Analysis Of Correlation Research Articles

CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial.

Chimeric antigen receptor (CAR) macrophages (CAR-Ms) mediate antitumor immunity via phagocytosis, cytokine release, activation of the tumor microenvironment and antigen presentation. We report results from a non-prespecified interim analysis of a first-in-human, phase 1 clinical trial of CT-0508, an anti-human epidermal growth factor receptor 2 (HER2) CAR-M in patients with advanced HER2-overexpressing tumors. Fourteen patients were treated across two different regimens. Patients with breast cancer and gastroesophageal cancer were primarily enrolled and had to have demonstrated overexpression of HER2 according to the American Society of Clinical Oncology/College of American Pathologists guidelines (HER2 immunohistochemistry 3+ or immunohistochemistry 2+/in situ hybridization-amplified). No lymphodepletion chemotherapy was used before infusion. The primary endpoints were safety and CAR-M manufacturability. Secondary endpoints included cellular kinetics and efficacy using objective response rate, overall survival, progression-free survival and duration of response. No dose-limiting toxicities, severe cytokine release syndrome (≥grade 3) or immune effector cell-associated neurotoxicity syndrome were observed; 44% (n = 4 of 9, 95% confidence interval = 14-79%) of HER2 3+ tumors achieved stable disease as best overall response 8 weeks after treatment. No meaningful activity was observed in the HER2 2+ population (n = 5). Correlative analyses of serial biopsies confirmed that CT-0508 traffics to and remodels the tumor microenvironment, resulting in expansion of CD8+ T cells. These findings demonstrate the preliminary safety, tolerability and manufacturing feasibility of CT-0508 for HER2+ tumors. ClinicalTrials.gov registration: NCT04660929 .

Investigation of the Influence of the Extraction System and Seasonality on the Pharmacological Potential of Eugenia punicifolia Leaves

The chemical complexity of natural products, such as Eugenia punicifolia (Kunth) DC. plant, presents a challenge when extracting and identifying bioactive compounds. This study investigates the impact of different extraction systems and seasonal variations on the chemical profile and pharmacological potential of E. punicifolia leaves using NMR spectroscopy for chemical analysis and canonical correlation analysis (CCA) for bioactivity correlation. Extracts obtained with methanol (M), ethanol (E), methanol/ethanol (1:1, ME), and methanol/ethanol/water (3:1:1, MEW) were analyzed for antioxidant, antiglycation, and antiviral activities. Quantitative ¹H NMR, combined with the PULCON method, was used to quantify phenolic compounds such as quercetin, myricetin, catechin, and gallic acid. The results showed that the MEW extract obtained in the rainy season exhibited the highest antioxidant and antiglycation activities, with a greater than 93% of advanced-glycation end-products (AGEs) inhibition capacity. Furthermore, our results showed that all the extracts were able to inhibit over 94% of the Zika virus (ZIKV) infection in Vero E6 cells. The CCA established strong correlations between the phenolic compounds and bioactivities, identifying gallic acid, catechin, quercetin, and myricetin as key chemical markers. This study demonstrates the importance of selecting appropriate extraction systems and considering seasonality to optimize the pharmacological potential of E. punicifolia leaves and highlights the efficacy of NMR in linking chemical composition with bioactivities.

Identification of disease-specific gut microbial markers in vitiligo

There is a potential correlation between vitiligo and gut microbiota, although research in this area is currently limited. The research employed high-throughput sequencing of 16S rRNA to examine the gut microbiome in the stool samples of 49 individuals with vitiligo and 49 without the condition. The study encompassed four comparison groups: (1) DI (disease) group vs. HC (healthy control) group; (2) DI_m group (disease group of minors) vs. HC_m group (healthy control group of minors); (3) DI_a group (adult disease group) vs. HC_a group (adult healthy control group); (4) DI_m group vs. DI_a group. Research findings have indicated the presence of spatial heterogeneity in the gut microbiota composition between individuals with vitiligo and healthy controls. A significant reduction in gut microbiota diversity has been observed in vitiligo patients across both minors and adult groups. However, variations have been noted in the composition of disease-related differential microbial markers among different age groups. Specifically, Bacteroides and Parabacteroides have been identified as specific markers of the intestinal microbiota of vitiligo patients in both minor and adult groups. Correlative analyses have revealed a positive correlation of these two genera with the Vitiligo Area Scoring Index (VASI) and disease duration. It is noteworthy that there are no significant differences in diversity between the DI_m group and the DI_a group, with similarities in microbiota composition and functional characteristics. Nevertheless, correlative analyses suggest a declining trend in Bacteroides and Parabacteroides with increasing age. Individuals with vitiligo exhibit distinct features in their gut microbiome when contrasted with those in the healthy control group. Additionally, the microbial marker genera that show variances between patients and healthy controls vary among different age groups. Disease-specific microbial marker genera (Bacteroides and Parabacteroides) are associated with VASI, duration of the condition, and age. These findings are essential for improving early diagnosis and developing potential treatment strategies for individuals with vitiligo.

