Modifiable Risk Factors in Hispanic Adults With Gastric Cancer in the United States.

BACKGROUND: Hispanics make up 19% of the U.S. population and are experiencing rising rates of cancer, primarily due to an increase in infection-related cancers (gastric, hepatic, cervical) and advanced cancers secondary to delayed screening (colorectal, cervical, breast). There is an increased incidence of gastric cancer (associated with infection, obesity, alcohol, and tobacco use) in Hispanics, especially at a young age, highlighting the need to consider ethnicity as a risk factor. METHODS: This study utilized the 2016-2019 National Inpatient Sample database to examine all patients admitted with gastric cancer. Individuals were stratified by race, age, and comorbidities, including modifiable risk factors that are associated with gastric cancer. RESULTS: There were 5,785 (7.44%) patients aged 18-44, 28,370 (36.49%) aged 45-64, and 43,590 (56.07%) over 65 years of age. Notably, 34.3% of the youngest group were Hispanic, contrasted with 19.7% and 12.9% in the older groups, respectively. Younger Hispanic patients showed a higher prevalence of H. pylori infection (8.6%) compared with older Hispanics (3.6% in the middle age group and 2.1% in the oldest, p<0.01). There was a high prevalence of obesity, tobacco use, and gastric ulcers in this cohort. Other risk factors such as alcohol use and gastric polyps were present at a lesser prevalence. CONCLUSIONS: This study reveals that Hispanic patients tend to have a younger age of onset of gastric cancer, coupled with an increased incidence of H. pylori infection at a younger age. This finding underscores the potential benefit of H. pylori screening among asymptomatic young Hispanics with the aim of reducing gastric cancer morbidity and mortality in this population.

Rescue of nucleus pulposus cells from an oxidative stress microenvironment via glutathione-derived carbon dots to alleviate intervertebral disc degeneration.

The senescence of nucleus pulposus (NP) cells (NPCs), which is induced by the anomalous accumulation of reactive oxygen species (ROS), is a major cause of intervertebral disc degeneration (IVDD). In this research, glutathione-doped carbon dots (GSH-CDs), which are novel carbon dot antioxidant nanozymes, were successfully constructed to remove large amounts of ROS for the maintenance of NP tissue at the physical redox level. After significantly scavenging endogenous ROS via exerting antioxidant activities, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and total antioxidant capacity, GSH-CDs with good biocompatibility have been demonstrated to effectively improve mitochondrial dysfunction and rescue NPCs from senescence, catabolism, and inflammatory factors in vivo and in vitro. In vivo imaging data and histomorphological indicators, such as the disc height index (DHI) and Pfirrmann grade, demonstrated prominent improvements in the progression of IVDD after the topical application of GSH-CDs. In summary, this study investigated the GSH-CDs nanozyme, which possesses excellent potential to inhibit the senescence of NPCs with mitochondrial lesions induced by the excessive accumulation of ROS and improve the progression of IVDD, providing potential therapeutic options for clinical treatment.

