Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration.

BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, whereas expression of the erythroid regulator GATA1 directs SMAD1 loss on nonerythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity.

Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

Intrinsic capacity and survival among older adults with gastrointestinal malignancies: The Cancer and Aging Resilience Evaluation registry.

BACKGROUND: Intrinsic capacity (IC) was introduced by the World Health Organization (WHO) as a marker of healthy aging, and is defined as the combination of an individual's physical, mental, and psychological capacities. This study aimed to assess IC via a patient-reported geriatric assessment (GA) and evaluate its association with survival among older adults with gastrointestinal (GI) malignancies. METHODS: Data were used from a single-institution prospective registry of older adults undergoing GA before cancer therapy. Key domains of IC (vitality, locomotion, and sensory [hearing and visual], psychological, and cognitive capacities) were captured via GA, and each was given a score of 0 or 1 (0, impaired) to compute the total IC score (range, 0-6, where 6 indicates no impairment and ≤5 indicates impairment in ≥1 domains). A frailty index (FI) was measured via the deficit accumulation method. Cox regression models and Kaplan-Meier curves were used to examine the impact of IC impairment on survival. RESULTS: The study included 665 patients; the median age was 68 years, 57.4% were men, and 72.9% were White. The median IC score was 4, and 79.3% of participants showed impairment in ≥1 domains of IC. Most commonly impaired domains were locomotion (48.7%) and vitality (43.9%). IC was inversely associated with FI (Spearman coefficient, -0.75; p < .001). IC impairment was associated with inferior overall survival (score, 4-5: adjusted hazard ratio [aHR], 1.7; 95% CI, 1.11-2.48; score, 2-3: aHR, 1.9; 95% CI, 1.30-2.85; score, 0-1: aHR, 1.9; 95% CI, 1.11-2.48). CONCLUSIONS: IC impairment is associated with frailty and reduced overall survival in older patients with GI malignancies. GA can be used to screen for IC impairment as recommended by the WHO. PLAIN LANGUAGE SUMMARY: The World Health Organization introduced intrinsic capacity as a marker of healthy aging. Intrinsic capacity is the combination of an individual's physical, mental, and psychological capacities. It contains six key domains: vitality, locomotion, and sensory (hearing and visual), psychological, and cognitive capacities. Older adults with cancer are susceptible to a decrease in intrinsic capacity as a result of cancer and the aging process. In this study, we aimed to assess the intrinsic capacity for patients with gastrointestinal cancer and also identify whether there exists any association of intrinsic capacity with overall survival. We identified that approximately 80% of this population had one or more impaired domains, and more intrinsic capacity impairment was associated with reduced overall survival.

COVID-19 infection in children, adolescents, and young adults with Down syndrome and hematologic malignancies.

INTRODUCTION: Children, adolescents, and young adults (CAYAs) with Down syndrome (DS) and hematologic malignancies are particularly vulnerable to infections and related complications. There are limited data regarding COVID-19 infections in this group. We aimed to understand the clinical course of COVID-19 in this population. METHODS: This observational study leverages the de-identified clinical and sociodemographic data captured by the Pediatric Oncology COVID-19 Case Report Registry (POCC) regarding CAYAs with cancer and COVID-19. We evaluated CAYAs (≤21 years at COVID-19 infection) with hematologic malignancies and COVID-19 reported from April 1, 2020 to May 2, 2023, comparing those with and without DS. Using multivariable logistic regression, we examined rates of hospitalization, intensive care unit (ICU) admission, respiratory support, and changes in cancer-directed therapy. RESULTS: Among 1408 CAYAs with hematologic malignancies, 55 had DS (CAYA-DS). CAYA-DS had higher rates of hospitalization, ICU admission, and respiratory support (p < .001) than CAYAs without DS. Similarly, multivariable analyses found higher odds of hospitalization (odds ratio [OR] = 2.8, 95% confidence interval [CI]: 1.5-5.1), ICU admission (OR = 4.2, 95% CI: 1.9-9.1), and need for respiratory support (OR = 4.2, 95% CI: 2.0-8.8) among CAYA-DS. Modifications to cancer-directed therapy were more common among CAYA-DS when related to neutropenia (p = .001), but not when unrelated to neutropenia (p = .88); CAYA-DS did not have higher odds of changes to cancer-directed therapy (OR = 1.20, 95% CI: 0.7-2.1). CONCLUSIONS: We identify CAYA-DS with hematologic malignancies as a vulnerable subpopulation at greater risk for severe COVID-19 infection. This can inform conversations with patients and families regarding therapeutic and preventive measures, as well as the risks and benefits of modifying chemotherapy in the setting of COVID-19.

