Olverembatinib treatment in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib is a novel orally administered third-generation tyrosine kinase inhibitor (TKI) with definitive responses in T315I-mutant chronic myeloid leukemia (CML) patients. However, its value in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remained unclarified. In this multiple-center study, 20 patients with de novo Ph + ALL were treated with olverembatinib-based regimens as frontline therapy. All patients acquired complete remission (CR) after induction. 85% of patients achieved complete molecular response (CMR) within three months, contributed mainly by the addition of blinatumomab. A total of 45% of patients experienced mild hematological treatment-related adverse events (TRAEs). Olverembatinib-based treatment led to promising outcomes in de novo Ph + ALL patients but warranted further studies to investigate the best-combined strategy.

Single-Dose Physically Cross-Linked Hyaluronic Acid and Lipid Hybrid Nanoparticles Containing Cyclic Guanosine Monophosphate-Adenosine Monophosphate Eliminate Established Tumors.

Activating the STING pathway in the cytosol of tumor-infiltrating antigen-presenting cells (APCs) represents a promising strategy to elicit potent antitumor immune responses for cancer therapy. However, STING agonists are mostly small hydrophilic molecules that suffer from rapid clearance and poor cytosolic delivery following systemic administration. While various nanoparticles have been developed to promote cytosolic delivery, they often exhibit premature drug release during circulation. Alternatively, stable nanoparticles with sustained release during circulation have poor cytosolic delivery. In this study, we have developed physically cross-linked hyaluronic acid (HA) and lipid hybrid nanoparticles containing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), denoted as HLHC, to address these challenges. The HLH delivery system has sustained drug release due to multiple lipid layers physically cross-linked by HA. HLHC efficiently delivers cGAMP to the cytosol of APCs, inducing more IFNß than cGAMP and liposomal cGAMP. HLH also improves the drug circulation time and biodistribution to the tumor compared with the liposomal formulation and free drug. Strikingly, a single dose of HLHC, but not liposomal cGAMP or free cGAMP, elicits potent antitumor immunity and regresses established MC38 tumors. A single dose of HLHC even regresses established B16F10 tumors upon combination with αPD-L1. Moreover, cured animals were protected from rechallenge with the same tumor cells. HLHC represents an efficient strategy to address delivery challenges associated with STING agonists and may have broad applications for the delivery of drugs acting in the cytosol.

Exogenous hydrogen sulfide enhances myogenic differentiation of C2C12 myoblasts under high palmitate stress.

Skeletal muscle atrophy was one of main complications of type 2 diabetes mellitus. Hydrogen sulfide (H2S) is involved in various physiological functions, such as anti-hypertension and anti-oxidant. Skeletal muscle atrophy caused by type 2 diabetes could lead to the regeneration of muscle fibers. Wnt signaling pathway plays a crucial important role in this process. H2S maybe regulate the Wnt signaling pathway to alleviate skeletal muscle atrophy, however, this role has not been clarified. The aim of this study is to investigate the potential regulatory role of H2S in the Wnt signaling pathway. C2C12 myoblasts treated with 500 µmol palmitate as an in vitro model. Western blot was used to detect the levels of CSE, PKM1, ß-catenin, MuRF1, MYOG, MYF6 and MYOD1. In addition, MuRF1 was mutated at Cys44 and MuRF1 S-sulfhydration was detected by biotin switch assay. The interaction between PKM1 and MuRF1 was assessed via Co-immunoprecipitation. Differentiation of C2C12 myoblasts was evaluated using LAMININ staining. These data showed the levels of CSE, ß-catenin, PKM1, MYOG, MYF6 and MYOD1 were decreased in pal group, compared with control and pal + NaHS groups. MuRF1 Cys44 mutants increased the protein levels of ß-catenin, MYOG, MYF6 and MYOD1 in pal group. Our results suggest that H2S regulates the S-sulfhydration levels of MuRF1 at Cys44, influencing the ubiquitination levels of PKM1 and ultimately promoting myoblast differentiation.

TP53AIP1 induce autophagy via the AKT/mTOR signaling pathway in the breast cancer cells.