Racial and ethnic disparities in gallbladder cancer: A two-decade analysis of incidence and mortality rates in the US.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive malignancy that is usually diagnosed at a late stage. Prior data showed increasing incidence of GBC in the US. However, little is known about race/ethnic-specific incidence and mortality trends of GBC per stage at diagnosis. Therefore, we aimed to conduct a time-trend analysis of GBC incidence and mortality rates categorized by race/ethnicity and stage-at-diagnosis. METHODS: Age-adjusted GBC incidence and mortality rates were calculated using SEER*Stat software from the United States Cancer Statistics database (covers ~98% of US population between 2001 and 2020) and NCHS (covers ~100% of the US population between 2000 and 2020) databases, respectively. Race/Ethnic groups were Non-Hispanic-White (NHW), Non-Hispanic-Black (NHB), Hispanic, Non-Hispanic-Asian/Pacific-Islander (NHAPI), and Non-Hispanic-American-Indian/Alaska-Native (NHAIAN). Stage-at-diagnoses were all stages, early, regional, and distant stages. Joinpoint regression was used to generate time-trends [annual percentage change (APC) and average APC (AAPC)] with parametric estimations and a two-sided t-test (p-value cut-off 0.05). RESULTS: 76,873 patients were diagnosed with GBC with decreasing incidence rates in all races/ethnicities except NHB who experienced an increasing trend between 2001 and 2014 (APC = 2.08, p < 0.01) and plateauing afterward (APC = -1.21, p = 0.31); (AAPC = 1.03, p = 0.03). Among early-stage tumors (9927 patients), incidence rates were decreasing only in Hispanic (AAPC = -4.24, p = 0.006) while stable in other races/ethnicities (NHW: AAPC = -2.61, p = 0.39; NHB: AAPC = -1.73, p = 0.36). For regional-stage tumors (29,690 patients), GBC incidence rates were decreasing only in NHW (AAPC = -1.61, p < 0.001) while stable in other races/ethnicities (NHB: AAPC = 0.73, p = 0.34; Hispanic: AAPC = -1.58, p = 0.24; NHAPI: AAPC = -1.22, p = 0.07). For distant-stage tumors (31,735 patients), incidence rates were increasing in NHB (AAPC = 2.72, p < 0.001), decreasing in Hispanic (AAPC = -0.64, p = 0.04), and stable in NHW (AAPC = 0.07, p = 0.84) and NHAPI (AAPC = 0.79, p = 0.13). There were 43,411 deaths attributed to GBC with decreasing mortality rates in all races/ethnicities except NHB who experienced a stable trend (AAPC = 0.25, p = 0.25). CONCLUSION: Nationwide data over the last two decades show that NHB patients experienced increasing GBC incidence between 2001 and 2014 followed by stabilization of the rates. This increase was driven by late-stage tumors and occurred in the first decade. NHB also experienced non-improving GBC mortality, compared to other race and ethnic groups who had decreasing mortality. This can be due to lack of timely-access to healthcare leading to delayed diagnosis and worse outcomes. Future studies are warranted to investigate contributions to the revealed racial and ethnic disparities, especially in NHB, to improve early detection.

Esophageal cancer mortality disparities between Black and White adults in the United States, 1999-2020: insights from CDC-WONDER.

BACKGROUND AND AIM: Esophageal cancer significantly contributes to US cancer mortality, with notable racial disparities. This study aims to provide updated esophageal cancer mortality trends among Black and White adults from 1999 to 2020. METHODS: CDC-WONDER was used to identify Black and White adults in the United States from 1999 to 2020. We calculated age-standardized mortality rates, absolute rate differences, and rate ratios to compare the mortality differences between these populations. RESULTS: From 1999 to 2020 in the United States, there were 303 267 esophageal cancer deaths, with significant racial disparities. The age-adjusted mortality rate for Black adults fell from 6.52 to 2.62 per 100 000, while for White adults, it declined from 4.19 to 3.97 per 100 000, narrowing the racial mortality gap. Gender-wise, the study showed a decrease in the mortality rate from 3.31 to 2.29 per 100 000 in Black women, but an increase from 1.52 to 1.99 per 100 000 in White women. Among young men, the rate dropped in Black men from 12.82 to 6.26 per 100 000 but rose in White men from 9.90 to 10.57 per 100 000. Regionally, Black adults in the Midwest and South initially had higher mortality rates than Whites, but this gap reduced over time. By 2020, Black men had lower mortality rates across all regions. CONCLUSIONS: Over the last two decades, age-adjusted esophageal cancer mortality decreased in Black adults but stabilized in White adults, reflecting distinct cancer trends and risk factors. The study highlights the importance of tailored public health strategies for healthcare access and risk factor management.

Sarcopenia is associated with short- and long-term mortality in patients with acute-on-chronic liver failure.