FTIR Spectroscopic Analysis of Plant Proteins and Correlation with Functional Properties.

Development of plant-based products faces challenges like raw material standardization and time-consuming functionality measurements. Fourier Transform Infrared (FTIR) spectroscopy provides a quick, non-destructive way to analyze protein molecular characteristics. This study explored the classification capability of FTIR in analyzing five plant protein isolates-soy, mung bean, pea, fava bean, and lentil-and assessed its predictive ability for functional property measurement such as water absorption capacity (WAC), oil absorption capacity (OAC), Solubility (SOL), foaming, and emulsification. Functional properties were calculated using traditional methods of measurements. Principal Component Analysis (PCA) and Partial Least Square (PLS) Regression Analysis were used to study FTIR spectra and its correlation with functional properties. PCA revealed distinct clusters for each protein source based on their FTIR spectra, indicating molecular differences. WAC and OAC prediction models showed strong correlations, with prediction correlation coefficients (Rp) of more than 0.99 and cross-validation correlation coefficients (Rcv) ranging from 0.85 to 0.92. As sample size increases, SOL, emulsifying, and foaming properties display promising potential. Moreover, WAC and OAC predictions exhibited robust results with protein blends of various ratios. The expanded WAC model predicted with an Rp of 0.99 and an Rcv of 0.95, while the expanded OAC model had an Rp of 0.99 and an Rcv of 0.84. The results underscore FTIR has the potential to identify plant proteins aiding in raw material verification and quality control as well as being an alternative to analyzing functional properties of plant proteins.

Tubular ER structures shaped by ER-phagy receptors engage in stress-induced Golgi bypass.

Cellular stresses, particularly endoplasmic reticulum (ER) stress induced by ER-to-Golgi transport blockade, trigger Golgi-independent secretion of cytosolic and transmembrane proteins. However, the molecular mechanisms underlying this unconventional protein secretion (UPS) remain largely elusive. Here, we report that an ER tubulovesicular structure (ER tubular body [ER-TB]), shaped by the tubular ER-phagy receptors ATL3 and RTN3L, plays an important role in stress-induced UPS of transmembrane proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Correlative light-electron microscopy analyses demonstrate the formation of ER-TB under UPS-inducing conditions in HEK293 and HeLa cells. Individual gene knockdowns of ATL3 and RTN3 inhibit ER-TB formation and the UPS of trafficking-deficient ΔF508-CFTR. Combined supplementation of ATL3 and RTN3L induces ER-TB formation and UPS. ATL3 also participates in the SARS-CoV-2-associated convoluted membrane formation and Golgi-independent trafficking of SARS-CoV-2 spike protein. These findings suggest that ER-TB serves a common function in mediating stress-induced UPS, which participates in various physiological and pathophysiological processes.

The Influence of Principal Leadership and Organizational Culture on School Excellence in Vocational Schools in Ende City: Case Study at SMK Negeri 1 Ende

