had grade 3 TRAE which were infusion reaction, skin itching, rash, fever, abdominal distension, anemia, and thrombocytopenia. 1 patient (3.2%) had grade 4 AE, thrombocytopenia. On-treatment scan for efficacy was available for 20 patients, and 7 had stable disease. Target lesion shrinkage was observed in 2 pts, including one PDAC patient whose sum of target lesion reduced by 32.9% from baseline. PK was generally dose proportional, with t½ ~2 days. The immune activating Th1 cytokine IL-18 was elevated in 77.8% of patients treated with LB4330. Updated data will be presented. Conclusions: LB4330 has manageable safety and shows preliminary efficacy at tolerable doses. Dose and efficacy expansion study is ongoing in more PDACs and other solid tumors. In the meantime, Phase I study of LB4330 in combination with PD1/TIM-3 bispecific antibody LB1410 has been initiated in different tumor types as well. Clinical trial information: NCT05707676 .
Role of artificial intelligence in ocular tumors: A systematic review.
Authors: Shadi Farabi Maleki, Milad Yousefi, Zanyar Hajiesmailpoor, Ali Jafarizadeh, Siamak Pedrammehr, Roohallah Alizadehsani, Juan Manuel Gorriz Saez
Journal: Journal of Clinical Oncology (2024)

e15070 Background: Integrating oncology and artificial intelligence (AI) shows significant potential in improving treatments and early detection of ocular tumors. This systematic review aims to strengthen existing evidence regarding the application of AI in diagnosing and treating ocular tumors. Methods: We systematically searched PubMed, Embase, Web of Science, Scopus, and Google Scholar until January 15, 2024. Inclusion criteria comprised original peer-reviewed human studies (retrospective or prospective) investigating AI approaches in patients with ocular tumors such as retinoblastoma, uveal melanoma, conjunctival melanoma, and choroidal melanoma. The quality of the literature was assessed using JBI checklists. The eligibility criteria involved assessing studies that explored the application of AI in ocular tumor detection, classification, and treatment planning. We employed a rigorous screening process, and subsequent data extraction focused on key characteristics, including tumor types, sample sizes, AI input data specifications, and study aims. Exclusion criteria encompassed studies not meeting the inclusion criteria, lacking relevant outcome measures, exhibiting insufficient methodological quality, or inadequate reporting. Results: The initial database search yielded 903 records, of which 37 studies (retrospective = 24 and prospective = 13) were included. Most studies selected the retinoblastoma (n = 12) and uveal melanoma (n = 14). Other studies utilized other types of ocular tumors, including ocular metastasis (n = 2), ocular surface squamous neoplasia (n = 2), and ocular lymphoma (n = 2). The conjunctival melanoma, choroidal melanoma, intraocular melanoma, cavernous hemangioma, and schwannoma patients were utilized once. The AI-based models were employed for the classification (n = 22), prognosis prediction (n = 6), lesion segmentation (n = 5), and predicting the gene expression (n = 4) tasks. The data types used Included magnetic resonance imaging (MRI), computed tomography (CT), whole-slide imaging (WSI), clinical data, and fundus images. A meta-analysis was precluded because of the significant heterogeneity observed across the included studies in terms of demographics, study design, interventions, and outcome measures. Conclusions: Although imaging and patient presentation have played a crucial role in ocular tumor diagnostics, AI presents promising results in prediction, prognosis, and disease management. Meanwhile, AI's primary role has been in classification, demonstrating significant success. Additionally, continued exploration of less-discussed eye tumors is essential for enhancing AI's predictive and therapeutic capabilities. The absence of reported evaluation criteria and low evaluation parameter rates in certain studies underscores the importance of standardized reporting practices for robust assessments in future ocular oncology research.
Prognostication of ß-catenin (<i>CTNNB1)</i> in patients with HCC treated with first line immunotherapy.
Authors: Priyanshi M. Shah, Anina Peersen, Aminah Jatoi, Robert R. McWilliams, Zhaohui Jin, Michael S. Torbenson, Thorvardur Ragnar Halfdanarson, Hani M. Babiker, Caitlin Conboy, Lionel Aurelien Kankeu Fonkoua, Leslie Washburn, Lewis R. Roberts, Gregory J. Gores, Tanios S. Bekaii-Saab, Mitesh J. Borad, Fang-Shu Ou, Nguyen H. Tran
Journal: Journal of Clinical Oncology (2024)