BACKGROUND: While sarcopenia is recognized as a predictor of mortality in cirrhosis, its influence on acute-on-chronic liver failure (ACLF) remains uncertain. Despite multiple studies examining the impact of sarcopenia on short-term mortality in patients with ACLF, the sample size of these studies was limited, and their outcomes were inconsistent. Therefore, this study aimed to explore the impact of sarcopenia on both short- and long-term mortality in patients with ACLF. METHODS: This retrospective cohort study included 414 patients with ACLF that were treated between January 2016 and September 2022. Sarcopenia was diagnosed based on the measurement of the skeletal muscle index at the third lumbar vertebra (L3-SMI). Subsequently, the patients were divided into sarcopenia and non-sarcopenia groups. We analysed the basic clinical data of the two groups. Multivariate Cox proportional analysis was used to analyse short-term (28 days) and long-term (1 year and overall) mortality rates. RESULTS: A total of 414 patients were included, with a mean age of 52.88 ± 13.41 years. Among them, 318 (76.8%) were male, and 239 (57.7%) had sarcopenia. A total of 280 (67.6%) patients died during the study period. Among them, 153 patients died within 28 days (37%) and 209 patients died within 1 year (50.5%). We found that the 28-day, 1-year and overall mortality rates in the sarcopenia group were significantly higher than those in the non-sarcopenia group (37% vs. 22.3%, P < 0.01; 50.5% vs. 34.9%, P < 0.01; and 67.6% vs. 53.1%, P < 0.01, respectively). Multivariate Cox regression analysis revealed that sarcopenia was significantly associated with increased mortality. The hazard ratios for sarcopenia were 2.05 (95% confidence interval [CI] 1.41-3.00, P < 0.01) for 28-day mortality, 1.81 (95% CI 1.29-2.54, P < 0.01) for 1-year mortality and 1.82 (95% CI 1.30-2.55, P < 0.01) for overall mortality. In addition, muscle density and international normalized ratio were associated with short- and long-term mortality. CONCLUSIONS: Sarcopenia is associated with both short- and long-term mortality in patients with ACLF. Therefore, regular monitoring for sarcopenia is important for these patients.

Antipsychotic medications and severe sepsis in schizophrenia: A nested case-control study.

BACKGROUND: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case-control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. METHODS: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000-2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic-severe sepsis associations. RESULTS: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin-angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. CONCLUSION: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients.

Leveraging a rationally designed veliparib-based anilide eliciting anti-leukemic effects for the design of pH-responsive polymer nanoformulation.

Careful recruitment of the components of the HDAC inhibitory template culminated in veliparib-based anilide 8 that elicited remarkable cell growth inhibitory effects against HL-60 cell lines mediated via dual modulation of PARP [(IC50 (PARP1) = 0.02 nM) and IC50 (PARP2) = 1 nM)] and HDACs (IC50 value = 0.05, 0.147 and 0.393 µM (HDAC1, 2 and 3). Compound 8 downregulated the expression levels of signatory biomarkers of PARP and HDAC inhibition. Also, compound 8 arrested the cell cycle at the G0/G1 phase and induced autophagy. Polymer nanoformulation (mPEG-PCl copolymeric micelles loaded with compound 8) was prepared by the nanoprecipitation technique. The mPEG-PCL diblock copolymer was prepared by ring-opening polymerization method using stannous octoate as a catalyst. The morphology of the compound 8@mPEG-PCL was examined using TEM and the substance was determined to be monodispersed, spherical in form, and had an average diameter of 138 nm. The polymer nanoformulation manifested pH-sensitive behaviour as a greater release of compound 8 was observed at 6.2 pH as compared to 7.4 pH mimicking physiological settings. The aforementioned findings indicate that the acidic pH of the tumour microenvironment might stimulate the nanomedicine release which in turn can attenuate the off-target effects precedentially claimed to be associated with HDAC inhibitors.

Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling.

Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.

Effect of Jianpi Shengxue Tablet on Iron Metabolism and Nutritional Status in Patients with Renal Anemia: A Prospective, Randomized, Open, Parallel Controlled and Multicenter Clinical Study.