This study aims to determine and analyze the magnitude of the influence of the principal's leadership on the excellence of the State Vocational High School 1 Ende. In addition, to determine and analyze the magnitude of the influence of organizational culture on the excellence of the State Vocational High School 1 Ende. As well as, to know and analyze the magnitude of the influence of the principal's leadership and school organizational culture on the excellence of the State Vocational High School 1 Ende. This study used a quantitative approach with a survey research design. Data were collected through questionnaires distributed to teachers and employees at SMK Negeri 1 Ende. Furthermore, the data were processed using SPSS software version 25 for windows 2010 including descriptive, correlative, and simple regression analysis. Based on the analysis, it is known that school excellence at SMK Negeri 1 Ende is good. This is indicated by the accreditation score owned by SMK Negeri 1 Ende. Through simple regression analysis, it is found that the principal leadership variable (X1) and organizational culture (X2) have an effect of 50.2% on school excellence, and the coefficient of determination is 0.502. Based on the results of the study, it is concluded that school excellence is influenced, among others, by the leadership of the principal, school organizational culture. However, outside of these two variables, there are still many other factors that influence. For this reason, it is recommended that the principal of Smk Negeri 1 Ende improve human resources by continuing studies for teachers, trainings, leadership training, motivating students and teachers who excel, revitalizing cultural values as well as filtering potential children's input.

Correlation between serum YKL-40 and VILIP 1 levels and brain volume in dementia patients.

Alzheimer's disease (AD) is a chronic, progressive cognitive disorder characterized by prominent episodic memory impairment. The contribution of neuronal damage and neuroinflammation to this process has been investigated by measuring various substances. Two of the most promising substances in serum and plasma studies are visinin-like protein 1 (VILIP-1) and tyrosine (Y), lysine (K), leucine (L)-40 (YKL-40). These markers may lead to early diagnosis and new treatment options. Serum VILIP-1 and YKL-40 levels were analyzed in 33 probable AD patients and 23 healthy controls. Cranial magnetic resonance imaging (MRI) was used for volumetric measurements. The results were compared with the control group and then the correlation analyze between markers and volumetric measurements of the patient group was achieved. The right and left hippocampus and amygdala, left medial temporal, right rostral anterior cingulate, total brain, cortex, white matter, gray matter, subcortical gray matter, right and left total cortex volumes of the probable AD group were significantly lower than those of the control group. In the correlation analysis, the YKL-40 level and left posterior cingulate volume and the VILIP-1 level and left amygdala volume were negatively correlated. In AD, there is atrophy of the limbic structures, cortex, and white matter. While the relationship between these regions and neurodegenerative markers remains unclear, our findings highlight a notable correlation between YKL-40 and VILIP-1 levels and the left amygdala and left posterior cingulate cortex, respectively. Geriatr Gerontol Int 2025; ••: ••-••.

Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (mCRC).

277 Background: While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore the landscape and frequency of genetic alterations putatively associated with acquired resistance to anti-HER2 therapy in HER2-positive mCRC. Methods: In this retrospective-multicenter international study involving Mayo Clinic, Duke Cancer Center and National Cancer Center Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples of pts with HER2-positive CRC pre-treatment and post-treatment with HER2-targeting agents. Results: A total of 36 pts were included in this study. 29 (80%) had HER2-positive mCRC as confirmed by immunohistochemistry (IHC) and fluorescent in situ hybridization (ISH), the remaining pts had HER2 amplification detected on blood or tissue . 34/36 (94%) pts were administered their first anti-HER2 agent after progressing on ≥2 prior lines of treatment. The most common anti-HER2 regimen administered was trastuzumab/pertuzumab (50%, 18/36), followed by trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib or neratinib) (30%, 11/36) and trastuzumab deruxtecan (14%, 5/36). Putative genomic mechanisms of acquired resistance were detected in 72% (26/36), while the remaining pts lacked new genomic alterations that might explain resistance to anti-HER2 therapy, suggesting alternative escape mechanisms. Acquired alterations in downstream or alternate bypass pathways were identified in 72% (26/36) of pts; most commonly in the RAS/RAF pathway and in EGFR (34.6%, 9/26 each), followed by 27% (7/26) of pts with MET point mutations (mts) and amplification; activating muts in PI3K/AKT and in 27% (7/26), most commonly CDK12 (60%, 4/7) . HER2 receptor alterations were detected in 3 pts (8.3%), all of whom received trastuzumab-tucatinib and included HER2 L755S, HER2 V777L, HER2 D769Y, HER2 G727A and HER2 S310F, which are known to cause resistance to , however, information about tucatinib resistance is not yet available. Other altered pathways included AR, RB, NOTCH and HRD. Two pts lost HER2 expression on blood and tissue NGS post anti-HER2 therapy. Conclusions: The emergence of resistance might be in part related to acquired alterations that constitutively activate signaling pathways parallel or downstream of HER2, bypassing HER2 inhibition. Additional histologic studies, deep mutational scanning, larger populations and correlative analysis are needed to validate these findings.

