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The prevalence of cardiovascular diseases (CVDs) is increasing in most parts of the world. Several studies suggest that type 2 diabetes mellitus (T2DM) and CVD are induced by lifestyle behaviours and genetic factors. This study investigated the association between a genetic risk score (GRS) and cardio-metabolic risk factors among diabetic patients. The current cross-sectional study involved 700 diabetic patients. The genetic risk score was created by combining three single nucleotide polymorphisms [Apolipoprotein A2 (APOA2) (rs5082), Ins/Del (rs17240441) and EcoR1polymorphism (rs1042031) variants]. This polygenic risk score (PRS) was developed to predict cardiometabolic risks based on the presence of these common genetic variants. Standard protocols were used to measure anthropometric measurements and blood parameters. A significant association was observed between the GRS and several cardiometabolic risk factors, including BMI (β = 0.006, 95% CI = 0.001 to 0.01, p = 0.05) and WC (β = 0.006, 95% CI = 0.001 to 0.01, p = 0.02), in both crude and adjusted models. Additionally, a significant result was found between hs-CRP and GRS in the crude and adjusted models (β = 0.52, 95% CI = 0.2 to 0.83, p = 0.001). This study also revealed a reverse association between GRS and antioxidant markers such as PTX3 (β = -0.14, 95% CI= -0.23 to -0.04, p = 0.005), TAC (β = -0.02, 95% CI= -0.04 to < 0.001, p = 0.04), and SOD (β = -0.02, 95% CI= -0.04 to -0.006, p = 0.008). After controlling for confounding factors, the significant reverse associations between PTX3 (P = 0.009) and SOD (P = 0.009) with GRS were maintained. We found a significant positive association between GRS, including [APOA2 (rs5082), Ins/Del (rs17240441) and EcoR1 (rs1042031) variants] and cardiometabolic risk factors among T2DM patients.

The oncogene hbz in human T-cell leukemia virus type 1 (HTLV-1) is encoded on the antisense strand, generating spliced and unspliced transcripts. We investigated splicing regulation in the context of cellular splice donors and the hbz splice acceptor when integrated within the host chromosomal DNA. In ATL cell line ED, the HTLV-1 provirus integrated into the 10th intron of the gene ift81, aligning transcriptionally with ift81. Both genes were actively transcribed, yielding ift81-hbz chimeric mRNA but not hbz-ift81. Splicing efficiency from the 10th exon of ift81 to the 2nd exon of hbz was 24.2% at most, suggesting reduced function of hbz splice signals on ift81-driven transcripts. This stochastic regulation may minimize disruption of cellular gene expression by proviral integration, potentially promoting survival of HTLV-1-infected cells and contributing to HTLV-1 pathogenesis.

BACKGROUND:

Cancer-related distress is associated with low quality of life and oncologic outcomes in cancer patients. At present, there are limited data regarding the clinical implications of distress in patients with pancreatic cancer. The present study aimed to investigate the association between distress at diagnosis and the surgical outcomes of patients with curative-intent surgery for pancreatic cancer.

METHODS:

Since 2014, distress thermometer (DT) surveys have been distributed to all patients with presumed cancer in the outpatient clinic of Samsung Medical Center. We retrospectively reviewed the clinicopathological data of patients who underwent curative-intent surgery for pancreatic cancer between 2014 and 2021. The survival of the patients according to DT score was analyzed using Kaplan-Meier graph and z-test. Risk factor analysis was performed to identify the impact of distress on postoperative complications.

RESULTS:

Among 1,050 patients with pancreatectomy, 130 patients responded to a DT survey. Thirty-three (25.4%), 67 (51.5%), and 30 (23.1%) patients presented with mild, moderate, and severe distress, respectively. In the stage II group, patients with moderate distress showed better survival compared to those with mild or severe distress. Higher body mass index (p = 0.043) and severe distress at diagnosis (p = 0.034) were found to be independent risk factors for major complications.

CONCLUSION:

More than 70% of the patients had moderate to severe distress at diagnosis. Distress was associated with increased risk of major complications after pancreatectomy. Further research is needed to explore the potential effect of distress on outcomes of patients with pancreatic cancer.

PURPOSE:

This retrospective cohort study aims to compare outcomes of Roux-en-Y gastric bypass (RYGB) versus semaglutide for treatment of recurrent weight gain (RWG) and suboptimal weight loss (SWL) after sleeve gastrectomy (SG).