Breast cancer ranks the first in the incidence of female cancer and is the most common cancer threatening the life and health of women worldwide.Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) is a pro-apoptotic gene downstream of p53. However, the role of TP53AIP1 in BC needs to be investigated. In vitro and in vivo experiments were conducted to assess the biological functions and associated mechanisms. Several bioinformatics analyses were made, CCK8 assay, wound healing, transwell assays, colony formation assay, EDU, flow cytometry, Immunofluorescence, qRT-PCR and Western-blotting were performed. In our study, we discovered that BC samples had low levels of TP53AIP1 expression, which correlated with a lower survival rate in BC patients. When TP53AIP1 was up-regulated, it caused a decrease in cell proliferation, migration, and invasion. It also induced epithelial-to-mesenchymal transition (EMT) and protective autophagy. Furthermore, the over-expression of TP53AIP1 suppressed tumor growth when tested in vivo. We also noticed that TP53AIP1 up-regulation resulted in decreased levels of phosphorylation in AKT and mTOR, suggesting a mechanistic role. In addition, we performed functional rescue experiments where the activation of AKT was able to counteract the impact of TP53AIP1 on the survival and autophagy in breast cancer cell lines. This suggests that TP53AIP1 acts as an oncogene by controlling the AKT/mTOR pathway. These findings reveal TP53AIP1 as a gene that suppresses tumor growth and triggers autophagy through the AKT/mTOR pathway in breast cancer cells. As a result, TP53AIP1 presents itself as a potential target for novel therapeutic approaches in treating breast cancer.

The genus Platydracus Thomson in Hainan, South China (Coleoptera, Staphylinidae, Staphylininae).

A study on Platydracus species of Hainan Province, China is presented. Platydracushainanensis sp. nov., Platydracusaureolus sp. nov. and Platydracuszhouchenglini sp. nov. are described as new species. Platydracusmarmorellus Fauvel, 1895 and Platydracussubirideus Kraatz, 1859 are recorded from China for the first time. Habitus and diagnostic characters of all species are photographed, and a key to Platydracus species of Hainan is provided.

Early statin use is associated with improved survival and cardiovascular outcomes in patients with atrial fibrillation and recent ischaemic stroke: A propensity-matched analysis of a global federated health database.

INTRODUCTION: Statins reduce recurrent stroke and cardiovascular events in patients with non-cardioembolic stroke. The benefits of statins in patients with AF and recent IS remain unclear. We aimed to investigate the benefits of statins in patients with AF and recent IS. PATIENTS AND METHODS: This retrospective, cohort study was conducted using deidentified electronic medical records within TriNetX platform. Patients with AF and recent IS, who received statins within 28 days of their index stroke were propensity score-matched with those who did not. Patients were followed up for up to 2 years. Primary outcomes were the 2-year risk of recurrent IS, all-cause mortality and the composite outcome of all-cause mortality, recurrent IS, transient ischaemic attack (TIA), and acute myocardial infarction (MI). Secondary outcomes were the 2-year risk of TIA, intracranial haemorrhage (ICH), acute MI, and hospital readmission. Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (95%CI). RESULTS: Of 20,902 patients with AF and recent IS, 7500 (35.9%) received statins within 28 days of their stroke and 13,402 (64.1%) did not. 11,182 patients (mean age 73.7 ± 11.5; 5277 (47.2%) female) remained after propensity score matching. Patients who received early statins had significantly lower risk of recurrent IS (HR: 0.45, 95%CI: 0.41-0.48, p < 0.001), mortality (HR: 0.75, 95%CI: 0.66-0.84, p < 0.001), the composite outcome (HR: 0.48, 95%CI: 0.45-0.52, p < 0.001), TIA (HR: 0.37, 95%CI: 0.30-0.44, p < 0.001), ICH (HR: 0.59, 95%CI: 0.47-0.72, p < 0.001 ), acute MI (HR: 0.35, 95%CI: 0.30-0.42, p < 0.001) and hospital readmission (HR: 0.46, 95%CI: 0.42-0.50, <0.001). Beneficial effects of early statins were evident in the elderly, different ethnic groups, statin dose intensity, and AF subtypes, large vessel occlusion and embolic strokes and within the context of statin lipophilicity, optimal LDL-cholesterol levels, various cardiovascular comorbidities, treatment with intravenous thrombolysis or endovascular thrombectomy, and NIHSS 0-5 and NIHSS > 5 subgroups. DISCUSSION AND CONCLUSION: Patients with AF and recent IS, who received early statins, had a lower risk of recurrent stroke, death, and other cardiovascular outcomes including ICH, compared to those who did not.