e15146 Background: Wnt/ß-catenin signaling dysregulation is found in approximately 25% of hepatocellular carcinoma (HCC) patients. The impact of B-catenin activation on HCC overall survival has remained controversial. Prior studies suggest activating CTNNB1 mutations may predict for immunotherapy (IO) resistance while others did not corroborate this finding. Here we describe the clinical outcomes of advanced HCC patients (pts) with CTNNB1 (+) and without CTNNB1 (-) mutations treated with novel first line IO/anti-VEGF therapies. Methods: We conducted a multicenter, retrospective analysis of pts with HCC who had molecular analysis performed between 2019 and 2023 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the IRB. Clinical and molecular features were compared descriptively. The primary outcomes were time to treatment failure (TTF), defined as time from first-line treatment initiation to off treatment or death, and overall survival (OS), defined as time from first-line treatment initiation to death, compared between the two cohorts using the Kaplan-Meier method. Results: We identified 29 CTNNB1+ and 62 CTNNB1- (wt) pts with HCC. Median age at diagnosis was 66 (range 30-86), 80 (88%) were Caucasian, 68 (75%) were male gender, and 22 (24%) had etiology as hepatitis B/hepatitis C, 82 (90%) were Child-Pugh A and 77 (85%) were Barcelona Clinic Liver Clinic (BCLC)=C at diagnosis. Eighteen (90%, n=20) CTNNB 1+ pts received first-line IO (Atezolizumab/bevacizumab [AB]) vs 39 (72%, n=54) in CTNNB1- pts. All pts were microsatellite stable (MSS). CTNNB1+ had a similar median tumor mutational burden (TMB), higher rate of TERT co-mutation, and lower rate of TP53 co-mutation (table) compared to CTNNB-. Of 57 AB pts, 5 (27%) of CTNNB1 + had an objective response, compared to 6 (16.7%) CTNNB1- pts. Time to treatment failure with first-line AB and overall survival were similar between the two cohorts (Table). Conclusions: Our study suggests CTNNB1 status is not prognostic in HCC pts receiving IO based therapy. Prospective study is warranted to further investigate predictive biomarkers for HCC sensitivity to immune checkpoint inhibitors and VEGF-targeted therapy. [Table: see text]
First-in-human study of ZG0895, a TLR8 selective agonist, as monotherapy in patients with advanced solid tumors.
Authors: Yan Sun, Xiaoli Chai, Zhen Wang, Song Qu, Lihua Wu, Linlin Liu, Yanyan Liu, Ji Zhu
Journal: Journal of Clinical Oncology (2024)

e15103 Background: ZG0895 is a potent and novel Toll-like receptor (TLR) agonist that shows a highly selective activation of TLR8. It inhibits tumor growth by launching TLR8 downstream signal cascades, thus activating both innate and adaptive immune systems. We report preliminary results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK) and antitumor activity of ZG0895 in patients with advanced solid tumors. Methods: Eligible patients previously treated with or intolerant to available standard systemic therapy(ies), received subcutaneous (s.c.) injection of ZG0895 weekly. If tolerated during the first treatment cycle (21 days per cycle), patients would continue weekly s.c. administrations of ZG0895 until disease progression, loss of clinical benefit, or development of unacceptable toxicity. Dose escalation scheme for ZG0895 was planned with eight dose levels (0.06, 0.18, 0.37, 0.75, 1.50, 2.25, 3.00, 3.75 mg/m 2 ) according to an accelerated titration in the first two dose levels and the standard “3+3” design in the rest dose levels. Primary end points are the safety, tolerability, and recommended phase 2 dose (RP2D) of ZG0895. Secondary endpoints include overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1, as well as pharmacokinetics. Results: At data cut-off (December 25, 2023), 7 patients (5 males and 2 females), with the median age of 59 (range: 38-74) years old, received weekly s.c. injections of ZG0895 at the dose levels from 0.06 mg/m 2 to 0.75 mg/m 2 and completed the DLT observation period. Of the 7 patients, 4 (57.1%) received at least 3 lines of prior antineoplastic therapies, and 3 (42.9%) had exposed to PD-(L)1 inhibitors previously. No dose limiting toxicity events were reported. Five patients (71.4%) experienced grade 1 or 2 treatment-related adverse event (TRAE), and the most frequent events were injection site pain, hypertriglyceridaemia and proteinuria. None of patients experienced ≥grade 3 TRAE. Two patients experienced SAEs (intestinal obstruction and tumour haemorrhage), and both events were not related to ZG0895. The C max and AUC increased from 0.06 to 0.18 mg/m 2 approximately in dose proportion. Conclusions: During the first 4 dose groups, ZG0895 was well tolerated in patients with advanced solid tumors. Phase I dose escalation of ZG0895 are underway in higher doses. Clinical trial information: NCT05877664 .