Clonal Hematopoiesis Is Associated With Adverse Clinical Outcomes and Left Ventricular Remodeling in Aortic Stenosis.

Clonal hematopoiesis of indeterminate potential (CHIP) has been linked to intensified systemic inflammation and represents a novel risk factor for atherosclerotic cardiovascular diseases, including aortic stenosis (AS). This study aimed to assess the clinical impact of CHIP in a cohort of severe AS patients undergoing transcatheter aortic valve implantation (TAVI). We enrolled 110 severe AS patients in this retrospective study. Targeted next-generation sequencing was employed to detect somatic mutations with a variant allele frequency >2% in 16 genes most frequently associated with CHIP. Correlative analyses on clinical, laboratory, and echocardiographic parameters were also performed. The primary endpoint was post-TAVI heart failure hospitalization. Multivariate Cox regression model was used to account for confounding effects of relevant clinical factors. CHIP was detected in 40 (36.4%) patients in our cohort. The most commonly mutated genes were DNMT3A, TET2, and ASXL1. With a median follow-up of 55.2months, patients carrying CHIP had a significantly higher heart failure hospitalization rate (adjusted HR: 3.060; 95% CI: 1.090-8.589; P=0.034) than those without CHIP. Additionally, patients harboring CHIP had higher serum ferritin levels, as well as echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction. Our study supports the adverse clinical impact of CHIP in AS patients undergoing TAVI, which could be attributed to systemic inflammation and maladaptive LV remodeling. Prospective trials are anticipated to validate our findings and provide further evidence that CHIP holds the potential of being an actionable therapeutic target in AS.

Tinengotinib in patients with advanced, metastatic cholangiocarcinoma: Overall survival results and biomarker correlative analysis from a phase 2 clinical trial.

608 Background: Tinengotinib, a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR , potently inhibited FGFR2 fusion/rearrangement and acquired resistant/gatekeeper mutations in pre-clinical models and exhibited antitumor activity in cholangiocarcinoma (CCA) patients (pts) in phase 1/2 trials. Here we present the overall survival (OS) data and biomarker correlative analysis from a phase 2 clinical trial of tinengotinib in CCA. Methods: Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy with ECOG PS 0-1 were treated with tinengotinib 10 mg QD across four Cohorts: A1: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor ( FGFR i); A2: FGFR2 fusion(s) with progression after prior response to FGFR i; B: FGFR alteration(s) without FGFR2 fusion(s); C: FGFR wild-type. Efficacy was evaluated per RECIST v1.1 and safety was assessed by CTCAE v5.0. Genomic alterations in circulating tumor DNA (ctDNA) were assessed by Foundation Medicine NGS panel at baseline, C3D1 and EOT. Planned correlative analyses of response (PR+SD>6 months) and PFS in pt subgroups based on ctDNA mutational status were performed. Results: 55 eligible pts were enrolled (18 in A1, 11 in A2, 13 in B, 13 in C) with median age 61.0 [range 24-81] years, ECOG PS 0 in 50.9% pts, 56.4% female, and 60.0% with ≥ 3 lines of prior therapy. Among 42 pts with FGFR alterations, 78.4% had ≥ 1 prior FGFR i, and 97.6% had prior chemotherapy. Median follow up time was 8.6 months (0.4-30.5). The median OS (months) was 17.1 (95%CI 7.5-19.5) in A1; not reached (95%CI 9.6, -) in A2; 18.0 (95%CI 9.6, -) in A1+A2; not reached (95%CI 8.0, -) in B; 6.5 (95%CI 4.8-16.4) in C. The OS rate in A, B and C was 100%, 91.7% and 75% at month 3; 83.7%, 83.3% and 66.7% at month 6, and 65.8%, 55.6% and 23.8% at month 12. Partial response was observed in 26% (10/39) of evaluable FGFR-altered pts (A1+A2+B). The safety profile was consistent with previous reports. The most common any-grade treatment-related AEs were hypertension (63.6%) and diarrhea (47.3%). Baseline ctDNA results were available in 46 pts, 35 in cohorts A+B and 11 in C. A positive correlation was shown in MED12 mutation vs response (P=0.03476). BCOR and ARID1A mutation were found to be negatively associated with PFS (P=0.01366 and P=0.0437). Acquired/secondary mutations at baseline were observed in cohort A, including V564F/I (3/24 and 5/24) and N549K/H (5/24 and 5/24); favorable anti-tumor activity was noted despite these resistant mutations, consistent with preclinical data. Conclusions: Tinengotinib has shown promising anti-tumor efficacy in CCA pts with FGFR fusion after prior FGFR i and in those with primary FGFR mutations. An ongoing randomized phase III study will investigate tinengotinib vs. chemotherapy in FGFR inhibitor refractory CCA (NCT05948475). Clinical trial information: NCT04919642 .