Advancements in understanding cardiotoxicity of EGFR- TKIs in non-small cell lung cancer treatment and beyond.

Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are a class of oral targeted anticancer drugs that have been demonstrated to significantly inhibit tumor progression and improve clinical prognosis in patients diagnosed with EGFR-mutated tumors, particularly in those with non-small cell lung cancer. However, the sustained usage of EGFR-TKIs may cause potential cardiotoxicity, thus limiting their applicability. The primary objective of this review is to systematically analyze the evolving landscape of research pertaining to EGFR-TKI-induced cardiotoxicity and elucidate its underlying mechanisms, such as PI3K signaling pathway inhibition, ion channel blockade, oxidative stress, inflammatory responses, and apoptosis. Additionally, the review includes an exploration of risk assessment for cardiotoxicity induced by EGFR-TKIs, along with management and response strategies. Prospective research directions are outlined, emphasizing the need for more accurate predictors of cardiotoxicity and the development of innovative intervention strategies. In summation, this review consolidates recent research advances, illuminates the risks associated with EGFR-TKI-induced cardiac toxicity and presents crucial insights for refining clinical dosage protocols, optimizing patient management strategies, and unraveling the intricate mechanisms governing EGFR-TKI-induced cardiotoxicity.

Nonlinear relationships of circulating polyunsaturated fatty acids with the complications of liver cirrhosis: A prospective, longitudinal cohort study.

BACKGROUND & AIMS: The role of circulating polyunsaturated fatty acids (PUFAs) in preventing liver cirrhosis complications remains unclear. METHODS: Between 2006 and 2010, 273,834 UK Biobank participants with plasma PUFA quantification data were enrolled and followed up until October 31, 2022. Plasma PUFAs were quantified using a high-throughput nuclear magnetic resonance-based metabolic profiling platform. Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with hepatocellular carcinoma. RESULTS: During a median follow-up of 13.9 years, 2026 participants developed liver cirrhosis complications. Total plasma PUFAs, omega-3 PUFAs, docosahexaenoic acid (DHA), omega-6 PUFAs, and linoleic acid (LA) were inversely associated with the risk of liver cirrhosis complications, whereas the plasma omega-6/omega-3 ratio was positively associated. Nonparametrically restricted cubic spline regression showed nonlinear associations of plasma PUFAs with liver cirrhosis complications. The inflection points were 4.78 mmol/L for total PUFAs, 0.73 mmol/L for omega-3 PUFAs, 0.25 mmol/L for DHA, 4.07 mmol/L for omega-6 PUFAs, and 2.99 mmol/L for LA. Plasma omega-3 PUFAs were negatively associated with the risk of liver cirrhosis complications when omega-3 PUFAs were <0.73 mmol/L (adjusted hazard ratio [HR], 0.11 [0.08-0.16]), whereas the association was inverted when omega-3 PUFAs were ≥0.73 mmol/L (adjusted HR, 1.87 [1.20-2.92]). CONCLUSIONS: The protective effect of plasma omega-3 PUFAs on liver cirrhosis complications is reversed after passing the corresponding inflection point, suggesting an optimal dietary omega-3 PUFA supplementation dose.

Glutaraldehyde crosslinked ternary carboxymethylcellulose/polyvinyl alcohol/polyethyleneimine film with enhanced mechanical properties, water resistance, antibacterial activity, and UV-shielding ability without any UV absorbents.