METHODS:

Patients at a tertiary care hospital who underwent RYGB conversion after SG (n = 87) were matched 1:1 to SG patients treated with semaglutide (n = 87) by: age, gender, race, ethnicity, pre-SG to pre-intervention total weight loss (%TWL), BMI, diabetes status, and time between SG and intervention. Semaglutide 'responders' (defined as ≥ 5% TWL at three months, n = 26) and non-responders were similarly compared to the overall RYGB cohort. Weight, comorbidity, and complication outcomes were collected for two years post-intervention.

RESULTS:

%TWL two years post-intervention was greater in the RYGB compared to the semaglutide cohort (17.1% vs. 7.6%, mean difference = 9.5%, 95% CI [2.6, 16.4], p = 0.002), as was the proportion of patients who achieved > 10% TWL (82.6% v. 40.9%, p < 0.001). Diabetes medications (p = 0.018) and mean HbA1c (p = 0.006) decreased significantly in the RYGB but not semaglutide cohort. RYGB patients had increased frequencies of GI surgeries and endoscopies. For semaglutide 'responders,' two-year %TWL was similar to RYGB (22.9% vs. 17.1%, p = 0.423).

CONCLUSIONS:

RYGB led to greater and more consistent weight loss and diabetes control than semaglutide in SG patients with RWG, at the cost of an increased need for GI interventions. While only a minority of patients responded to semaglutide, these patients had similar two-year weight outcomes as RYGB.

Estimated pulse wave velocity (ePWV) has been proposed as a potential substitute for carotid-femoral pulse wave velocity (cfPWV), serving as an indicator for assessing aortic stiffness. Arterial stiffness has emerged as a potential marker associated with adverse outcomes in various specific diseases, yet its relationship with mortality rates in the general adult population remains unstudied. This study aims to investigate the association between arterial stiffness and both all-cause and cardiovascular mortality among US adults. Data from 48,257 participants aged 20 and older in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were analyzed. Mortality details were obtained from the National Death Index (NDI). Restricted cubic spline (RCS) functions were used to visualize the association between estimated pulse wave velocity (ePWV) and mortality risk. Weighted Cox proportional hazards models were employed to assess the independent correlation between ePWV and mortality risk. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to evaluate the predictive ability of ePWV for survival. Further subgroup analyses were performed to validate the robustness of the associations. Participants were stratified into higher (> 10.92) and lower (≤ 10.92) ePWV groups. During a median follow-up of 133.69 ± 94.42 months, 8029 (16.6%) deaths, including 2641 (5.5%) cardiovascular deaths, occurred among the 48,257 participants. The weighted Cox proportional hazards model showed that after comprehensive adjustment for covariates, individuals with higher ePWV had significantly increased risks of all-cause mortality (HR 2.67, 95% confidence interval [CI] 2.50-2.84, P < 0.001) and cardiovascular mortality (HR 2.75, 95%CI 2.46-3.07, P < 0.001). RCS regression analysis revealed a nonlinear association between ePWV, a marker of arterial stiffness, and all-cause mortality with an inflection point at 8.267 (P for nonlinear = 0.0001), while a positive linear correlation was observed with cardiovascular mortality (P for nonlinear = 0.889). This association was consistent across subgroups based on age, gender, race, body mass index, education level, marital status, smoking, alcohol consumption, diabetes, and hypertension, with significant interactions observed for all-cause mortality in the hypertension subgroup (P for interaction = 0.012) and for cardiovascular mortality in smoking (P for interaction = 0.032), diabetes (P for interaction < 0.001), and hypertension subgroups (P for interaction = 0.012). The time-dependent ROC curves indicated areas under the curve (AUCs) of 0.73, 0.80, and 0.79 for 1-year, 6-year, and 10-year survival rates, respectively, for all-cause mortality, and 0.85, 0.83, and 0.83 for cardiovascular mortality. Elevated ePWV is independently associated with increased cardiovascular mortality in US adults and exhibits a significant positive correlation with all-cause mortality in US adults beyond an ePWV threshold of 8.267.

BACKGROUND:

Although nearly half of the US population has a chronic disease, many remain undiagnosed, leading to significant morbidity and mortality. Sociodemographic factors affect access to preventative healthcare, increasing rates of undiagnosed chronic disease. We hypothesize that emergency general surgery (EGS) is an important access point into the healthcare system and sought to characterize factors impacting the new diagnosis of chronic disease during admission for EGS.

METHODS:

This was a Level III retrospective cohort study conducted at a single, academic institution. Patients undergoing EGS intervention, including colectomies, cholecystectomy, hernia repair, and peptic ulcer surgeries, were identified during 2018-2019. Univariate descriptive statistics and bivariate analyses were conducted, with χ2 tests for categorical variables and Mann-Whitney U tests for continuous variables. We finally conducted a multivariable logistic regression to identify important factors related to the diagnosis of a new chronic disease.