The Prognostic and Therapeutic Roles of ARL-6 Gene in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers. ARL-6, a member of the ADP ribosylation factor (like) (ARF) protein family, has gained attention as a potential therapeutic target in various malignancies and a prognostic biomarker. However, its specific roles in HCC, both prognostically and biochemically, remain largely unclear. Methods: To examine the functional relevance of ARL-6 in HCC, we acquired data from GEPIA, UALCAN, TIMER, TCGA, GeneMANIA, and Metascape databases. Then, we conducted immunohistochemistry on a replication sample comprising 26 HCC specimens to assess the efficacy of the ARL-6 gene. To unravel the mechanistic intricacies, we employed diverse assays such as the cell counting kit 8 (CCK8), flow cytometry, and transwell invasion assessment. Results: Our findings demonstrated the mRNA expression of ARL-6 was significantly upregulated in HCC compared to normal tissue, as evidenced by comprehensive database analysis. Immunohistochemistry further revealed that ARL-6 expression was remarkably higher in HCC than in para-carcinoma tissues. Moreover, ARL-6 expression exhibited noteworthy variations across diverse LIHC characteristics, including sample type, histological subtype, TP53 mutation status, nodal metastatic status, and cancer stage. In addition, high transcriptional levels of ARL-6 were correlated with diminished overall survival (OS) and disease-free survival (DFS) in HCC patients. Furthermore, our study indicated positive correlations between ARL-6 expression levels and the activities of tumor-infiltrating immune cells such as B cells, myeloid dendritic cells, macrophages, neutrophils, CD8+T cells, and CD4+T cells. Substantiating our findings, database analysis uncovered additional evidence of ARL-6 gene co-expression and its functional significance in HCC cases. Finally, we demonstrated the involvement of the ARL-6 gene in HCC cell invasion, proliferation, and apoptosis. Conclusions: In conclusion, our investigation sheds light on the pivotal role of ARL-6 in influencing HCC prognosis and treatment by modulating the biological activities of tumor cells. These discoveries hold promise for the development of predictive biomarkers and novel therapeutic avenues for affected patients.

Assessment of longitudinal changes in body composition of children with lymphoma and rhabdomyosarcoma.

BACKGROUND: Studies examining changes in skeletal muscle and adipose tissue during treatment for cancer in children, adolescents, and young adults and their effect on the risk of chemotherapy toxicity (chemotoxicity) are limited. METHODS: Among 78 patients with lymphoma (79.5%) and rhabdomyosarcoma (20.5%), changes were measured in skeletal muscle (skeletal muscle index [SMI]; skeletal muscle density [SMD]) and adipose tissue (height-adjusted total adipose tissue [hTAT]) between baseline and first subsequent computed tomography scans at the third lumbar vertebral level by using commercially available software. Body mass index (BMI; operationalized as a percentile [BMI%ile]) and body surface area (BSA) were examined at each time point. The association of changes in body composition with chemotoxicities was examined by using linear regression. RESULTS: The median age at cancer diagnosis of this cohort (62.8% male; 55.1% non-Hispanic White) was 12.7 years (2.5-21.1 years). The median time between scans was 48 days (range, 8-207 days). By adjusting for demographics and disease characteristics, this study found that patients undergo a significant decline in SMD (ß ± standard error [SE] = -4.1 ± 1.4; p < .01). No significant changes in SMI (ß ± SE = -0.5 ± 1.0; p = .7), hTAT (ß ± SE = 5.5 ± 3.9; p = .2), BMI% (ß ± SE = 4.1 ± 4.8; p = .3), or BSA (ß ± SE = -0.02 ± 0.01; p = .3) were observed. Decline in SMD (per Hounsfield unit) was associated with a greater proportion of chemotherapy cycles with grade ≥3 nonhematologic toxicity (ß ± SE = 1.09 ± 0.51; p = .04). CONCLUSIONS: This study shows that children, adolescents, and young adults with lymphoma and rhabdomyosarcoma undergo a decline in SMD early during treatment, which is associated with a risk of chemotoxicities. Future studies should focus on interventions designed at preventing the loss of muscle during treatment. PLAIN LANGUAGE SUMMARY: We show that among children, adolescents, and young adults with lymphoma and rhabdomyosarcoma receiving chemotherapy, skeletal muscle density declines early during treatment. Additionally, a decline in skeletal muscle density is associated with a greater risk of nonhematologic chemotoxicities.

Potentially inappropriate medications in geriatric blood or marrow transplantation (BMT) survivors: A BMT Survivor Study report.

BACKGROUND: Blood or marrow transplantation (BMT) is increasingly offered to older individuals with hematologic malignancies. The high prevalence of chronic health conditions in such individuals necessitates use of multiple medications. Beers Criteria represent a list of potentially inappropriate medications (PIMs) shown to increase the risk of health problems in the elderly. We sought to determine the prevalence and predictors of PIM use in older BMT survivors and identify associations with health problems. METHODS: Study participants were drawn from the BMT Survivor Study, a cohort study of patients transplanted at three US transplant centers between 1974 and 2014 and surviving ≥2 years. For this report, the survivors were aged ≥65 years. Siblings served as a comparison group. Participants self-reported sociodemographics, chronic health conditions, and medication use. Logistic regression analyses identified predictors of PIM use and associations with health problems. RESULTS: Overall, PIM use was comparable between BMT survivors (49.4%) and siblings (49.3%) (odds ratio [OR] = 0.9; 95% CI, 0.7-1.2); however, BMT survivors were more likely to use >1 PIM (17.4% vs. 12.4%; OR = 1.5; 95% CI, 1.01-2.4) and central nervous system-related PIMs (8.3% vs. 4.3%; OR = 2.18; 95% CI, 1.17-4.09). Predictors of PIM use included presence of severe/life-threatening chronic health conditions (OR = 1.5; 95% CI, 1.1-2.0), and chronic graft versus host disease (OR = 1.7; 95% CI, 1.1-2.7). Survivors taking >1 PIM reported more issues with vertigo (OR = 2.3; 95% CI, 1.1-4.7), balance (OR = 2.6; 95% CI, 1.7-4.1), faintness/dizziness (OR = 2.8; 95% CI, 1.8-4.6), and personal care (OR = 4.5; 95% CI, 1.4-14.8). CONCLUSIONS: This study shows the health problems associated with PIM use and identifies vulnerable populations at higher risk for PIM use, providing evidence for caution in using PIMs in high-risk populations.

Image-free target identification using a single-point single-photon LiDAR.

Single-photon light detection and ranging (LiDAR) - offering single-photon sensitivity and picosecond temporal resolution - has become one of the most promising technologies for 3D imaging and target detection. Generally, target detection and identification requires the construction of an image, performed by a raster-scanned or an array-based LiDAR system. In contrast, we demonstrate an image-free target identification approach based on a single-point single-photon LiDAR. The idea is to identify the object from the temporal data equipped with an efficient neural network. Specifically, the target is flood-illuminated by a pulsed laser and a single-point single-photon detector is used to record the time-of-flight (ToF) of back-scattering photons. A deep-learning method is then employed to analyze the ToF data and perform the identification task. Simulations with indoor and outdoor experiments show that our approach can identify the class and pose of the target with high accuracy. Importantly, we construct a compact single-point single-photon LiDAR system and demonstrate the practical capability to identify the types and poses of drones in outdoor environments over hundreds of meters. We believe our approach will be useful in applications for sensing dynamic targets with low-power optical detection.

Long range 3D imaging through atmospheric obscurants using array-based single-photon LiDAR.

Single-photon light detection and ranging (LiDAR) has emerged as a strong candidate technology for active imaging applications. In particular, the single-photon sensitivity and picosecond timing resolution permits high-precision three-dimensional (3D) imaging capability through atmospheric obscurants including fog, haze and smoke. Here we demonstrate an array-based single-photon LiDAR system, which is capable of performing 3D imaging in atmospheric obscurant over long ranges. By adopting the optical optimization of system and the photon-efficient imaging algorithm, we acquire depth and intensity images through dense fog equivalent to 2.74 attenuation lengths at distances of 13.4 km and 20.0 km. Furthermore, we demonstrate real-time 3D imaging for moving targets at 20 frames per second in mist weather conditions over 10.5 km. The results indicate great potential for practical applications of vehicle navigation and target recognition in challenging weather.

Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics.

INTRODUCTION: Human respiratory syncytial virus (HRSV) infection causes significant morbidity, and no effective treatments are currently available. Viral infections induce substantial metabolic changes in the infected cells to optimize viral production. Metabolites that reflect the interactions between host cells and viruses provided an opportunity to identify the pathways underlying severe infections. OBJECTIVE: To better understand the metabolic changes caused by HRSV infection, we analyzed temporal metabolic profiling to provide novel targets for therapeutic strategies for inhaled HRSV infection. METHODS: The epithelial cells and BALB/c mice were infected with HRSV. Protein and mRNA levels of inflammation factors were measured by using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Untargeted metabolomics, lipidomics and proteomics were performed using liquid chromatography coupled with mass spectrometry to profile the metabolic phenotypic alterations in HRSV infection. RESULTS: In this study, we evaluated the inflammatory responses in vivo and in vitro and investigated the temporal metabolic rewiring of HRSV infection in epithelial cells. We combined metabolomics and proteomic analyses to demonstrate that the redox imbalance was further provoked by increasing glycolysis and anaplerotic reactions. These responses created an oxidant-rich microenvironment that elevated reactive oxygen species levels and exacerbated glutathione consumption. CONCLUSION: These observations indicate that adjusting for metabolic events during a viral infection could represent a valuable approach for reshaping the outcome of infections.

Long-range photon-efficient 3D imaging without range ambiguity.

Single-photon light detection and ranging (LiDAR) has broad applications ranging from remote sensing to target recognition. In most cases, however, the repetition period of the pulsed laser limits the maximum distance that can be unambiguously determined. The relative distances are normally obtained using a depth map. Here, we propose and demonstrate a photon-efficient three-dimensional (3D) imaging framework which permits the operation of high laser pulse repetition rates for long-range depth imaging without range ambiguity. Our approach uses only one laser period per pixel and borrows the information from neighboring pixels to reconstruct the absolute depth map of the scene. We demonstrate the absolute depth map recovery at ranges between 2.2 km and 13.8 km using ∼1.41 signal photons per pixel. We also show the capability to image the absolute distances of moving targets in real time.

Recent advances in structure-based enzyme engineering for functional reconstruction.

Structural information can help engineer enzymes. Usually, specific amino acids in particular regions are targeted for functional reconstruction to enhance the catalytic performance, including activity, stereoselectivity, and thermostability. Appropriate selection of target sites is the key to structure-based design, which requires elucidation of the structure-function relationships. Here, we summarize the mutations of residues in different specific regions, including active center, access tunnels, and flexible loops, on fine-tuning the catalytic performance of enzymes, and discuss the effects of altering the local structural environment on the functions. In addition, we keep up with the recent progress of structure-based approaches for enzyme engineering, aiming to provide some guidance on how to take advantage of the structural information.

Structural-guided design to improve the catalytic performance of aldo-keto reductase KdAKR.

Aldo-keto reductases (AKRs) are important biocatalysts that can be used to synthesize chiral pharmaceutical alcohols. In this study, the catalytic activity and stereoselectivity of a NADPH-dependent AKR from Kluyveromyces dobzhanskii (KdAKR) toward t-butyl 6-chloro (5S)-hydroxy-3-oxohexanoate ((5S)-CHOH) were improved by mutating its residues in the loop regions around the substrate-binding pocket. And the thermostability of KdAKR was improved by a consensus sequence method targeted on the flexible regions. The best mutant M6 (Y28A/L58I/I63L/G223P/Y296W/W297H) exhibited a 67-fold higher catalytic efficiency compared to the wild-type (WT) KdAKR, and improved R-selectivity toward (5S)-CHOH (dep value from 47.6% to >99.5%). Moreover, M6 exhibited a 6.3-fold increase in half-life (t1/2 ) at 40°C compared to WT. Under the optimal conditions, M6 completely converted 200 g/L (5S)-CHOH to diastereomeric pure t-butyl 6-chloro-(3R, 5S)-dihydroxyhexanoate ((3R, 5S)-CDHH) within 8.0 h, with a space-time yield of 300.7 g/L/day. Our results deepen the understandings of the structure-function relationship of AKRs, providing a certain guidance for the modification of other AKRs.

Disulfiram reduces the severity of mouse acute pancreatitis by inhibiting RIPK1-dependent acinar cell necrosis.

