OBJECTIVE: To investigate the relationship between C-reactive protein and albumin ratios (CAR) and all-cause and cardiovascular disease(CVD)-specific mortality in individuals with coronary heart disease(CHD).
METHODS: The data from 1895 patients were extracted from the National Health and Nutrition Examination Survey (NHANES) database from 1999-2010. We used weighted COX regression analyses to explore the association between CAR, all-cause, and CVD-specific mortality. Restricted cubic spline(RCS) regression models and threshold effects analysis were used to analyze nonlinear relationships. Subgroup analyses were also performed to explore these relationships further.
RESULTS: During a mean follow-up of 115.78 months, 61.48% of deaths occurred, and 21.85% were due to CVD. After adjusting for potential confounders, each 1-unit increase in CAR was associated with a 65% increase in all-cause mortality and a 67% increase in CVD-specific mortality. The RCS model revealed a non-linear association between CAR and the risk of all-cause mortality and CVD-specific mortality in CHD patients (all non-linear P < 0.001). Threshold effects analysis identified inflection points in regression models of all-cause mortality (0.04, P < 0.001) and CVD-specific mortality (0.05, P = 0.0024). The interaction tests found sex, smoking and diabetes influenced the association between CAR and all-cause mortality and sex, smoking and HF influenced its association with CVD-specific mortality (all P < 0.05).
CONCLUSIONS: There was a nonlinear association between CAR and all-cause mortality and CVD mortality in patients with CHD, with a higher hazard ratio before the inflection point. Sex, smoking, diabetes, and HF might have an effect on the associations between CAR and death risks.

Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We hypothesized that the transcription factor PU.1, a master regulator of innate cell functionality, may augment pro-inflammatory CAR T cell activation. T cells were engineered with a CEA-specific CAR together with the constitutive expression of PU.1. CAR-redirected T cell activation was recorded for canonical functionality in vitro under conditions of prolonged repetitive antigen exposure. Ectopic PU.1 expression in CAR T cells upregulated the costimulatory receptors CD40, CD80, CD86, and CD70, which, unexpectedly, did not augment effector functions but hampered the upregulation of 4-1BB, decreased IL-2 production, reduced CAR T cell proliferation, and impaired their cytotoxic capacities. Under \"stress\" conditions of repetitive engagement of cognate tumor cells, CAR T cells with ectopic PU.1 showed reduced persistence, and finally failed to control the growth of cancer cells. Mechanistically, PU.1 caused CAR T cells to secrete IFN-β, a cytokine known to promote CAR T cell attrition and apoptosis. Collectively, PU.1 can polarize the functional capacities of CAR T cells towards innate cells.

Adoptive T-cell therapies (ACTs) including tumor-infiltrating lymphocytes and engineered T cells (transgenic T-cell receptor and chimeric antigen receptor T cells), have made an important impact in the field of cancer treatment over the past years. Most of these therapies are typically administered systemically in approaches that facilitate the elimination of hematologic malignancies. Therapeutical efficacy against solid tumors, however, with the exception of tumor-infiltrating lymphocytes against melanoma, remains limited due to several barriers preventing lymphocyte access to the tumor bed. Building upon the experience of regional administration in other immunotherapies, the regional administration of adoptive cell therapies is being assessed to overcome this challenge, granting a first round of access of the transferred T cells to the tumor niche and thereby ensuring their activation and expansion. Intralesional and intracavitary routes of delivery have been tested with promising antitumor objective responses in preclinical and clinical studies. Additionally, several strategies are being developed to further improve T-cell activity after reinfusing them back to the patient such as combinations with other immunotherapy agents or direct engineering of the transferred T cells, achieving long-term immune memory. Clinical trials testing different regional adoptive T-cell therapies are ongoing but some issues related to methodology of administration and correct selection of the target antigen to avoid on-target/off-tumor side-effects need to be further evaluated and improved. Herein, we discuss the current preclinical and clinical landscape of intratumoral and locoregional delivery of adoptive T-cell therapies.

UNASSIGNED: C-reactive protein (CRP) levels increase and albumin levels decrease in patients with inflammation. CRP/albumin ratio (CAR) is a new inflammation-associated prognostic indicator. The prognostic nutritional index (PNI) was described as a simple and neutral indicator of adverse outcomes not only in chronic diseases but also in acute conditions. The aim of this study was to investigate the clinical significance of the CAR and PNI value in differentiating complicated acute appendicitis (AA).
UNASSIGNED: We retrospectively examined the medical records of 187 patients with AA. Patients were divided into two groups according to pathological results [non-complicated (n= 161) and complicated (n= 26)]. Demographic, clinical, laboratory, and pathological data were examined and compared between the groups. Logistic regression analyses were performed to determine the independent predictors for complicated AA.
UNASSIGNED: Median age of the study group was 32 (23-41) years, and most of the patients were males (n= 101, 54%). Patients in the complicated AA group were significantly older compared to the patients in the non-complicated AA group [38 (32-49.5) years vs. 30 (22-41) years, p= 0.002]. The complicated AA group had significantly higher CAR level compared to the non-complicated AA group (p= 0.001). The length of hospital stay was significantly longer in the complicated AA group compared to the non-complicated AA group [2.5 (2-4.25) days vs. 1 (1-2) days, p <0.001]. Other variables (including PNI) did not significantly differ between the groups. In univariate logistic regression analysis, only age was found to be a significant variable (OR= 1.045, 95% CI= 1.016-10.74, p= 0.002), but in multiple variate logistic regression analysis, no variable was found to be significant in predicting complicated AA.
UNASSIGNED: We concluded that CAR and PNI value are not independent predictors of complicated AA.

Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce T cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a chimeric antigen receptor (CAR) targeting CD5, a prominent pan-T cell antigen, induces rapid internalization and complete loss of the CD5 protein on T cells, protecting them from self-targeting. Notably, exposure of healthy and malignant T cells to CD5.CART cells induces similar internalization of CD5 on target cells, transiently shielding them from cytotoxicity. However, this protection is short-lived, as sustained activity of CD5.CART cells in patients with T cell malignancies results in full ablation of CD5+ T cells while sparing healthy T cells naturally lacking CD5. These results indicate that continuous downmodulation of the target antigen in CD5.CART cells produces effective fratricide resistance without undermining their on-target cytotoxicity.

Chimeric antigen receptor (CAR) therapy has emerged as a ground-breaking advancement in cancer treatment, harnessing the power of engineered human immune cells to target and eliminate cancer cells. The escalating interest and investment in CAR therapy in recent years emphasize its profound significance in clinical research, positioning it as a rapidly expanding frontier in the field of personalized cancer therapies. A crucial step in CAR therapy design is choosing the right target as it determines the therapy\'s effectiveness, safety and specificity against cancer cells, while sparing healthy tissues. Herein, we propose a suite of tools for the identification and analysis of potential CAR targets leveraging expression data from The Cancer Genome Atlas and Genotype-Tissue Expression Project, which are implemented in CARTAR website. These tools focus on pinpointing tumor-associated antigens, ensuring target selectivity and assessing specificity to avoid off-tumor toxicities and can be used to rationally designing dual CARs. In addition, candidate target expression can be explored in cancer cell lines using the expression data for the Cancer Cell Line Encyclopedia. To our best knowledge, CARTAR is the first website dedicated to the systematic search of suitable candidate targets for CAR therapy. CARTAR is publicly accessible at https://gmxenomica.github.io/CARTAR/.

Materials in car cabins contain performance-enhancing semi-volatile organic compounds (SVOCs). As these SVOCs are not chemically bound to the materials, they can emit from the materials at slow rates to the surrounding, causing human exposure. This study aimed at increasing the understanding on abundance of SVOCs in car cabins by studying 18 potential endocrine disrupting chemicals in car cabin air (gas phase and airborne particles) and dust. We also studied how levels of these chemicals varied by temperature inside the car cabin along with ventilation settings, relevant to human exposure. A positive correlation was observed between temperature and SVOC concentration in both the gas and the particle phase, where average gas phase levels at 80 °C were a factor of 18-16,000 higher than average levels at 25 °C, while average particle phase levels were a factor of 4.6-40,000 higher for the studied substances. This study also showed that levels were below the limit of detection for several SVOCs during realistic driving conditions, i.e., with the ventilation activated. To limit human exposure to SVOCs in car cabins, it is recommended to ventilate a warm car before entering and have the ventilation on during driving, as both temperature and ventilation have a significant impact on SVOC levels.

Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy.

Introduction Postoperative bile leakage (POBL) has emerged as a complication following hepatectomy. POBL is associated with an elevated risk of liver failure and surgical death. This study aimed to examine risk factors for POBL in primary hepatocellular carcinoma (HCC) patients. Methods A total of 296 patients who had surgical resection for a preoperative diagnosis of primary HCC from January 2013 to December 2022 at Ehime Prefectural Central Hospital were included in this study. The patients were categorized into two groups based on the presence of POBL. The preoperative, operative, and histopathological findings were analyzed between the two groups. Risk factors were determined using multivariable analysis. Results Regarding preoperative findings, statistically significant differences were observed in white blood cell count, platelet count, C-reactive protein (CRP) level, and CRP-to-Albumin ratio (CAR) between the two groups (p = 0.023, p = 0.025, p = 0.011, and p = 0.012, respectively). As for intraoperative variables, only operation time (p = 0.017) was statistically correlated with the risk of POBL. Regarding pathological variables, there were no statistically significant differences between the two groups. The optimal cut-off value of CAR, as determined by ROC curve analysis, was 0.053. This value had a sensitivity of 80.0% and a specificity of 72.8%. Multivariate logistic regression analysis indicated that CAR ≥ 0.053 (p = 0.030) and operation time ≥ 308 min (p = 0.023) were independent potential markers for POBL after hepatectomy. Conclusion A high CAR level can be an effective predictor for POBL following hepatectomy.

HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity in vitro and in vivo specifically against HER2-amplified (HER2amp)/CEA+ CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade.