Upregulation of circ_0076684 in osteosarcoma facilitates malignant processes by mediating miRNAs/CUX1.

Circular RNAs (circRNAs) are a newly appreciated type of endogenous noncoding RNAs that play vital roles in the development of various human cancers, including osteosarcoma (OS). In this study, we investigated three circRNAs (circ_0076684, circ_0003563, circ_0076691) from the RUNX Family Transcription Factor 2 (RUNX2) gene locus in OS. We found that the expression of circ_0076684, circ_0003563, circ_0076691, and RUNX2 mRNA is upregulated in OS, which is a consequence of CBX4-mediated transcriptional activation. Among these three RUNX2-circRNAs, only circ_0076684 is significantly associated with the clinical features and prognosis of OS patients. Functional experiments indicate that circ_0076684 promotes OS progression in vitro and in vivo. Circ_0076684 acts as a sponge for miR-370-3p, miR-140-3p, and miR-193a-5p, raising Cut Like Homeobox 1 (CUX1) expression by sponging these three miRNAs. Furthermore, we presented that circ_0076684 facilitates OS progression via CUX1. In conclusion, this study found that the expression of three circRNAs and RUNX2 mRNA from the RUNX2 gene locus is significantly upregulated in OS, as a result of CBX4-mediated transcriptional activation. Circ_0076684 raises CUX1 expression by sponging miR-370-3p, miR-140-3p, and miR-193a-5p, and facilitates OS progression via CUX1.

Paradoxical herniation associated with hyperbaric oxygen therapy after decompressive craniectomy: A case report.

BACKGROUND: Whether hyperbaric oxygen therapy (HBOT) can cause paradoxical herniation is still unclear. CASE SUMMARY: A 65-year-old patient who was comatose due to brain trauma underwent decompressive craniotomy and gradually regained consciousness after surgery. HBOT was administered 22 d after surgery due to speech impairment. Paradoxical herniation appeared on the second day after treatment, and the patient's condition worsened after receiving mannitol treatment at the rehabilitation hospital. After timely skull repair, the paradoxical herniation was resolved, and the patient regained consciousness and had a good recovery as observed at the follow-up visit. CONCLUSION: Paradoxical herniation is rare and may be caused by HBOT. However, the underlying mechanism is unknown, and the understanding of this phenomenon is insufficient. The use of mannitol may worsen this condition. Timely skull repair can treat paradoxical herniation and prevent serious complications.

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma.

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

Relationship between the microenvironment and survival in kidney transplantation: a bibliometric analysis from 2013 to 2023.

Background: Kidney transplantation is considered the most effective treatment for end-stage renal failure. Recent studies have shown that the significance of the immune microenvironment after kidney transplantation in determining prognosis of patients. Therefore, this study aimed to conduct a bibliometric analysis to provide an overview of the knowledge structure and research trends regarding the immune microenvironment and survival in kidney transplantation. Methods: Our search included relevant publications from 2013 to 2023 retrieved from the Web of Science core repository and finally included 865 articles. To perform the bibliometric analysis, we utilized tools such as VOSviewer, CiteSpace, and the R package "bibliometrix". The analysis focused on various aspects, including country, author, year, topic, reference, and keyword clustering. Results: Based on the inclusion criteria, a total of 865 articles were found, with a trend of steady increase. China and the United States were the countries with the most publications. Nanjing Medical University was the most productive institution. High-frequency keywords were clustered into 6 areas, including kidney transplantation, transforming growth factor ß, macrophage, antibody-mediated rejection, necrosis factor alpha, and dysfunction. Antibody mediated rejection (2019-2023) was the main area of research in recent years. Conclusion: This groundbreaking bibliometric study comprehensively summarizes the research trends and advances related to the immune microenvironment and survival after kidney transplantation. It identifies recent frontiers of research and highlights promising directions for future studies, potentially offering fresh perspectives to scholars in the field.

Deep learning assists detection of esophageal cancer and precursor lesions in a prospective, randomized controlled study.

Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.

Building Uniformly Structured Polymer Memristors via a 2D Conjugation Strategy for Neuromorphic Computing.

Polymer memristors represent a highly promising avenue for the advancement of next-generation computing systems. However, the intrinsic structural heterogeneity characteristic of most polymers often results in organic polymer memristors displaying erratic resistive switching phenomena, which in turn lead to diminished production yields and compromised reliability. In this study, a 2D conjugated polymer, named PBDTT-BPQTPA, is synthesized by integrating the coplanar bis(thiophene)-4,8-dihydrobenzo[1,2-b:4,5-b]dithiophene (BDTT) as an electron-donating unit with a quinoxaline derivative serving as an electron-accepting unit. The incorporation of triphenylamine groups at the quinoxaline termini significantly enhances the polymer's conjugation and planarity, thereby facilitating more efficient charge transport. The fabricated polymer memristor with the structure of Al/PBDTT-BPQTPA/ITO exhibits typical non-volatile resistive switching behavior under high voltage conditions, along with history-dependent memristive properties at lower voltages. The unique memristive behavior of the device enables the simulation of synaptic enhancement/inhibition, learning algorithms, and memory operations. Additionally, the memristor demonstrates its capability for executing logical operations and handling decimal calculations. This study offers a promising and innovative approach for the development of artificial neuromorphic computing systems.

Hollow Layered Iron-Based Prussian Blue Cathode with Reduced Defects for High-Performance Sodium-Ion Batteries.

Fe-based Prussian blue (Fe-PB) analogues have emerged as promising cathode materials for sodium-ion batteries, owing to their cost-effectiveness, high theoretical capacity, and environmental friendliness. However, their practical application is hindered by [Fe(CN)6] defects, negatively impacting capacity and cycle stability. This work reports a hollow layered Fe-PB composite material using 1,3,5-benzenetricarboxylic acid (BTA) as a chelating and etching agent by the hydrothermal method. Compared to benzoic acid, our approach significantly reduces defects and enhances the yield of Fe-PB. Notably, the hollow layered structure shortens the diffusion path of sodium ions, enhances the activity of low-spin Fe in the Fe-PB lattice, and mitigates volume changes during Na-ion insertion/extraction into/from Fe-PB. As a sodium-ion battery cathode, this hollow layered Fe-PB exhibits an impressive initial capacity of 95.9 mAh g-1 at a high current density of 1 A g-1. Even after 500 cycles, it still maintains a considerable discharge capacity of 73.1 mAh g-1, showing a significantly lower capacity decay rate (0.048%) compared to the control sample (0.089%). Moreover, the full cell with BTA-PB-1.6 as the cathode and HC as the anode provides a considerable energy density of 312.2 Wh kg-1 at a power density of 291.0 W kg-1. This research not only enhances the Na storage performance of Fe-PB but also increases the yield of products obtained by hydrothermal methods, providing some technical reference for the production of PB materials using the low-yield hydrothermal method.

Naoxueshu Oral Liquid Accelerates Post-Craniotomy Hematoma Absorption in Patients: An Open-Label, Multicenter, and Randomized Controlled Trial.

OBJECTIVE: To investigate whether Naoxueshu Oral Liquid (NXS) could promote hematoma absorption in post-craniotomy hematoma (PCH) patients. METHODS: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18-80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS (10 mL thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage (ICH). RESULTS: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients (60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set (FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median (Q1, Q3): 85% (71%, 97%) vs. 76% (53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set (P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH (all P<0.05). CONCLUSIONS: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics. (Registration No. ChiCTR1800017981).

Calculation method of spherically expanding flame propagation radius to consider ignition electrode effects.

Ignition electrodes have an immense impact on the accurate measurement of the flame propagation spherical radius. In this study, a flame-radius calculation method is designed. The method is able to eliminate effects due to the ignition electrodes. The adaptability and optimization effects of the proposed method are analyzed. The results show that the ratio of the angle is affected by the ignition electrodes under the Han II method. There are three obvious divisions include a high-value area, a sharp-variation area, and a mild-variation area. The ratio of the angle affected by the ignition electrodes is only applicable to the mild-variation region when the flame presents respective convex and concave distributions. For these distributions, the increment rate of the mean radius is 0.4-0.85% and 0.42-3.19%. The reduced rate of the standard deviation of the radius extraction value is 11.91-22.1% and 5.13-17.99%, and the reduced rate of the radius extraction value range is 20.32-39.51% and 0.32-8.09%.

Co-culture of RhoA-overexpressed Microtia Chondrocytes and Adipose-Derived Stem Cells in the Construction of Tissue-engineered Ear-shaped Cartilage.

Microtia is a congenital auricle dysplasia with a high incidence and tissue engineering technology provides a promising strategy to reconstruct auricles. We previously described that the engineered cartilage constructed from microtia chondrocytes exhibited inferior levels of biochemical and biomechanical properties, which was proposed to be resulted from the decreased migration ability of microtia chondrocytes. In the current study, we found that Rho GTPase members were deficient in microtia chondrocytes. By overexpressing RhoA, Rac1 and CDC42, respectively, we further demonstrated that RhoA took great responsibility for the decreased migration ability of microtia chondrocytes. Moreover, we constructed PGA/PLA scaffold-based cartilages to verify the chondrogenic ability of RhoA overexpressed microtia chondrocytes, and the results showed that overexpressing RhoA was of limited help to improve the quality of microtia chondrocyte engineered cartilage. However, co-culture of ADSCs significantly improved the biochemical and biomechanical property of engineered cartilage. Especially, co-culture of RhoA overexpressed microtia chondrocytes and ADSCs produced an excellent effect on the wet weight, cartilage-specific extracellular matrix and biomechanical property of engineered cartilage. Furthermore, we presented that co-culture of RhoA overexpressed microtia chondrocytes and ADSCs combined with human ear-shaped PGA/PLA scaffold and titanium alloy stent fabricated by CAD/CAM and 3D printing technology effectively constructed and maintained auricle structure in vivo. Collectively, our results provide evidence for the essential role of RhoA in microtia chondrocytes and a developed strategy for the construction of patient-specific tissue-engineered auricular cartilage.

Identification, heterologous expression and characterization of a new unspecific peroxygenase from Marasmius fiardii PR-910.

Unspecific peroxygenases (UPOs) are glycosylated enzymes that provide an efficient method for oxyfunctionalizing a variety of substrates using only hydrogen peroxide (H2O2) as the oxygen donor. However, their poor heterologous expression has hindered their practical application. Here, a novel UPO from Marasmius fiardii PR910 (MfiUPO) was identified and heterologously expressed in Pichia pastoris. By employing a two-copy expression cassette, the protein titer reached 1.18 g L-1 in a 5 L bioreactor, marking the highest record. The glycoprotein rMfiUPO exhibited a smeared band in the 40 to 55 kDa range and demonstrated hydroxylation, epoxidation and alcohol oxidation. Moreover, the peroxidative activity was enhanced by 150% after exposure to 50% (v/v) acetone for 40 h. A semi-preparative production of 4-OH-ß-ionone on a 100 mL scale resulted in a 54.2% isolated yield with 95% purity. With its high expression level, rMfiUPO is a promising candidate as an excellent parental template for enhancing desirable traits such as increased stability and selectivity through directed evolution, thereby meeting the necessary criteria for practical application.

Machine learning-based identification of colorectal advanced adenoma using clinical and laboratory data: a phase I exploratory study in accordance with updated World Endoscopy Organization guidelines for noninvasive colorectal cancer screening tests.

Objective: The recent World Endoscopy Organization (WEO) guidelines now recognize precursor lesions of colorectal cancer (CRC) as legitimate screening targets. However, an optimal screening method for detecting advanced adenoma (AA), a significant precursor lesion, remains elusive. Methods: We employed five machine learning methods, using clinical and laboratory data, to develop and validate a diagnostic model for identifying patients with AA (569 AAs vs. 3228 controls with normal colonoscopy). The best-performing model was selected based on sensitivity and specificity assessments. Its performance in recognizing adenoma-carcinoma sequence was evaluated in line with guidelines, and adjustable thresholds were established. For comparison, the Fecal Occult Blood Test (FOBT) was also selected. Results: The XGBoost model demonstrated superior performance in identifying AA, with a sensitivity of 70.8% and a specificity of 83.4%. It successfully detected 42.7% of non-advanced adenoma (NAA) and 80.1% of CRC. The model-transformed risk assessment scale provided diagnostic performance at different positivity thresholds. Compared to FOBT, the XGBoost model better identified AA and NAA, however, was less effective in CRC. Conclusion: The XGBoost model, compared to FOBT, offers improved accuracy in identifying AA patients. While it may not meet the recommendations of some organizations, it provides value for individuals who are unable to use FOBT for various reasons.

Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction.

Incorporation of a trifluoromethyl group with 1,2,3-triazoles motifs was described. We explored a click reaction approach for regioselective synthesis of 1-susbstituted-4-trifluoromethyl-1,2,3-triazoles in which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reacts with commercial 2-bromo-3,3,3-trifluoropropene (BTP) to form 3,3,3-trifloropropyne (TFP) in situ. Arising from merits associated with the availability and stability of BTP, and the high efficiencies of CuI/1,10-Phenanthroline (Phen)-catalyzed cycloaddition reactions of azides with alkynes, this readily performed click process takes place to form the target 1,2,3-triazoles in high yields, and with a wide azide substrate scope. The potential value of this protocol was demonstrated by its application to a gram-scale reaction.

YY1-induced lncRNA00511 promotes melanoma progression via the miR-150-5p/ADAM19 axis.

Increasing evidence indicates that long noncoding RNAs (lncRNAs) are therapeutic targets and key regulators of tumors development and progression, including melanoma. Long intergenic non-protein-coding RNA 511 (LINC00511) has been demonstrated as an oncogenic molecule in breast, stomach, colorectal, and lung cancers. However, the precise role and functional mechanisms of LINC00511 in melanoma remain unknown. This study confirmed that LINC00511 was highly expressed in melanoma cells (A375 and SK-Mel-28 cells) and tissues, knockdown of LINC00511 could inhibit melanoma cell migration and invasion, as well as the growth of subcutaneous tumor xenografts in vivo. By using Chromatin immunoprecipitation (ChIP) assay, it was demonstrated that the transcription factor Yin Yang 1 (YY1) is capable of binding to the LINC00511 promoter and enhancing its expression in cis. Further mechanistic investigation showed that LINC00511 was mainly enriched in the cytoplasm of melanoma cells and interacted directly with microRNA-150-5p (miR-150-5p). Consistently, the knockdown of miR-150-5p could recover the effects of LINC00511 knockdown on melanoma cells. Furthermore, ADAM metallopeptidase domain expression 19 (ADAM19) was identified as a downstream target of miR-150-5p, and overexpression of ADAM19 could promote melanoma cell proliferation. Rescue assays indicated that LINC00511 acted as a competing endogenous RNA (ceRNA) to sponge miR-150-5p and increase the expression of ADAM19, thereby activating the PI3K/AKT pathway. In summary, we identified LINC00511 as an oncogenic lncRNA in melanoma and defined the LINC00511/miR-150-5p/ADAM19 axis, which might be considered a potential therapeutic target and novel molecular mechanism the treatment of patients with melanoma.

Identification and effective regulation of scarb1 gene involved in pigmentation change in autotetraploid Carassius auratus.

The autotetraploid Carassius auratus (4nRR, 4 n=200, RRRR) is derived from whole-genome duplication of Carassius auratus red var. (RCC, 2 n=100, RR). In the current study, we demonstrated that chromatophores and pigment changes directly caused the coloration and variation of 4nRR skin (red in RCC, brownish-yellow in 4nRR). To further explore the molecular mechanisms underlying coloration formation and variation in 4nRR, we performed transcriptome profiling and molecular functional verification in RCC and 4nRR. Results revealed that scarb1, associated with carotenoid metabolism, underwent significant down-regulation in 4nRR. Efficient editing of this candidate pigment gene provided clear evidence of its significant role in RCC coloration. Subsequently, we identified four divergent scarb1 homeologs in 4nRR: two original scarb1 homeologs from RCC and two duplicated ones. Notably, three of these homeologs possessed two highly conserved alleles, exhibiting biased and allele-specific expression in the skin. Remarkably, after precise editing of both the original and duplicated scarb1 homeologs and/or alleles, 4nRR individuals, whether singly or multiply mutated, displayed a transition from brownish-yellow skin to a cyan-gray phenotype. Concurrently, the proportional areas of the cyan-gray regions displayed a gene-dose correlation. These findings illustrate the subfunctionalization of duplicated scarb1, with all scarb1 genes synergistically and equally contributing to the pigmentation of 4nRR. This is the first report concerning the functional differentiation of duplicated homeologs in an autopolyploid fish, substantially enriching our understanding of coloration formation and change within this group of organisms.

Interleukin-6 classic and trans-signaling utilize glucose metabolism reprogramming to achieve anti- or pro-inflammatory effects.

Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 classic and trans-signaling, respectively. Differences in the downstream signaling mechanism between IL-6 classic and trans-signaling have not been identified. Here, we report that IL-6 activates glycolysis to regulate the inflammatory response. IL-6 regulates glucose metabolism by forming a complex containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 signaling promotes STAT3 translocation into mitochondria to interact with pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase α (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas IL-6 trans-signaling promotes the differentiation of Th17 cells via the SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 trans-signaling generates pro-inflammatory functions by shifting energy metabolism to anaerobic glycolysis.

Diagnosis and treatment of recurrent syncope in a middle-aged women.

A 50-year-old female patient, presented with repeated syncope for more than 2 years. Prior assessments were conducted at different hospitals, but no definite abnormalities were found. The patient's fear and anxiety about possible future attacks were escalating. Through a Head-up tilt test, the cause was finally identified as vasovagal syncope. Following a 5-min administration of nitroglycerin, the patient reported palpitations, nausea, and deep, rapid breathing. The electrocardiogram initially showed a first-degree atrioventricular block, progressing swiftly to a second-degree type I atrioventricular block-high atrioventricular block. Immediate intervention was undertaken, but blood pressure was not instantly ascertainable, coinciding with an abrupt loss of consciousness. Subsequent electrocardiographic findings included paroxysmal third-degree atrioventricular block, sinus arrest, and complete cardiac arrest, prompting the initiation of external cardiac compressions. The longest recorded ventricular arrest approximated 15 s, with sinus rhythm resuming post 10 s of cardiac compressions and the patient regaining consciousness. The patient underwent vagal ablation and no longer experienced syncope.

Evaluation of weak genotoxicity of hydroxychloroquine in human TK6 cells.

Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 µM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 µM for CQ and 16.3 µM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs.

Gastrointestinal manifestations of critical ill heatstroke patients and their associations with outcomes: A multicentre, retrospective, observational study.

BACKGROUND: Extreme heat exposure is a growing health problem, and the effects of heat on the gastrointestinal (GI) tract is unknown. This study aimed to assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes. AIM: To assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes. METHODS: Patients admitted to the intensive care unit (ICU) due to heatstroke were included from 83 centres. Patient history, laboratory results, and clinically relevant outcomes were recorded at ICU admission and daily until up to day 15, ICU discharge, or death. GI symptoms, including nausea/vomiting, diarrhoea, flatulence, and bloody stools, were recorded. The characteristics of patients with heatstroke concomitant with GI symptoms were described. Multivariable regression analyses were performed to determine significant predictors of GI symptoms. RESULTS: A total of 713 patients were included in the final analysis, of whom 132 (18.5%) patients had at least one GI symptom during their ICU stay, while 26 (3.6%) suffered from more than one symptom. Patients with GI symptoms had a significantly higher ICU stay compared with those without. The mortality of patients who had two or more GI symptoms simultaneously was significantly higher than that in those with one GI symptom. Multivariable logistic regression analysis revealed that older patients with a lower GCS score on admission were more likely to experience GI symptoms. CONCLUSION: The GI manifestations of heatstroke are common and appear to impact clinically relevant hospitalization outcomes.