OBJECTIVE: This study aimed to analyze the clinical efficacy of the Jianpi Shengxue tablet for treating renal anemia. METHODS: A total of 200 patients with renal anemia from December 2020 to December 2022 were enrolled and randomly divided into two groups. Patients in the control group were treated with polysaccharide-iron complex, and those in the experimental group were administered Jianpi Shengxue tablet. After 8 weeks of continuous treatment, the therapeutic outcomes regarding anemia were compared between the two groups. RESULTS: After treatment, the red blood cell (RBC) count, hematocrit (HCT), reticulocyte percentage (RET), ferritin (SF), serum iron (SI), transferrin saturation (TSAT), and serum albumin (ALB) all increased (P<0.01), and the clinical symptom score and total iron binding capacity decreased (P<0.01) in the experimental group. Moreover, the improvements in RBC, HCT, RET, SF, SI, TAST, ALB, and clinical symptoms (fatigue, anorexia, dull skin complexion, numbness of hands and feet) in the experimental group were significantly greater than those in the control group (P<0.05). The total effective rate for treating renal anemia was significantly higher in the experimental group than in the control group (P<0.01). CONCLUSION: The Jianpi Shengxue tablet demonstrates efficacy in treating renal anemia, leading to significant improvements in the laboratory examination results and clinical symptoms of patients with renal anemia.

Recent advances and future directions on small molecule VEGFR inhibitors in oncological conditions.

"A journey of mixed emotions" is a quote that best describes the progress chart of vascular endothelial growth factor receptor (VEGFR) inhibitors as cancer therapeutics in the last decade. Exhilarated with the Food and Drug Administration (FDA) approvals of numerous VEGFR inhibitors coupled with the annoyance of encountering the complications associated with their use, drug discovery enthusiasts are on their toes with an unswerving determination to enhance the rate of translation of VEGFR inhibitors from preclinical to clinical stage. The recently crafted armory of VEGFR inhibitors is a testament to their growing dominance over other antiangiogenic therapies for cancer treatment. This review perspicuously underscores the earnest attempts of the researchers to extract the antiproliferative potential of VEGFR inhibitors through the design of mechanistically diverse structural assemblages. Moreover, this review encompasses sections on structural/molecular properties and physiological functions of VEGFR, FDA-approved VEGFR inhibitors, and hurdles restricting the activity range/clinical applicability of VEGFR targeting antitumor agents. In addition, tactics to overcome the limitations of VEGFR inhibitors are discussed. A clear-cut viewpoint transmitted through this compilation can provide practical directions to push the cart of VEGFR inhibitors to advanced-stage clinical investigations in diverse malignancies.

Exosomal MALAT1 from macrophages treated with high levels of glucose upregulates LC3B expression via miR-204-5p downregulation.

BACKGROUND: Metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) plays a critical role in the pathophysiology of diabetes-related complications. However, whether macrophage-derived MALAT1 affects autophagic activity under hyperglycemic conditions is unclear. Therefore, we investigated the molecular regulatory mechanisms of macrophage-derived MALAT1 and autophagy under hyperglycemic conditions. METHODS: Hyperglycemia was induced by culturing macrophages in 25 mM glucose for 1 hour. Exosomes were extracted from the culture media. A rat model of carotid artery balloon injury was established to assess the effect of MALAT1 on vascular injury. Reverse transcription, real-time quantitative polymerase chain reaction, western blotting, immunohistochemical staining, and luciferase activity assays were performed. RESULTS: Stimulation with high levels of glucose significantly enhanced MALAT1 expression in macrophage-derived exosomes. MALAT1 inhibited miR-204-5p expression in macrophage-derived exosomes under hyperglycemic conditions. siRNA-induced silencing of MALAT1 significantly reversed macrophage-derived exosome-induced miR-204-5p expression. Hyperglycemic treatment caused a significant, exosome-induced increase in the expression of the autophagy marker LC3B in macrophages. Silencing MALAT1 and overexpression of miR-204-5p significantly decreased LC3B expression induced by macrophage-derived exosomes. Overexpression of miR-204-5p significantly reduced LC3B luciferase activity induced by macrophage-derived exosomes. Balloon injury to the carotid artery in rats significantly enhanced MALAT1 and LC3B expression, and significantly reduced miR-204-5p expression in carotid artery tissue. Silencing MALAT1 significantly reversed miR-204-5p expression in carotid artery tissue after balloon injury. MALAT1 silencing or miR-204-5p overexpression significantly reduced LC3B expression after balloon injury. CONCLUSION: This study demonstrated that hyperglycemia upregulates MALAT1 . MALAT1 suppresses miR-204-5p expression and counteracts the inhibitory effect of miR-204-5p on LC3B expression in macrophages to promote vascular disease.