A phase 2 study of intravenous pembrolizumab and intratumorally injected autologous dendritic cells (DCs) in refractory colorectal cancer (CRC).

TPS319 Background: Immune checkpoint inhibitors (ICIs) have shown limited benefit in CRC outside the microsatellite instability high (MSI-H) population. Deficient cytotoxic T lymphocyte (CTL) trafficking to the tumor microenvironment (TME) and excess pro-tumorigenic cytokines and immunosuppressive cells may contribute to primary ICI resistance in microsatellite stable (MSS) CRC. Selective enrichment of T cells with specific chemokine receptors may enhance antitumor immunity. Studies highlight the role of IL-12 in improving progression-free survival (PFS) and overall survival (OS) in patients on DC therapies. Our group developed ST-aDC1s, optimized for high production of high levels of IL-12 and CTL-attracting chemokines when injected intratumorally. In preclinical models, ST-aDC1s combined with anti-PD-1/PD-L1 therapy showed therapeutic synergy, suggesting ST-aDC1s as a promising alternative to traditional DC vaccines for inducing CTL entry into tumors. Methods: We designed an open-label, non-randomized, phase 2 study of intratumoral autologous ST-αDC1 combined with pembrolizumab in recurrent/metastatic unresectable MSS CRC. Eligible patients must have prior treatment with, or contraindication to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, and anti-EGFR therapy (if RAS wild type), be anti-PD-1/PD-L1 therapy naïve, have ECOG PS ≤1, and have at least two target lesions, one amendable to biopsy and injection. Leukapheresis will collect monocytes for ST-αDC1 generation. Patients will receive intratumoral ST-αDC1s (6 million) on days 1 and 8 with biopsies, and an optional dose on day 50 before a third pembrolizumab dose. Pembrolizumab 200 mg IV will start on day 8, given every 3 weeks for 4 doses during the study period. Pembrolizumab will continue as conventional care afterwards. CT scans will occur after 2 and 4 doses of pembrolizumab. A safety lead-in cohort will include six patients, with up to 17 patients enrolled. The primary endpoint is objective response rate (ORR) at 12 weeks per RECIST 1.1. Secondary endpoints are safety, PFS, OS, and ORR per iRECIST. Correlative analysis will assess baseline levels and post-treatment changes in infiltrating T cells, CD4/CD8 ratios, FoxP3+ Tregs, and Teff-attracting and Treg-favoring chemokines from biopsy specimens, and immune cell subsets and cytokine levels from peripheral blood. With an expected ORR under 5% for standard treatment, 17 patients are required to show at least a 25% ORR with 81.2% power and a one-sided type I error rate of 0.05. A Simon two-stage Optimal design will enroll 9 patients in stage 1, and if ≥1 response occurs, 8 more patients will be added in stage 2. If ≥3 responses are observed, the treatment will be deemed promising for further study. Clinical trial information: NCT05518032 .

Pembrolizumab and stereotactic radiotherapy combined in subjects with advanced HCC: A phase II study (PEMRAD).