Acute pancreatitis (AP) is a frequent abdominal inflammatory disease. Despite the high morbidity and mortality, the management of AP remains unsatisfactory. Disulfiram (DSF) is an FDA-proved drug with potential therapeutic effects on inflammatory diseases. In this study, we aim to investigate the effect of DSF on pancreatic acinar cell necrosis, and to explore the underlying mechanisms. Cell necrosis was induced by sodium taurocholate or caerulein, AP mice model was induced by nine hourly injections of caerulein. Network pharmacology, molecular docking, and molecular dynamics simulation were used to explore the potential targets of DSF in protecting against cell necrosis. The results indicated that DSF significantly inhibited acinar cell necrosis as evidenced by a decreased ratio of necrotic cells in the pancreas. Network pharmacology, molecular docking, and molecular dynamics simulation identified RIPK1 as a potent target of DSF in protecting against acinar cell necrosis. qRT-PCR analysis revealed that DSF decreased the mRNA levels of RIPK1 in freshly isolated pancreatic acinar cells and the pancreas of AP mice. Western blot showed that DSF treatment decreased the expressions of RIPK1 and MLKL proteins. Moreover, DSF inhibited NF-κB activation in acini. It also decreased the protein expression of TLR4 and the formation of neutrophils extracellular traps (NETs) induced by damage-associated molecular patterns released by necrotic acinar cells. Collectively, DSF could ameliorate the severity of mouse acute pancreatitis by inhibiting RIPK-dependent acinar cell necrosis and the following formation of NETs.

M-Type Phospholipase A2 Receptor Autoantibody Measured by ELISA has Diagnostic Value in Patients with Idiopathic Membranous Nephropathy.

BACKGROUND: This study investigated the diagnosis value of phospholipase A2 receptor autoantibodies (PLA2R-AB) for idiopathic membranous nephropathy (IMN). METHODS: Patients with IMN, lupus nephritis, hepatitis B virus-associated nephropathy and IgA nephropathy and healthy participants were included. Receiver operating characteristics (ROC) curve was plotted for PLA2R-AB to diagnose IMN. RESULT: The level of serum PLA2R-AB was significantly higher in patients with IMN than with other MN, and was positively correlated to urine albumin-creatinine ratio and proteinuria in patients with IMN. The area under the ROC curve displaying the performance of PLA2R-AB to diagnose IMN was 0.907 with a sensitivity and specificity of 94.3% and 82.1%, respectively. CONCLUSIONS: PLA2R-AB is a reliable biomarker to diagnose Chinese patients with IMN.

Effects of potassium channel knockdown on peripheral blood T lymphocytes and NFAT signaling pathway in Xinjiang Kazak patients with hypertension.

BACKGROUD AND AIM: T lymphocytes are involved in the occurrence and development of essential hypertension, and potassium channels are thought to be critical for lymphocyte activation. This study is to examine the roles of the voltage-gated potassium channels (Kv1.3) and calcium-activated potassium channels (KCa3.1) in peripheral blood T lymphocytes in Kazakh hypertensive patients of Xinjiang, China, mainly focusing on the effects of these channels on nuclear factor of activated T cells (NFAT) and inflammatory cytokines of T lymphocytes. METHOD: Kv1.3 and KCa3.1 gene silencing were performed in cultured T lymphocytes from Kazakh patients with severe hypertension. T cell proliferation after gene silencing was measured using CCK-8. The mRNA and protein expression levels were measured using RT-qPCR and Western blot analysis, respectively. Nuclear translocation of NFAT was observed using laser confocal fluorescence microscopy. Inflammatory cytokine levels were detected with ELISA. RESULTS: Compared with control group, gene silencing of Kv1.3 and KCa3.1 respectively inhibited the proliferation of T cells. Moreover, compared with the control group, the mRNA expression levels of NFAT, IL-6 and IFN-γ were significantly decreased after gene silencing. Furthermore, the NFAT protein expression level was significantly down-regulated. In addition, the levels of IFN-γ and IL-6 in the cell culture supernatant were significantly decreased. CONCLUSION: Both Kv1.3 and KCa3.1 potassium channels activated T lymphocytes and enhanced the cytokine secretion possibly through CaN/NFAT signaling pathway, which may in turn induce micro-inflammatory responses and trigger the occurrence and progression of hypertension.

Association between body composition and chemotherapy-related toxicity in children with lymphoma and rhabdomyosarcoma.

