tbuckley/cabot-search huggingface dataset:
Engagement of N6-methyladenisine methylation of Gng4 mRNA in astrocyte dysfunction regulated by CircHECW2
Authors: Ying Bai, Di Chang, Hui Ren, Minzi Ju, Yu Wang, Biling Chen, Han Li, Xue Liu, Daxing Li, Xinchen Huo, Xiaofei Guo, Mengze Tong, Ying Tan, Honghong Yao, Bing Han
Journal: Acta Pharmaceutica Sinica B (2024)

The N6-methyladenosine (m6A) modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs. Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder (MDD), a common neuropsychiatric disorder with an unclear aetiology. Here, we found that the levels of the circular RNA HECW2 (circHECW2) were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress (CUS) mouse model. Notably, the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS. Furthermore, we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP, leading to an increase in GNG4 expression via m6A modifications. Our findings provide functional insight into the correlation between circHECW2 and m6A methylation, suggesting that circHECW2 may represent a potential target for MDD treatment.
Initial efficacy evaluation of fruquintinib plus capecitabine versus capecitabine as maintenance treatment for metastatic colorectal cancer (mCRC): A randomized, controlled, phase Ib/II study.
Authors: Wenhua Li, Jinjia Chang, Chenchen Wang, Junjie Peng
Journal: Journal of Clinical Oncology (2024)

119 Background: The standard first-line therapy followed by maintenance treatment is an optional approach to balance the efficacy and toxicity for mCRC. Fruquintinib (Fru), a highly specific inhibitor of VEGFR1/2/3, has demonstrated favorable safety and efficacy outcomes in the treatment of mCRC. In this study, we present findings from an investigation into the comparative efficacy and safety of Fru in combination with capecitabine (Cap) versus Cap as a maintenance therapy for patients (pts) with mCRC. Methods: Pts with histologically confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy were included in the study. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m 2 , p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was progression-free survival (PFS). Results: By Sep 10, 2023, a total of 34 pts were enrolled in the study, and 26 pts were considered evaluable for efficacy. During Fru plus Cap (n=14) and Cap (n=12), the median age was 61.5 (39-78) and 57.5 (32-75) years. The main primary tumor side was left (64.3% / 66.7%) and approximately half of the pts harbored a RAS mutation (50.0% / 58.3%). Most pts had previously received bevacizumab therapy (57.1% /58.3%) or cetuximab (35.7% /25.0%), respectively. The mPFS was significantly improved in Fru plus Cap vs Cap (9.1 vs 3.8 months, HR: 0.289, 95% CI 0.083 to 1.01, p=0.039). Consistently, ORR (21.4% vs 0%) and DCR (92.9% vs 66.7%) were improved with Fru plus Cap. Grades 3 and 4 treatment-emergent adverse events (TEAEs) were hypertension (11.1%), oral mucositis (5.6%), voice alteration (5.6%), small intestinal obstruction (5.6%), acrodynia (5.6%) and blood bilirubin increased (5.6%) in Fru plus Cap, and diarrhea (6.3%), oral mucositis (6.3%) and acrodynia (6.3%) in Cap therapy. Conclusions: The findings suggest that Fruquintinib plus Capecitabine can be considered as a first-line maintenance therapy for metastatic colorectal cancer, as it demonstrated a promising improvement in mPFS by 5.3 months while maintaining a controlled level of safety. Clinical trial information: NCT05451719 .
Disparities in survival in Asian American, Native Hawaiian, and Pacific Islander patients with gastric adenocarcinoma: An NCDB analysis.
Authors: Anjali Mishra, Robert Hu, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2024)