Circulating Immune Landscape Profiling in Psoriasis Vulgaris and Psoriatic Arthritis by Mass Cytometry.

Background: Psoriasis, a systemic disorder mediated by the immune system, can appear on the skin, joints, or both. Individuals with cutaneous psoriasis (PsC) have an elevated risk of developing psoriatic arthritis (PsA) during their lifetime. Despite this known association, the cellular and molecular mechanisms underlying this progression remain unclear. Methods: We performed high-dimensional, in-depth immunophenotyping of peripheral blood mononuclear cells (PBMCs) in patients with PsA and psoriasis vulgaris (PsV) by mass cytometry. Blood samples were collected before and after therapy for a longitudinal study. Then three sets of comparisons were made here: active PsA vs. active PsV, untreated PsV vs. treated PsV, and untreated PsA vs. treated PsA. Results: Marked differences were observed in multiple lymphocyte subsets of PsA related to PsV, with expansion of CD4+ T cells, CD16- NK cells, and B cells. Notably, two critical markers, CD28 and CD127, specifically differentiated PsA from PsV. The expression levels of CD28 and CD127 on both Naïve T cells (TN) and central memory CD4+ T cells (TCM) were considerably higher in PsA than PsV. Meanwhile, after treatment, patients with PsV had higher levels of CD28hi CD127hi CD4+ TCM cells, CD28hi CD127hi CD4+ TN cells, and CD16- NK cells. Conclusion: In the circulation of PsA patients, the TN and CD4+ TCM are characterized with more abundant CD28 and CD127, which effectively distinguished PsA from PsV. This may indicate that individuals undergoing PsV could be stratified at high risk of developing PsA based on the circulating levels of CD28 and CD127 on specific cell subsets.

Case Report: Can preoperative implantation of veno-arterial extracorporeal membrane oxygenation lead to embolic events in infective endocarditis?

Early-stage infective endocarditis (IE) can lead to severe complications, including infarctions and metastatic infections caused by inflammatory embolus shedding. Common embolism sites include the brain, spleen, kidneys, lungs, and intestines. Additionally, acute heart failure (AHF) can occur in up to 40% of cases, and its presence can impact the clinical outcomes of patients with IE. Cardiogenic shock (CGS) is often more likely to occur after AHF has taken place. If bacteria invade the blood, infectious shock can occur. Patients with IE can experience simple CGS, septic shock, or a combination of the two. Extracorporeal membrane oxygenation (ECMO) typically serves as a Bridge for Heart failure and Cardiogenic shock. Previous research indicates that there are limited reports of ECMO support for patients with IE after CGS has occurred. Because CGS may occur at any time during IE treatment, it is important to understand the timing of ECMO auxiliary support and how to carry out comprehensive treatment after support. Timely treatment can help to reduce or avoid the occurrence of serious complications and improve the prognosis of patients with IE. Our work combines a case study to review the ECMO support of IE patients after CGS through a literature review. Overall, we suggest that when patients with IE have large bacterial thrombosis and a greater risk of shedding, it is recommended to carefully evaluate the indications and contraindications for ECMO after discussion by a multidisciplinary team (MDT). Still, active surgical treatment at an early stage is recommended.

Reactive Oxygen Species Scavenging Injectable Hydrogel Potentiates the Therapeutic Potential of Mesenchymal Stem Cells in Skin Flap Regeneration.