602 Background: Combination approaches of immune-checkpoint inhibitors and locoregional therapies have an increasing role in advanced HCC. Methods: The PEMRAD phase II trial investigated the efficacy of combination pembrolizumab and stereotactic body radiation (SBRT) following progression on sorafenib. Patients with advanced HCC, ECOG 0-1 and Childs-Pugh A were eligible. Patients received pembrolizumab on day 1 followed by SBRT starting Day 2 and delivered in five fractions. Pembrolizumab was continued every 21 days until progression, unacceptable toxicity or patient withdrawal. The primary endpoint was objective response rate (ORR) as measured by RECISTv 1.1. hypothesizing an increase to 40% with the combination. Tissue and liquid biopsies were collected for correlative analyses including multiplex IHC, longitudinal CyTOF and dynamic cytokine changes. Results: The trial was stopped early due to a shift in the treatment landscape. Between March 2018 and March 2023 18 patients of a planned 22 patients were enrolled and treated with combination therapy. Of these 10 (55%) had evidence of macrovascular invasion (MVI) and 15 (83%) had extrahepatic disease; viral hepatitis was the underlying etiology in 50%. The ORR was 41% meeting the proposed endpoint. Median number of cycles of pembrolizumab was 7.5 (2-35) .The median number of lesions treated by SBRT was 3 (1-5) and the median dominant gross tumour volume was 184 cc (IQR 69-285). The median PFS was 5.4 (2.8-9.9) months and median OS 12.6 (5.7-25.8) months. Of the 10 patients with macrovascular invasion 5 (50%) had evidence of a vascular thrombus response by RECIST criteria including 1 complete response. Treatment related adverse events ≥ grade 3 were reported in 5 patients (28%). One death due to myocarditis was attributed to treatment. Conclusions: In a poor prognostic group of patients in the second line setting, the combination of SBRT and pembrolizumab demonstrated high ORR and may have a specific role in patients with MVI. Correlative analyses will be presented at the meeting. Clinical trial information: NCT03316872 .

Dietary Variation Among Herculaneum's Victims of Mt. Vesuvius via Dental Microwear Texture Analysis.

The current study addresses three primary hypotheses: (1) Subadult diets changed as children aged, (2) adult diets differed from subadult diets, and (3) male and female diets differed as they age. This study includes dental microwear texture data from 58 adults (age 16+) and 23 subadults (age 0-16) recovered by Sarah Bisel from within and near to storage rooms adjacent to Herculaneum's beach. The adults include 27 females and 31 males. Dental microwear texture analysis (DMTA) employed standard procedures: data collection used a white-light confocal profiler at 100×. The DMTA variables were complexity, anisotropy, textural fill volume, and scale of maximum complexity. Statistical methods used Bayesian versions of analysis of variance and correlation (Bayes factors above 1.5 were considered meaningful and above 3.0 significant) as well as discriminant function analysis and binary logistic regression. No differences emerged among the children. Adult diets were significantly lower than the subadults for anisotropy. Among the adults, age affected the females more, particularly for anisotropy. Subadult diets did not vary by age, but they did vary. The lower adult anisotropy indicates each adult ate a greater variety of foods compared to the subadults. As females aged, however, their diets became more restricted compared to the males. Overall, age and sex affected the Herculaneum diet.

Introducing tribo-data map as a novel analysis for a detailed correlation between friction data and wear surface features

Introducing tribo-data map as a novel analysis for a detailed correlation between friction data and wear surface features

A phase II double window of opportunity trial evaluating the oral TGF-beta receptor I inhibitor vactosertib in patients undergoing standard of care preoperative therapy for locally advanced esophageal adenocarcinoma.

TPS516 Background: Esophageal adenocarcinoma (EAC) is the seventh most common cancer globally and ranks sixth in overall mortality. Despite improvements in pre-operative therapy, EAC has a high recurrence rate, especially among patients whose tumors do not achieve pathologic complete response (pCR), thus there is a critical need to enhance pCR rate and improve long-term outcomes. We recently discovered that a subset of EACs are driven by tumor-intrinsic oncogenic TGFβ signaling and have identified two potential biomarkers to predict response to anti-TGFβ therapy. One of these biomarkers is enriched in poorly differentiated EAC. We hypothesize that TGFβ signaling blockade will exert a tumor-inhibitory effect in patients with EAC and propose a double window-of-opportunity trial to test if TGFβ receptor I inhibitor vactosertib can improve pCR and induce tumor metabolic response in patients undergoing neoadjuvant therapy for localized EAC. Methods: This phase II double window of opportunity study assesses the efficacy and pharmacodynamics of the oral TGFβ Receptor I inhibitor vactosertib in patients with locally advanced esophageal adenocarcinoma (EAC). Patients will be treated with single-agent vactosertib in two windows of opportunity: the first will be prior to initiation of standard of care neoadjuvant therapy and the second after completion of neoadjuvant therapy prior to surgery. Patients will be eligible if they have poorly differentiated EAC and are appropriate for neoadjuvant therapy followed by resection as per standard of care. The primary objectives are improvement in pCR compared to historical controls and metabolic response (decrease in fluorodeoxyglucose uptake by PET CT) in the primary tumor after the first window. Secondary objectives will evaluate biomarkers of response identified in preclinical studies. Pre- and post-first window of opportunity treatment biopsies will be obtained for correlative and exploratory analyses. Clinical trial information: NCT06044311 .