253 Background: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) individuals exhibit stark disparities in gastric cancer mortality rates, with AANHPI men facing a two-fold higher risk of death and AANHPI women encountering a 2.5-fold elevated risk compared to their Non-Hispanic White (NHW) counterparts. However, the AANHPI community is a diverse group, including over 21 ethnic groups. Here, we identify disparities among AANHPI subpopulations with gastric adenocarcinoma. Methods: Using the National Cancer Database, which gathers data from over 1,500 accredited hospitals and facilities across the United States, this retrospective cohort study identified 141,906 patients with gastric adenocarcinoma (ICD code “8140”). Races listed as “unknown/other” or “Other Asian” were excluded. Kaplan Meier and Cox Regression model were performed. Results: This study compared mean overall survival (OS) of NHW (n=111,137), East Asian (EA) (n=3,745), South Asian (SA) (n=760), Southeast Asian (SEA) (n=1,379), and Native Hawaiian or Pacific Islander (NHPI) (n=325) patients with gastric adenocarcinoma. When aggregated, AANHPI had statistically significant improved OS compared to NHW (21.6 months vs 14.1 months, p &lt; 0.001). After disaggregating, the mean OS was 26.9 months for EA; 21.3 months for SA; 14.5 months for SEA; and 14.3 months for NHPI. Only SA and EA had significantly improved OS than NHW (p&lt;0.001 for both). SEA and NHPI had significantly worse outcomes than EA (p&lt;0.001 for both) and SA (p&lt;0.001 for SEA, and p = 0.033 for NHPI). Multivariate analysis accounted for age at diagnosis, insurance status, median income quartile, Charlson-Deyo comorbidity score, facility type, stage at diagnosis, and time to treatment. SA (HR=0.82; 95% CI, 0.726 to 0.925; p&lt;0.001)), EA (HR=0.644; 95% CI, 0.609 to 0.68; p&lt;0.001), and SEA (HR=0.896; 95% CI, 0.821 to 0.978, p=0.014) had lower survival hazard ratios compared to NHW. NHPI (HR=0.931, 95% CI 0.775 to 1.119, p=0.448) did not have a statistically significant relationship compared to NHW. EA (HR = 0.637; 95% CI 0.548 to 0.741, p&lt;0.001) and SA (HR = 0.793; 95% CI 0.667 to 0.943, p=0.007) had significantly lower survival hazard ratios compared to NHPI. Conclusions: Survival disparities exist among AANHPI subgroups with gastric adenocarcinoma. At first glance, OS appeared significantly greater for AANHPI patients compared to NHW. However, disaggregation of AANHPI subpopulations revealed that Southeast Asian and NHPI actually had comparable OS with NHW. After controlling for socioeconomic factors, NHPI had significantly worse hazard ratios compared to South Asian and East Asian. This highlights the need to disaggregate AANHPI data so that disparities among these diverse subpopulations can be identified, investigated and ultimately addressed.
A quality-adjusted time without symptoms and toxicity (Q-TWiST) analysis comparing nivolumab plus ipilimumab (N+I) or nivolumab plus chemotherapy (N+CT) versus CT in patients (pts) with advanced esophageal squamous cell carcinoma (ESCC): CheckMate 648.
Authors: Ian Chau, John A Bridgewater, Lucjan Wyrwicz, Mike Greenwood, Steven I. Blum, Alejandro Moreno-Koehler, Gill Worthy, Fiona Taylor, Catherine Davis, Clara Chen
Journal: Journal of Clinical Oncology (2024)