Cell-based therapies offer tremendous potential for skin flap regeneration. However, the hostile microenvironment of the injured tissue adversely affects the longevity and paracrine effects of the implanted cells, severely reducing their therapeutic effectiveness. Here, an injectable hydrogel (nGk) with reactive oxygen species (ROS) scavenging capability, which can amplify the cell viability and functions of encapsulated mesenchymal stem cells (MSCs), is employed to promote skin flap repair. nGk is formulated by dispersing manganese dioxide nanoparticles (MnO2 NPs) in a gelatin/κ-carrageenan hydrogel, which exhibits satisfactory injectable properties and undergoes a sol-gel phase transition at around 40 °C, leading to the formation of a solid gel at physiological temperature. MnO2 NPs enhance the mechanical properties of the hydrogel and give it the ability to scavenge ROS, thus providing a cell-protective system for MSCs. Cell culture studies show that nGk can mitigate the oxidative stress, improve cell viability, and boost stem cell paracrine function to promote angiogenesis. Furthermore, MSC-loaded nGk (nGk@MSCs) can improve the survival of skin flaps by promoting angiogenesis, reducing inflammatory reactions, and attenuating necrosis, providing an effective approach for tissue regeneration. Collectively, injectable nGk has substantial potential to enhance the therapeutic benefits of MSCs, making it a valuable delivery system for cell-based therapies.

Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Biomechanical effects of Evans versus Hintermann osteotomy for treating adult acquired flatfoot deformity: a patient-specific finite element investigation.

BACKGROUND: Evans and Hintermann lateral column lengthening (LCL) procedures are both widely used to correct adult acquired flatfoot deformity (AAFD), and have both shown good clinical results. The aim of this study was to compare these two procedures in terms of corrective ability and biomechanics influence on the Chopart and subtalar joints through finite element (FE) analysis. METHODS: Twelve patient-specific FE models were established and validated. The Hintermann osteotomy was performed between the medial and posterior facets of the subtalar joint; while, the Evans osteotomy was performed on the anterior neck of the calcaneus around 10 mm from the calcaneocuboid joint surface. In each procedure, a triangular wedge of varying size was inserted at the lateral edge. The two procedures were then compared based on the measured strains of superomedial calcaneonavicular ligaments and planter facia, the talus-first metatarsal angle, and the contact characteristics of talonavicular, calcaneocuboid and subtalar joints. RESULTS: The Hintermann procedure achieved a greater correction of the talus-first metatarsal angle than Evans when using grafts of the same size, indicating that Hintermann had stronger corrective ability. However, its distributions of von-Mises stress in the subtalar, talonavicular and calcaneocuboid joints were less homogeneous than those of Evans. In addition, the strains of superomedial calcaneonavicular ligaments and planter facia of Hintermann were also greater than those of Evans, but both generally within the safe range (less than 6%). CONCLUSION: This FE analysis study indicates that both Evans and Hintermann procedures have good corrective ability for AAFD. Compared to Evans, Hintermann procedure can provide a stronger corrective effect while causing greater disturbance to the biomechanics of Chopart joints, which may be an important mechanism of arthritis. Nevertheless, it yields a better protection to the subtalar joint than Evans osteotomy. CLINICAL RELEVANCE: Both Evans and Hintermann LCL surgeries have a considerable impact on adjacent joints and ligament tissues. Such effects alongside the overcorrection problem should be cautiously considered when choosing the specific surgical method. LEVEL OF EVIDENCE: Level III, case-control study.

Prevalence and 3-year incidence of physical illnesses after schizophrenia diagnosis: Comparison with general population.