A phase Ib study of immunotherapy with ex-vivo pre-activated and expanded CBNK cells in combination with cetuximab, in patients with colorectal cancer (CRC) with minimal residual disease (MRD): Final report.

176 Background: Colorectal cancer (CRC) is the second most common type of cancer. Even following successful curative treatment, patients often relapse, likely because of undetected micro-metastatic foci. Tumor-informed ctDNA testing has helped to identify those patients before they developed radiographic evidence of disease, introducing the concept of minimal residual disease (MRD) in solid tumors. No standard-of-care treatment options are available for MRD patients. Therefore, we have designed a phase IB trial of the combination of in vitro pre-activated and pre-expanded cord blood natural killer (pre-A+E CBNK) cells with cetuximab. We hypothesized that we could achieve CAR-like efficacy without genetic engineering, by pre-activating NK cells with inflammatory cytokines and by using antibodies to redirect NK cell specificity and antibody-dependent cellular cytotoxicity. The highly immunosuppressive CRC tumor microenvironment is understudied, and novel NK-cell therapy could be highly effective in MRD clearance. Methods: 15 patients with CRC-MRD were enrolled in this trial and completed treatment. All the patients received immunodepleting treatment prior to an infusion of pre-A+E CBNK cells, up to a dose of 1x10^8/kg. Patients were monitored inpatient for 24 hours after treatment for infusion-related reaction, and were then seen for toxicity follow-up in the outpatient clinic twice/week for 4 weeks (DLT window). Samples for correlative analysis were collected at different times. Results: 8/15 patients enrolled were female and 7 were male, age range 26-69. They all had no measurable radiographic evidence of disease and a positive ctDNA Signatera test at baseline. 11/15 were previously treated for metastatic disease; 13 patients had a history of metastases (including 7 liver, 2 lymph nodal, 2 peritoneal). All of them received 5-FU-based chemotherapy. 7/15 were RAS/RAF WT, 4/10 were KRAS mut, 1/10 had BRAF mutation, 1/10 had HER2 amplification. They were all pMMR. No DLT was observed, only 1 patient had G2 CRS requiring tocilizumab. 9/15 patients treated so far had ctDNA clearance at some point. One patient had negative ctDNA at 3 and 6 months, 4/15 were negative at d28 and 7/15 at d14. 4/15 patients have not met the 90-day time point yet. 10/12 patients analyzed up to the primary endpoint had decreased ctDNA over baseline CBNK cells in blood peaked 3 hours post-infusion and persisted at 3 days. Phenotype analysis of CBNK pre-post, donor NK and other immune cells is ongoing. Conclusions: Cetuximab in combination with pre-A+E CBNK is safe and showed promising results for the treatment of MRD-CRC. Clinical trial information: NCT050468 .

Structural and functional responses of soil fungal and bacterial communities to a lithium contamination gradient.

The use of lithium (Li) in decarbonization strategies has positioned it as a central component of modern technological advances, particularly in battery applications. However, the increasing demand for Li has raised concerns about its environmental consequences, which are poorly documented. This study aimed to fill this knowledge gap by examining the impact of Li on soil bacterial/fungal communities. Using a microcosm approach, we explored the impacts of increasing Li concentrations on both microbial community structure and activities. Our results revealed significant changes in bacterial/fungal communities, particularly in the bacterial communities. Most of the indicator species were negatively correlated with the Li gradient, reinforcing the harmful effect of Li. Proteobacteria dominated at low concentrations, whereas Firmicutes were the most abundant at high concentrations. OTUs affiliated with the genus Alicyclobacillus represented >29% of the total affiliated OTUs at the highest Li concentrations. Moreover, Alicyclobacillus fastidiosus showed resilience and specific adaptation to Li. Fungal communities showed less pronounced changes, with Mucoromycota remaining the dominant phylum at all concentrations. Nevertheless, some genera presented correlations with Li concentration, particularly the plant mutualists Leptodontidium, Oidiodendron, and Solicoccozyma. In addition, rapid decreases in several enzymatic activities crucial for the functioning of the carbon, nitrogen and phosphorus cycles were noted. Accordingly, microbial respiration was also impacted by high Li concentrations. Finally, a correlative analysis linked the decreases in enzyme activity to decreases in the abundances of both Proteobacteria and Ascomycota. These results underline the multiple impacts of Li on bacterial/fungal communities, highlighting both structural alterations and changes in microbial activities.