Despite the plethora of methods reported for fabricating ultraviolet (UV) shielding films using various UV absorbers to date, it remains a major challenge for the development of novel UV shielding films that simultaneously exhibit excellent transparency. In this work, a novel composite film (GA-x-CMC/PVA/PEI) is fabricated by integrating anionic carboxymethylcellulose (CMC), cationic polyethyleneimine (PEI), and polyvinyl alcohol (PVA) via electrostatic and hydrogen bond interactions and further cross-linking with glutaraldehyde (GA). Herein, PVA expands hydrogen bonding networks, reduces film haze, and enhances its mechanical strength. GA acts as a crosslinker in producing Schiff bases with PEI and acetals with CMC and PVA. The synthesized GA-x-CMC/PVA/PEI composite film possesses a notable amount of unsaturated -CH=N- bonds of Schiff base, resulting from the condensation of PEI and GA, which exhibit superior shielding efficiency against both UV-A and UV-B rays while maintaining exceptional transparency, visibility, and simultaneously enhancing mechanical properties and thermal stability. Notably, increasing the content of PEI leads to almost complete shielding of the entire UV spectrum (<400 nm) due to the increasing of the number of -CH=N- unsaturated bonds. Furthermore, the obtained film without any UV-shielding additives has exceptional mechanical properties, hydrophobicity, and antibacterial properties, rendering it a wide application prospect.

The association of haemoglobin A1c variability with adverse outcomes in patients with atrial fibrillation prescribed anticoagulants.

AIMS: The association of haemoglobin A1c (HbA1c) variability with the risk of adverse outcomes in patients with atrial fibrillation (AF) prescribed anticoagulants remains unclear. This study aimed to evaluate the association of HbA1c variability with the risk of ischaemic stroke (IS)/systemic embolism (SE) and all-cause mortality among patients with non-valvular AF prescribed anticoagulants. METHODS AND RESULTS: Patients newly diagnosed with AF from 2013 to 2018 were included. Variability in HbA1c, indexed by the coefficient of variation (CV), was determined for those with at least three HbA1c measurements available from the time of study enrolment to the end of follow-up. To evaluate whether prevalent diabetes would modify the relationship between HbA1c variability and outcomes, participants were divided into diabetes and non-diabetes groups. The study included 8790 patients (mean age 72.7% and 48.5% female). Over a median follow-up of 5.5 years (interquartile range 5.2, 5.8), the incident rate was 3.74 per 100 person-years for IS/SE and 4.89 for all-cause mortality in the diabetes group. The corresponding incident rates in the non-diabetes group were 2.41 and 2.42 per 100 person-years. In the diabetes group, after adjusting for covariates including mean HbA1c, greater HbA1c variability was significantly associated with increased risk of IS/SE [hazard ratio (HR) = 1.65, 95% confidence interval (CI): 1.27-2.13) and all-cause mortality (HR = 1.24, 95% CI: 1.05-1.47) compared with the lowest CV tertile. A similar pattern was evident in the non-diabetes group (IS/SE: HR = 1.58, 95% CI: 1.23-2.02; all-cause mortality: HR = 1.35, 95% CI: 1.10-1.64). CONCLUSION: Greater HbA1c variability was independently associated with increased risk of IS/SE and all-cause mortality among patients with AF, regardless of diabetic status.

In patients with atrial fibrillation (AF), greater haemoglobin A1c (HbA1c) variability was independently associated with increased risk of ischaemic stroke/systemic embolism and all-cause mortality, regardless of diabetic status. The usefulness of HbA1c variability as a risk predictor is significant and could be integrated into the stratification of patients with AF. Even if HbA1c measurements are within standard guideline limits, patients with larger fluctuations in HbA1c level may be at higher risk of thromboembolism and death than patients with more stable HbA1c level.

A Comprehensive Investigation of Dietary Micronutrient Intakes and Risk of Alcoholic Liver Disease.

BACKGROUND: The investigation of dietary micronutrient intakes and risk of alcoholic liver disease (ALD) based on observational studies was limited. OBJECTIVES: Our study aimed to explore the associations of 30 dietary micronutrients intakes with risk of ALD, interactions between dietary micronutrients and genetic variation, and mediation effects of blood and urinary biomarkers on the associations between dietary micronutrients and risk of ALD. METHODS: A case-control study was conducted within the UK Biobank cohort, with 231 incident ALD cases and 1386 controls. Dietary data were collected using a dietary questionnaire that relied on a 24-h dietary recall of the previous day. Logistic regression models were employed to assess the associations of dietary micronutrient intakes with risk of ALD. We conducted stratified analyses on the associations between dietary micronutrient intakes and risk of ALD by PNPLA3 rs738409 and tested the interactions between dietary micronutrients and genetic variation. In addition, we conducted mediation analyses to investigate the mediating effects of biomarkers on the associations between dietary micronutrients and risk of ALD. RESULTS: Our findings indicated significant inverse associations of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese with risk of ALD (all false discovery rate-Ptrend < 0.050). We also found a significant interaction between PNPLA3 rs738409 and magnesium (Pinteraction = 0.028). Creatinine (enzymatic) in urine, aspartate aminotransferase, and insulin-like growth factor 1 were the top 3 biomarkers with the highest number of significant mediation effects on the associations between the dietary micronutrients and risk of ALD. CONCLUSIONS: Dietary intakes of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese were inversely associated with risk of ALD.