AIM: People with schizophrenia are at a greater risk of poor physical health than the general population. This study investigated the annual incidence of physical illnesses after a new schizophrenia diagnosis, which has rarely been investigated in the literature. METHODS: The authors collected data from Taiwan's National Health Insurance Research Database from January 1, 1996, to December 31, 2013, and enrolled 1910 patients with newly diagnosed schizophrenia cases aged 10-40 years and 7640 age- and sex-matched controls from the general population. They estimated the 1-year prevalence and annual incidence rate ratio (IRR) of specified physical diseases across 3 years in the schizophrenia group compared with the controls. RESULTS: Several physical illnesses were prevalent within 1 year of schizophrenia diagnosis. Regarding incident physical illnesses, patients had a moderate to strong risk of numerous physical illnesses (IRR > 3.0: ischemic heart disease, cerebrovascular disease, diabetes mellitus, and cancer; IRR 1.8-3.0: other forms of heart disease, vein and lymphatic diseases, pneumonia, chronic hepatic disease, and ulcer disease) within the first year after schizophrenia diagnosis. The IRRs of most physical illnesses declined over 3 years, except for that of cerebrovascular disease, which significantly increased (IRR > 3.0) over the 3 years after schizophrenia diagnosis. Cerebrovascular disease had a significant incidence risk (IRR > 3) persistently across the 3 years. CONCLUSION: Various comorbid physical illnesses can occur in the early stages of schizophrenia. Clinicians should consider these vulnerabilities to physical illnesses during the evaluation of patients with newly diagnosed schizophrenia by attempting to prevent, screen for, and manage them.

Misdiagnosed gastric diverticulum as a left adrenal lesion on imaging.

Key Clinical Message: Gastric diverticulum in the posterior wall of the stomach is very rare, and it is easy to be misdiagnosed as a left adrenal mass on imaging. Therefore, we must consider the possibility of gastric diverticulum when diagnosing a left adrenal mass. Abstract: This paper reports a case of gastric diverticulum that was misdiagnosed as a left adrenal mass on abdominal enhanced CT. The patient underwent laparoscopic adrenalectomy, but there was no mass in the left adrenal found during surgery. After the incision of the retroperitoneum, a cystic mass was found adjacent to the posterior gastric wall which turned out to be gastric diverticulum. This case suggests that gastric diverticulum, a rare disease, may be interpreted as an adrenal mass on imaging. Therefore, as a urologist, the gastric diverticulum must be excluded when CT suggests a mass in the left adrenal region.

Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD. SIGNIFICANCE: Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy. This article is featured in Selected Articles from This Issue, p. 201.

Chanling Gao suppresses colorectal cancer via PI3K/Akt/mTOR pathway modulation and enhances quality of survival.

The Chinese medicine formula Chanling Gao (CLG) exhibits significant tumor inhibitory effects in colorectal cancer (CRC) nude mice. However, the detailed mechanisms remain elusive. CRC in situ nude mouse models were treated with CLG. Small animal magnetic resonance imaging (MRI) tracked tumor progression, and overall health metrics such as food and water intake, body weight, and survival were monitored. Posttreatment, tissues and blood were analyzed for indicators of tumor inhibition and systemic effects. Changes in vital organs were observed via stereoscope and hematoxylin-eosin staining. Immunohistochemistry quantified HIF-1α and P70S6K1 protein expression in xenografts. Double labeling was used to statistically analyze vascular endothelial growth factor (VEGF) and CD31 neovascularization. Enzyme-linked immunosorbent assay was used to determine the levels of VEGF, MMP-2, MMP-9, IL-6, and IL-10 in serum, tumors, and liver. Western blotting was used to assess the expression of the PI3K/Akt/mTOR signaling pathway-related factors TGF-ß1 and smad4 in liver tissues. CLG inhibited tumor growth, improved overall health metrics, and ameliorated abnormal blood cell counts in CRC nude mice. CLG significantly reduced tumor neovascularization and VEGF expression in tumors and blood. It also suppressed HIF-1α, EGFR, p-PI3K, Akt, p-Akt, and p-mTOR expression in tumors while enhancing PTEN oncogene expression. Systemic improvements were noted, with CLG limiting liver metastasis, reducing pro-inflammatory cytokines IL-6 and IL-10 in liver tissues, decreasing MMP-2 in blood and MMP-2 and MMP-9 in tumors, and inhibiting TGF-ß1 expression in liver tissues. CLG can enhance survival quality and inhibit tumor growth in CRC nude mice, likely through the regulation of the PI3K/Akt/mTOR signaling pathway.