251 Background: In CheckMate 648, pts with advanced ESCC treated with first-line N+I or N+CT had significantly longer overall survival (OS) vs CT and maintained quality of life (QoL) with no new safety signals. Here we compare between-treatment differences in quality-adjusted survival using a Q-TWiST analysis in all randomized pts (29-month minimum follow-up). Methods: Survival time was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse (REL). TOX was defined as time spent with all-cause grade 3/4 adverse events after randomization, prior to disease progression. TWiST was defined as time prior to REL where pts did not experience TOX. REL was defined as time between disease progression and death, or the last known date alive. Mean duration of time in each state was calculated for each treatment group using descriptive statistics and Kaplan-Meier analysis. Utility values from the 3-level EQ-5D (EQ-5D-3L) questionnaire were used to adjust the time spent within each health state for QoL and to calculate Q-TWiST as the utility-weighted sum of the mean health state durations. Bootstrapping (500 samples) was used to estimate time in each health state and to compare mean Q-TWiST estimates between treatments. A between-group difference in Q-TWiST of 5 weeks was prespecified as being clinically important (defined as 10% of OS; based on a median OS in CT group of 10.7 months). Sensitivity analyses were conducted using different combinations of prespecified utility weights for each health state. Results: 970 pts were randomized 1:1:1 to N+I (n = 325), N+CT (n = 321), or CT (n = 324) and included in the Q-TWiST analysis. Median duration of follow-up for survivors was 155 weeks. Mean time in each health state was significantly longer for pts treated with N+I or N+CT compared to CT (Table). Between-group differences in Q-TWiST score were considered clinically important: 5.7 weeks (95% CI 5.5–6.0) favoring N+I vs CT and 7.6 weeks (95% CI 7.4–7.9) favoring N+CT vs CT. Sensitivity analyses supported these findings. Conclusions: In CheckMate 648, pts with unresectable advanced ESCC treated with N+I or N+CT had significantly longer OS compared with those treated with CT. Quality-adjusted survival using Q-TWiST also significantly favored N+I and N+CT compared to CT alone. Pts treated with N+I and N+CT not only experienced increased survival time, but also better QoL during their survival time. Clinical trial information: NCT03143153 . [Table: see text]
Prevalence of modifiable risk factors of Hispanic adult patients admitted with gastric cancer in the US.
Authors: Alejandro Nieto Dominguez, Sarah Elizabeth Eichinger, Daniel Guifarro Rivera
Journal: Journal of Clinical Oncology (2024)

254 Background: More than 19% of the US population is comprised of Hispanic individuals. For decades, cancer incidence has been increasing in this population, including cancers associated with infection (gastric, hepatic, cervical) and resulting from delayed screening (colorectal, cervical and breast). Risk factors associated with gastric cancer include H. pylori, obesity, alcohol, and tobacco use. However, ethnicity has not been a commonly reported risk factor despite the fact that studies have shown increasing incidence of gastric cancer in Hispanics at a younger age. Methods: We used the 2016-2019 National Inpatient Sample (NIS) database to stratify patients with gastric cancer by age, ethnicity, and comorbidities. Results: There were 77,745 adults with gastric cancer. Of these, 578 (7.45%) were ages 18-44 (group 1), 28,370 (36.47%) 45-64 years old (group 2), and 43,590 (55.08%) were over 65 (group 3). Group 1 was comprised of 29.4% White, 34.3% Hispanic, 14.5% Black, and 21.8% Asian or Pacific Islander patients. Group 2 consisted of 46.7% White, 19.7% Hispanic, 17.4% Black, and 16.2% Asian or Pacific Islander individuals. Group 3 had the highest percentage of White patients (56.0%) and lowest percentage of Hispanic individuals (12.9%). Group 3 also consisted of 15.1% Black and 16.0% Asian or Pacific Islander patients. In Hispanics with gastric cancer, there was a predominance of H. pylori among younger patients (8.6% in group 1 vs 3.6% and 2.1% in groups 2 and 3 respectively) (p = 0.00). Incidence of smoking increased with age (19.9% in group 1, 28.1% in group 2 and 31.1% in group 3) (p = 0.00) as did incidence of diabetes (8.1% in group 1, 26.4% in group 2 and 36.0% in group 3) (p = 0.00). Alcohol use was 3.0% in group 1, 4.3% in group 2 and 2.3% in group 3 (p = 0.035). The differences between all groups for gastric ulcer, gastric polyp and obesity were not statistically significant. Conclusions: Gastric cancer accounts for approximately 1.5% of all new cancers diagnosed in the US, with a high incidence in older White populations. However, this study demonstrates that there is a large proportion of young Hispanics with gastric cancer who have higher associated instances of H. pylori. This suggests the need for further research to determine if there is utility in screening for H. pylori in asymptomatic young Hispanics to decrease the burden of gastric cancer in this population. [Table: see text]
Unveiling survival strategies: The impact of treatment modalities on patients with esophageal cancer and the role of racial disparities.
Authors: Dani Ran Castillo, Won Jin Jeon, Esther G Chong, Jae Y. Kim, S.Peter Wu
Journal: Journal of Clinical Oncology (2024)

257 Background: Managing esophageal cancer (EC) involves neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy as the standard of care. However, some patients may remain unsuitable for esophagectomy. This study explores real-world outcomes in EC patients across different treatments, considers prognostic factors, and examines potential racial disparities. Methods: Data from 44,181 patients diagnosed with locally advanced EC between 2004-2017 were extracted from the National Cancer Database. The cohort was stratified into three groups: nCRT followed by esophagectomy, definitive RT (dCRT), single-modality RT. The dataset included 24,676 patients who received nCRT with esophagectomy or dCRT (N=17,534) and 1,971 patients who received single-modality RT. Endpoints included overall survival (OS). Cox Proportional Hazards Model was employed for multivariate survival analysis. Chi-square test was applied to the covariate demographic data. Results: nCRT followed by esophagectomy significantly improved OS compared to dCRT (mOS 43.5 vs. 20.1 months, p &lt; 0.001). Single-modality RT had an mOS of 14.4 months. In the RT group, 73% were over 65 years old compared to 59% in the dCRT group (p &lt; 0.001). Over 60% of patients had node-positive disease in both RT and dCRT groups (69% vs. 61.4%). More privately insured patients received multimodal treatment compared to publicly insured patients (27.3% vs. 16.8%, p &lt; 0.001). Over 70% of patients were willing to travel within 20 miles for treatment, 60% underwent treatment in community programs. Racial disparities were observed, with Black patients experiencing worse outcomes compared to all other groups, while Asian and Hispanic patients had better outcomes (table1). In the squamous cell histology subset treated with dCRT, mOS was 22 (20.6 – 23.6 months) for Black patients, 27 (26 – 28) months for White patients, 36 (30-46) months for Hispanic patients, and 37 (30-44) months for Asian/Pacific Islander patients (p &lt; 0.001). Conclusions: This real-world data analysis underscores the effectiveness of nCRT followed by esophagectomy in providing the best survival benefit for EC patients compared to dCRT or RT alone. Racial disparities emerged as significant factors influencing cancer survival outcomes. These identified factors including race and age can assist clinicians in making better-informed decisions regarding treatment pathways for specific patient populations. [Table: see text]
Reliability of computed tomography to determine the eligibility of conversion surgery for gastric cancer with para-aortic lymph node metastasis.
Authors: Takeyuki Wada, Takaki Yoshikawa, Ryota Sakon, Tsutomu Hayashi, Yukinori Yamagata
Journal: Journal of Clinical Oncology (2024)