BACKGROUND: Body composition is associated with chemotherapy toxicity (chemotoxicity) in adults with cancer; this association remains unexplored in children with cancer. METHODS: Using baseline computed tomography scans of 107 children with Hodgkin lymphoma (n = 45), non-Hodgkin lymphoma (n = 42), or rhabdomyosarcoma (n = 20), this study examined body composition (skeletal muscle index [SMI], skeletal muscle density [SMD], and height-adjusted total adipose tissue [hTAT]) to determine its association with chemotoxicity. Clinical characteristics and chemotoxicities were abstracted from medical records. Primary outcomes included grade 4 or higher hematologic toxicities and grade 3 or higher nonhematologic toxicities within 6 months of the diagnosis. Logistic regression models accounting for repeated measures were constructed to examine the association between body composition indices and chemotoxicities; adjustments were made for age at diagnosis, sex, race/ethnicity, cancer type, risk group, body mass index (measured as a percentile), or body surface area. RESULTS: The median SMI was 41.0 cm2 /m2 (range, 25.8-68.6 cm2 /m2 ), the median SMD was 54.1 HU (range, 35-69.4 HU), and the median hTAT was 19.5 cm2 /m2 (range, 0-226.7 cm2 /m2 ). Grade 4 or higher hematologic toxicities and grade 3 or higher nonhematologic toxicities were observed in 74.7% and 66.3% of the chemotherapy cycles, respectively. A higher SMD at diagnosis was associated with lower odds of grade 4 or higher hematologic toxicity (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85-0.97; P = .004). SMI (OR, 0.99; 95% CI, 0.95-1.04; P = .7) and hTAT (OR, 1.00; 95% CI, 0.99-1.01; P = .9) were not associated with hematologic toxicities. Nonhematologic toxicities did not show any association with body composition. CONCLUSIONS: The association between low SMD and hematologic toxicities in children with lymphoma or rhabdomyosarcoma could be due to body composition-based biodistribution of chemotherapeutic agents and needs further investigation. LAY SUMMARY: Body composition at cancer diagnosis in children with lymphoma and rhabdomyosarcoma may provide information that could identify those at risk for serious side effects from chemotherapy. Routinely used measures such as body mass index and body surface area show poor correlations with body composition assessed via computed tomography scans.

Racial disparities in frailty and geriatric assessment impairments in older adults with cancer in the Deep South: Results from the CARE Registry.

BACKGROUND: Despite recent advances in cancer, racial disparities in treatment outcomes persist, and their mechanisms are still not fully understood. The objective of this study was to examine racial differences in frailty and geriatric assessment impairments in an unselected cohort of older adults with newly diagnosed gastrointestinal (GI) malignancies. METHODS: This study used data from the Cancer and Aging Resilience Evaluation Registry, a prospective cohort study that enrolled older adults (≥60 years) with GI malignancies who were presenting for their initial consultation. Participants who had a geriatric assessment completed before chemotherapy initiation and self-reported as either White or Black were included. Frailty was defined with a frailty index based on the deficit accumulation method. The differences in the prevalence and adjusted odds ratios for frailty and geriatric assessment impairments between Black and White participants were examined. RESULTS: Of the 710 eligible patients who were seen, 553 consented with sufficient data for analyses. The mean age at enrollment was 70 ± 7.1 years, 58% were male, and 23% were Black. Primary cancer diagnoses included colorectal cancer (32%), pancreatic cancer (27%), and hepatobiliary cancer (18%). Black participants were more likely to be frail (50.0% vs 32.7%; P < .001) and report limitations in activities of daily living (27.3% vs 14.1%; P = .001), instrumental activities of daily living (64.8% vs 47.3%; P = .002), and walking 1 block (62.5% vs 48.2%; P = .004). These associations persisted even after adjustments for age, sex, education, cancer type, cancer stage, and comorbidity. CONCLUSIONS: Black participants were frailer and reported more limitations in function in comparison with White participants. These findings may partially explain disparities in cancer outcomes and warrant further examination.

Ruthenium red attenuates acute pancreatitis by inhibiting MCU and improving mitochondrial function.

Acute pancreatitis (AP) is a common inflammatory disease of the digestive system. Mitochondrial calcium uniporter (MCU) mediates mitochondrial uptake of Ca2+ and plays an important role in calcium homeostasis. However, it is undefined whether AP can be relieved by inhibiting MCU. This study aimed to study the therapeutic potential of Ruthenium red (RuR), a MCU inhibitor, in AP mice model and primary acinar cells. Cell injury and AP mice model was induced by caerulein. RuR alleviated CER-AP evidenced by reduced serum lipase, TNF-α, and pancreatic MPO levels, less severe pancreatic pathology damage, and decreased inflammatory cell infiltration. In freshly isolated pancreatic acinar cells, RuR diminished cell necrosis with effect on suppressing the expression of MCU. RuR also decreased levels of cytosolic calcium and ROS, preventing mitochondrial membrane potential loss, ATP depletion and MPTP opening. The present findings indicate that inhibit MCU by RuR has a beneficial effect in AP by preventing calcium overload, mitochondrial dysfunction, and cell necrosis.