Electrochemical CO2 Reduction to Multicarbon Products on Non-Copper Based Catalysts.

Electrochemical CO2 reduction reaction (eCO2RR) to value-added multicarbon (C2+) products offers a promising approach for achieving carbon neutrality and storing intermittent renewable energy. Copper (Cu)-based electrocatalysts generally play the predominant role in this process. Yet recently, more and more non-Cu materials have demonstrated the capability to convert CO2 into C2+, which provides impressive production efficiency even exceeding those on Cu, and a wider variety of C2+ compounds not achievable with Cu counterparts. This motivates us to organize the present review to make a timely and tutorial summary of recent progresses on developing non-Cu based catalysts for CO2-to-C2+. We begin by elucidating the reaction pathways for C2+ formation, with an emphasis on the unique C-C coupling mechanisms in non-Cu electrocatalysts. Subsequently, we summarize the typical C2+-involved non-Cu catalysts, including ds-, d- and p-block metals, as well as metal-free materials, presenting the state-of-the-art design strategies to enhance C2+ efficiency. The system upgrading to promote C2+ productivity on non-Cu electrodes covering microbial electrosynthesis, electrolyte engineering, regulation of operational conditions, and synergistic co-electrolysis, is highlighted as well. Our review concludes with an exploration of the challenges and future opportunities in this rapidly evolving field.

Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice.

BACKGROUND: Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. METHODS: The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-ß1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-ß1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. RESULTS: CCl4 exposure or TGF-ß1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-ß1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-ß1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. CONCLUSION: GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3.

BACKGROUND: Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored. AIMS: To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3. METHODS: Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated ß-galactosidase (SA-ß-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification. RESULTS: The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process. CONCLUSIONS: Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.

HPLC combined with chemometrics for quality control of Huamoyan Granules or Capsules.

Objective: Huamaoyan Granules (HMYG) and Huamaoyan Capsules (HMYC) are Chinese patent medicines with different dosage forms of the same prescription. Due to the different preparation process, the chemical composition of these Chinese patent medicines varies greatly among different forms, but there were few studies on the difference comparison and quality control of them. In order to improve the effectiveness and safety in its clinical application, an idea combining high performance liquid chromatography (HPLC) and chemometrics was put forward to study the quality control of Chinese patent medicines in different dosage forms of the same prescription. Methods: The differential markers of HMYG and HMYC were explored based on HPLC fingerprint and chemometrics including orthogonal projections to latent structures-discriminant analysis (OPLS-DA), principal component analysis (PCA), and hierarchical cluster analysis (HCA). Finally, the quantitative analysis method of related components was established by HPLC. Results: A quality control method for HMYG and HMYC was established. Firstly, the chemical components of HMYG and HMYC were systematically analyzed by HPLC fingerprinting. Further exploration showed that there were 20 characteristic peaks and 57 common peaks. Then, the potential differential markers between HMYG and HMYC were explored by chemometrics, and the differential markers were screened after intersection with the 20 characteristic peaks. Finally, HPLC quantitative analysis methods for nine components were established, including seven differential markers (neochlorogenic acid, protocatechualdehyde, chlorogenic acid, cryptochlorogenic acid, caffeic acid, rosmarinic acid and salvianolic acid A). The results of HPLC quantitative analysis showed that the contents of eight components in HMYG and HMYC samples were significantly different. According to the above results, the differential markers between HMYG and HMYC screened based on HPLC fingerprint and chemometrics can effectively characterize the differences between the two dosage forms. Conclusion: The present work provides a rapid and effective method for routine quality evaluation and control of HMYG and HMYC. This work also provides feasible methods for the quality evaluation and control of Chinese patent medicines with different dosage forms of the same prescription.

Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach.

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials.

Anti-TL1A monoclonal antibody modulates the dysregulation of Th1/Th17 cells and attenuates granuloma formation in sarcoidosis by inhibiting the PI3K/AKT signaling pathway.

Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.

Analysis of gene expression in microglial apoptotic cell clearance following spinal cord injury based on machine learning algorithms.

Spinal cord injury (SCI) is a severe neurological complication following spinal fracture, which has long posed a challenge for clinicians. Microglia play a dual role in the pathophysiological process after SCI, both beneficial and detrimental. The underlying mechanisms of microglial actions following SCI require further exploration. The present study combined three different machine learning algorithms, namely weighted gene co-expression network analysis, random forest analysis and least absolute shrinkage and selection operator analysis, to screen for differentially expressed genes in the GSE96055 microglia dataset after SCI. It then used protein-protein interaction networks and gene set enrichment analysis with single genes to investigate the key genes and signaling pathways involved in microglial function following SCI. The results indicated that microglia not only participate in neuroinflammation but also serve a significant role in the clearance mechanism of apoptotic cells following SCI. Notably, bioinformatics analysis and lipopolysaccharide + UNC569 (a MerTK-specific inhibitor) stimulation of BV2 cell experiments showed that the expression levels of Anxa2, Myo1e and Spp1 in microglia were significantly upregulated following SCI, thus potentially involved in regulating the clearance mechanism of apoptotic cells. The present study suggested that Anxa2, Myo1e and Spp1 may serve as potential targets for the future treatment of SCI and provided a theoretical basis for the development of new methods and drugs for treating SCI.

A comprehensive survey of dimensionality reduction and clustering methods for single-cell and spatial transcriptomics data.

In recent years, the application of single-cell transcriptomics and spatial transcriptomics analysis techniques has become increasingly widespread. Whether dealing with single-cell transcriptomic or spatial transcriptomic data, dimensionality reduction and clustering are indispensable. Both single-cell and spatial transcriptomic data are often high-dimensional, making the analysis and visualization of such data challenging. Through dimensionality reduction, it becomes possible to visualize the data in a lower-dimensional space, allowing for the observation of relationships and differences between cell subpopulations. Clustering enables the grouping of similar cells into the same cluster, aiding in the identification of distinct cell subpopulations and revealing cellular diversity, providing guidance for downstream analyses. In this review, we systematically summarized the most widely recognized algorithms employed for the dimensionality reduction and clustering analysis of single-cell transcriptomic and spatial transcriptomic data. This endeavor provides valuable insights and ideas that can contribute to the development of novel tools in this rapidly evolving field.

Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most frequent leukemia in adults with a high mortality rate. Current diagnostic criteria and selections of therapeutic strategies are generally based on gene mutations and cytogenetic abnormalities. Chemotherapy, targeted therapies, and hematopoietic stem cell transplantation (HSCT) are the major therapeutic strategies for AML. Two dilemmas in the clinical management of AML are related to its poor prognosis. One is the inaccurate risk stratification at diagnosis, leading to incorrect treatment selections. The other is the frequent resistance to chemotherapy and/or targeted therapies. Genomic features have been the focus of AML studies. However, the DNA-level aberrations do not always predict the expression levels of genes and proteins and the latter is more closely linked to disease phenotypes. With the development of high-throughput sequencing and mass spectrometry technologies, studying downstream effectors including RNA, proteins, and metabolites becomes possible. Transcriptomics can reveal gene expression and regulatory networks, proteomics can discover protein expression and signaling pathways intimately associated with the disease, and metabolomics can reflect precise changes in metabolites during disease progression. Moreover, omics profiling at the single-cell level enables studying cellular components and hierarchies of the AML microenvironment. The abundance of data from different omics layers enables the better risk stratification of AML by identifying prognosis-related biomarkers, and has the prospective application in identifying drug targets, therefore potentially discovering solutions to the two dilemmas. In this review, we summarize the existing AML studies using omics methods, both separately and combined, covering research fields of disease diagnosis, risk stratification, prognosis prediction, chemotherapy, as well as targeted therapy. Finally, we discuss the directions and challenges in the application of multi-omics in precision medicine of AML. Our review may inspire both omics researchers and clinical physicians to study AML from a different angle.