259 Background: Although gastric cancer (GC) with para-aortic lymph node (PAN) metastasis is diagnosed as stage IV and basically treated with chemotherapy, it can be the candidate of conversion surgery when PAN metastasis was limited in localized area as oligometastatic status. Recently, we reported that pathological complete response at PAN (pCR at PAN) after chemotherapy was a good surrogate marker in conversion surgery for GC with PAN metastasis. However, it is difficult to predict pCR at PAN before surgery. Computed tomography (CT) is a standard procedure for clinical diagnosis of lymph node metastasis in GC.This study aimed to evaluate the reliability of CT to predict pCR at PAN after chemotherapy. Methods: The study examined patients who received radical gastrectomy with D2 and PAN dissection after chemotherapy for gastric cancer with PAN metastasis (#16a2/b1) from 2004 to 2020. PAN greater than 10mm in long axis was diagnosed as clinically positive. Patients were classified into 2 groups as pPAN-CR and pPAN-nonCR according to the pathological diagnosis of PAN. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive values for PAN diagnosis were retrospectively investigated. Moreover, the relationship between shrinkage ratio at PAN and pathological diagnosis was also investigated. Results: A total of 46 patients were examined in the present study. The number of pPAN-CR and pPAN-nonCR patients were 31 and 15, respectively. 5-year overall survival rate was 76% in pPAN-CR and 0% in pPAN-nonCR patients. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of PAN were 52.2%, 60.0%, 48.4%, 36.0%, and 28.6%, respectively. Median shrinkage ratio of PAN was 38% (-20%-88%) in pPAN-CR and 40% (-20%-75%) in pPAN-nonCR patients. There was no statistically significant relationship between shrinkage ratio and pathological diagnosis of PAN ( p=0.655). Conclusions: CT diagnosis for PAN after chemotherapy was not reliable. The indication of conversion surgery for GC with PAN metastasis should not be determined based on the size and shrinkage of PAN.
Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes
Authors: Xiong Chen, Jinfu Qian, Shiqi Liang, Jianchang Qian, Wu Luo, Yujuan Shi, Hong Zhu, Xiang Hu, Gaojun Wu, Xiaokun Li, Guang Liang
Journal: Acta Pharmaceutica Sinica B (2024)

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
The efficacy and safety of transarterial chemoembolization combined with cadonilimab and lenvatinib for unresectable hepatocellular carcinoma: A phase II clinical trial.
Authors: Guo Liang, Shanzhi Gu, Yabing Guo, Hailiang Li, Jingfeng Liu, Jibing Liu, Ming Huang, Yinghua Zou, Luke Huang, Yangyang Zhang, Ting Liu, Wei Liu, Zhongmin Wang, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2024)

478 Background: Immune-checkpoint inhibitors, in combination with targeted therapy and local therapy, have been developed as promising treatment for unresectable hepatocellular carcinoma (uHCC) of intermediate stage. This study aimed to assess the efficacy and safety of cadonilimab(a tetravalent PD-1/CTLA-4 bispecific antibody) plus Lenvatinib (Len) and transarterial chemoembolization (TACE) in the treatment of intermediate HCC. Methods: This open label, multicenter phase II trial enrolled patients with histologically or clinically confirmed intermediate uHCC to receive TACE followed by cadonilimab 10mg/kg every 3 weeks plus Len until disease progression or intolerable toxicity. The primary endpoint was progression free disease (PFS) according to RECIST v1.1. The secondary endpoint includes safety, overall survival (OS), PFS according to modified RECIST (mRECIST), and objective response rate (ORR), disease control rate (DCR) and duration of response (DoR) by both RECIST v1.1 and mRECIST. Results: From June 2022 to May 2023, 78 patients were screened and 60 patients enrolled. As of August 15, 2023, 60 patients received at least once cadonilimab and the median duration of follow-up was 5.1 months. The average number of TACE procedures per patient was 1.70. The median PFS and OS were not reached, while the 6-month PFS rate was 77.1% (95% CI, 60.8-87.3) per RECIST v1.1 and 75.6% (95% CI, 59.5-86.0) per mRECIST. The ORR and DCR were 35.0% (95% CI, 23.1-48.4) and 96.7% (95% CI, 88.5-99.6) according to RECIST v1.1 and 85.0% (95% CI, 73.4-92.9) and 95.0% (95% CI, 86.1-99.0) according to mRECIST. 9 patients (15.0%) achieved complete response per mRECIST. The incidence of grade≥3 treatment-related adverse events (TRAEs) was 68.9%. The incidence of grade≥3 adverse events related to cadonilimab was 45.9%.The most common TRAEs included thrombocytopenia, aspartate aminotransferase increased, and alanine aminotransferase increased. Conclusions: Combination of TACE and cadonilimab plus len showed promising efficacy and manageable toxicity in intermediate uHCC. Benefit of control on tumor progression after TACE and lasting survival can be expected. Clinical trial information: NCT05319431 . [Table: see text]