New era, new GOALs: cardiovascular screening and lipid management in cystic fibrosis.

Cardiovascular disease (CVD) risks are increasing in people with cystic fibrosis (pwCF). While cholesterol levels were historically low in pwCF, higher levels after initiating highly effective modulator therapy (HEMT) have been reported. Mechanisms are unclear and there is little guidance on screening. To evaluate serum lipid changes at multiple timepoints after ivacaftor initiation, and to assess current screening practices for CVD risk factors among CF providers. This was a post-hoc correlative analysis of prospectively collected clinical data and serum samples from the GOAL cohort study. Cross-sectional survey methodology was also employed. We evaluated serum lipids (total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)) at baseline, 3- and 18 months after ivacaftor initiation using samples from the GOAL study biorepository. We also surveyed CF providers across the United States on their CVD risk screening practices. Fifty GOAL participants' samples were analyzed. Using the repeated measures model, TC significantly varied by visit (p = 0.004), driven by a significant increase from baseline at 3 months (mean difference 9.4 mg/dL). This difference diminished by 18 months. BMI was a significant covariate for TC. No significant differences by visit were detected in LDL or HDL. Seventy-five respondents participated in the survey (response rate 5.6%; 41 adult providers, 18 pediatric providers, and 10 providers caring for both) with 67% reporting no lipid screening policy existed in their center. In the past year, 29% of adult providers prescribed lipid-lowering therapy, 54% started anti-hypertensive medications, and 48% initiated ischemic cardiac evaluations for pwCF. TC significantly increased within 3 months of initiating ivacaftor, but subsequently diminished toward baseline by 18 months. Lipid screening practices among CF providers were variable and providers are increasingly being confronted with managing CVD risk factors. Partnering with primary care providers is likely to become increasingly important in CF care models.

Retrospective cohort study- a gender-based analysis of symptom severity and age correlation in nasal septum deviation

Retrospective cohort study- a gender-based analysis of symptom severity and age correlation in nasal septum deviation

Image-Based Analysis of Correlation Between Valve Stent Deformation and Valve Function in Transcatheter Aortic Valve Replacement.

Currently, there remains a paucity of research on the deformation and valve function of transcatheter heart valves (THV) in patients with aortic regurgitation (AR) following transcatheter aortic valve replacement (TAVR). This study aimed to thoroughly explore the correlation between THV deformation and postoperative hemodynamics in these patients. In this study, we assessed 39 AR patients treated with the J-Valve THV system during TAVR. We utilized postoperative cardiac-enhanced computed tomography angiography (CTA) to examine the extent of stent deformation, correlating these measurements with concurrent echocardiographic data. Among patients with AR, the J-Valve exhibited three distinct configurations: rectangular, trapezoidal, and inverted trapezoidal shapes. The rectangular configuration showed a trend toward a larger effective orifice area (EOA) compared to the trapezoidal and inverted trapezoidal configurations (rectangular: 2.20 ± 0.11 cm², trapezoidal: 1.88 ± 0.08 cm², inverted trapezoidal: 2.04 ± 0.08 cm²; p = 0.068). Stratified analysis of the degree of inclined commissural posts indicated that THVs with all three commissural angles < 5° exhibited the highest standard EOA (sEOA). An increase in the number and degree of inclined commissural posts correlated with a decrease in sEOA. Furthermore, a higher EOA was observed when the expansion in the mid and transition level exceeded 80%. During the TAVR procedure, ensuring sufficient expansion in the mid and transition level of the stent, maintaining the stent in a rectangular configuration, and avoiding tilting of the commissural posts contribute to achieving favorable postoperative hemodynamics.