RESULTS:

A total of 978 patients were included. Of these, 42.7% received a new diagnosis of chronic disease during their EGS admission. The most common diagnoses were gastroesophageal reflux disease (n=120), obesity (n=116), type 2 diabetes (n=60), and hypertension (n=48). No significant associations were found with sociodemographic factors or prior healthcare visits. Length of stay was significantly longer for those with new diagnoses (p<0.001).

CONCLUSIONS:

Hospital admissions for EGS present a critical opportunity to identify undiagnosed chronic conditions, particularly in patients with limited healthcare access. Length of stay was associated with an increased likelihood of diagnosis. These findings suggest that emergency surgical care can serve as a gateway to preventive care. This study provides Level III evidence of the role of emergency general surgery in chronic disease diagnosis.

LEVEL OF EVIDENCE:

III.

BACKGROUND:

The tumor microenvironment (TME) poses challenges that limit the efficacy of conventional CAR-T cell therapies. Homing barriers, immunosuppressive factors, and target antigen heterogeneity can impair CAR-T cell functional activity within the TME. Alternative strategies have contemplated incorporating the use of gamma delta (γδ) T cells as a CAR-T cell approach to potentially overcome these limitations. γδ T cells possess both innate and adaptive immunity to facilitate broad tumor recognition, and their natural propensity for tissue tropism may allow for more effective tumor infiltration. Reported here is the preclinical characterization of ADI-270, an allogeneic γδ CAR-T cell product targeting CD70+ cancers, engineered with a third-generation CAR based on the natural CD27 receptor. ADI-270 is also double-armored to mitigate the immunosuppressive effects of TGFβ and reduce the potential for allogeneic rejection.

METHODS:

Vδ1 T cells engineered to express an anti-CD70 CAR and dominant negative TGFβ receptor II (dnTGFβRII) were expanded from healthy donor human PBMCs. The phenotype and functional characterization of ADI-270 were assessed with in vitro cell culture assays and in vivo tumor xenograft models.

RESULTS:

ADI-270 exhibited high levels of in vitro cytotoxicity against a panel of cancer cell lines and displayed a favorable inflammatory cytokine profile compared with reference scFv-based anti-CD70 CAR αβ T cells. Cytotoxicity remained potent despite low CD70 expression observed in multiple solid and hematologic tumor cell models. When armored with dnTGFβRII, ADI-270 exhibited functional resilience to TGFβ-mediated inhibition of T cell effector activity. In addition, the incorporation of potent and sensitive CD70-targeting decreased T cell-mediated alloreactive killing against ADI-270 in vitro without evidence of fratricide. Finally, ADI-270 displayed robust tumor tropism and control of primary and secondary tumor challenges in xenograft mouse models.

CONCLUSIONS:

These results demonstrate the robust potency and capacity of ADI-270 to extend antitumor activity to cancers with heterogeneous antigen expression. The functional armoring incorporated into ADI-270 provides a mechanism to overcome the limitations of reduced efficacy and persistence within the TME. ADI-270 has the potential to target multiple CD70+ cancers with initial clinical evaluation proceeding in relapsed/refractory clear cell renal cell carcinoma.

TRIAL REGISTRATION NUMBER:

NCT06480565.

INTRODUCTION:

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of refractory hematological malignancies, yet significant challenges persist in extending its success to solid tumors. This review aims to provide a comprehensive overview of the current landscape and future perspectives of CAR-T therapy in both hematological malignancies and solid tumors.

METHODS:

A thorough literature search was conducted to identify relevant preclinical and clinical studies, as well as review articles, focusing on CAR-T therapy in various hematological malignancies and solid tumors. The collected information was synthesized to discuss the current applications, challenges, and strategies for improving CAR-T therapy in these settings.

RESULTS:

CAR-T therapy has demonstrated impressive clinical outcomes in treating certain hematological malignancies, such as B-cell lymphoma, leukemia, and multiple myeloma. However, the efficacy of CAR-T cells in solid tumors has been limited due to various obstacles, including tumor heterogeneity, immunosuppressive microenvironment, and off-tumor toxicities. Strategies to overcome these challenges involve advanced CAR designs, combination therapies, and novel approaches to CAR-T cell manufacturing and engineering.

CONCLUSION:

While CAR-T therapy has revolutionized the treatment of some hematological malignancies, significant hurdles remain in extending its success to solid tumors. Continued research efforts focusing on improving CAR-T cell efficacy, safety, and accessibility will be crucial in unlocking the full potential of this innovative immunotherapeutic approach across a broad spectrum of cancer types.