Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) are approved to treat colorectal cancer (CRC) with mismatch-repair gene deficiency, but the response rate remains low. Value of current biomarkers to predict CRC patients' response to ICIs is unclear due to heterogeneous study designs and small sample sizes. Here, we aim to assess and quantify the magnitude of multiple biomarkers for predicting the efficacy of ICIs in CRC patients. We systematically searched MEDLINE, Embase, the Cochrane Library, and Web of Science databases (to June 2023) for clinical studies examining biomarkers for efficacy of ICIs in CRC patients. Random-effect models were performed for meta-analysis. We pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) for biomarkers predicting response rate and survival. 36 studies with 1867 patients were included in systematic review. We found that a lower pre-treatment blood neutrophil-to-lymphocyte ratio (n=4, HR 0.37, 95%CI 0.21-0.67) predicts good prognosis, higher tumor mutation burden (n=10, OR 4.83, 95%CI 2.16-10.78) predicts response to ICIs, and liver metastasis (n=16, OR 0.32, 95%CI 0.16-0.63) indicates resistance to ICIs, especially when combined with VEGFR inhibitors. But the predictive value of tumor PD-L1 expression (n=9, OR 1.01, 95%CI 0.48-2.14) was insignificant in CRC. Blood neutrophil-to-lymphocyte ratio, tumor mutation burden, and liver metastasis, but not tumor PD-L1 expression, function as significant biomarkers to predict efficacy of ICIs in CRC patients. These findings help stratify CRC patients suitable for ICI treatments, improving efficacy of immunotherapy through precise patient management. (PROSPERO, CRD42022346716).

Designing a highly efficient type III polyketide whole-cell catalyst with minimized byproduct formation.

BACKGROUND: Polyketide synthases (PKSs) are classified into three types based on their enzyme structures. Among them, type III PKSs, catalyzing the iterative condensation of malonyl-coenzyme A (CoA) with a CoA-linked starter molecule, are important synthases of valuable natural products. However, low efficiency and byproducts formation often limit their applications in recombinant overproduction. RESULTS: Herein, a rapid growth selection system is designed based on the accumulation and derepression of toxic acyl-CoA starter molecule intermediate products, which could be potentially applicable to most type III polyketides biosynthesis. This approach is validated by engineering both chalcone synthases (CHS) and host cell genome, to improve naringenin productions in Escherichia coli. From directed evolution of key enzyme CHS, beneficial mutant with ~ threefold improvement in capability of naringenin biosynthesis was selected and characterized. From directed genome evolution, effect of thioesterases on CHS catalysis is first discovered, expanding our understanding of byproduct formation mechanism in type III PKSs. Taken together, a whole-cell catalyst producing 1082 mg L-1 naringenin in flask with E value (evaluating product specificity) improved from 50.1% to 96.7% is obtained. CONCLUSIONS: The growth selection system has greatly contributed to both enhanced activity and discovery of byproduct formation mechanism in CHS. This research provides new insights in the catalytic mechanisms of CHS and sheds light on engineering highly efficient heterologous bio-factories to produce naringenin, and potentially more high-value type III polyketides, with minimized byproducts formation.

Systemic Lupus Erythematosus Complicated with Mycobacterium Leprae Infection: a Rare Case Report.

BACKGROUND: In December 2023, our hospital confirmed a case of systemic lupus erythematosus complicated with Mycobacterium leprae infection. The patient has extensive patchy erythema on the back and face, with obvious itching. There are multiple subcutaneous masses on both hands, some of which are accompanied by tenderness, wave sensation, and other symptoms. The patient's mother has a history of leprosy and close contact with the patient. The patient tested positive for syphilis antibodies 2 years ago and did not receive formal treatment. There is no other history of chronic illness. METHODS: Under local anesthesia, the left hand skin lesion was excised, followed by tissue pathological biopsy, acid-fast staining, mNGS, and serum Treponema pallidum antibody detection. RESULTS: Pathological biopsy results: A large number of foam-like histiocytes, lymphocytes, and plasma cells were mainly found in the superficial and deep layers of the dermis, as well as around the blood vessels and sweat glands in the subcutaneous fat. Cellulose-like degeneration is seen in some blood vessel walls. Tissue acid-fast staining: positive, tissue mNGS detection: Mycobacterium leprae. CLINICAL DIAGNOSIS: 1. Borderline leprosy, 2. Subacute cutaneous lupus erythematosus. Treat with methylprednisolone 32 mg qd po + aluminum magnesium suspension 15 mL tid po + calcium carbonate D3 tablets 0.6 g qd po + rifampicin 450 mg qd po + dapsone 100 mg qd. After 10 days of treatment, the patient improved and was discharged from the hospital. CONCLUSIONS: Mycobacterium leprae infection occurs during SLE treatment and is often difficult to distinguish from skin symptoms caused by SLE. In the clinical treatment of infectious diseases, the effect of conventional anti-bacterial drugs is not good. The auxiliary examination indicates severe infection and the routine culture is negative. The possibility of special pathogen infection should be considered in combination with the medical history. With the popularity of new detection methods such as mNGS, the importance of traditional smear detection methods cannot be ignored.

Thrombocytopenia in SFTS due to platelets with altered function undergoing cell death pathways.

BACKGROUND: Thrombocytopenia is the major clinical feature associated with the severity of SFTS, but the mechanism by which it occurs remains unclear. METHODS: RNA transcriptome analyses were performed on platelets purified from SFTS patients and SFTSV-infected mice. The functions of differentially expressed genes (DEGs) in the platelets were characterized. ELISA, flow cytometry, and qRT-PCR were used to measure the levels of platelet activation, SFTSV infection in platelets, formation of neutrophil extracellular traps (NETs), transcription of DEGs and percent of platelets undergoing cell death. RESULTS: Enhanced neutrophil activation and interferon (IFN) signaling involved in the viral life cycle were common platelet responses in SFTS, which may consume increasing numbers of platelets. Other functional changes may be associated with different outcomes of SFTS. SFTSV infection led to platelet destruction by pyroptosis, apoptosis, necroptosis, and autophagy. In contrast to SFTS patients, platelets in SFTSV-infected mice mainly play a role in adaptive immunity, and platelet death was not as severe as in humans. CONCLUSIONS: The altered functions of platelets, such as mediating leukocyte activation and undergoing cell death, contribute to thrombocytopenia in SFTS patients. The different mechanisms of thrombocytopenia in mice, suggest that platelet functions should be considered in experimental animal models.

Combined use of chemical dust suppressant and herbaceous plants for tailings dust control.

Tailings dust can negatively affect the surrounding environment and communities because the tailings are vulnerable to wind erosion. In this study, the effects of halides (sodium chloride [NaCl], calcium chloride [CaCl2], and magnesium chloride hexahydrate [MgCl2·6H2O]), and polymer materials (polyacrylamide [PAM], polyvinyl alcohol [PVA], and calcium lignosulfonate [LS]) were investigated for the stabilization of tailings for dust control. Erect milkvetch (Astragalus adsurgens), ryegrass (Lolium perenne L.), and Bermuda grass (Cynodon dactylon) were planted in the tailings and sprayed with chemical dust suppressants. The growth status of the plants and their effects on the mechanical properties of tailings were also studied. The results show that the weight loss of tailings was stabilized by halides and polymers, and decreased with increasing concentration and spraying amount of the solutions. The penetration resistance of tailings stabilized by halides and polymers increased with increasing concentration and spraying amount of the solutions. Among the halides and polymers tested, the use of CaCl2 and PAM resulted in the best control of tailings dust, respectively. CaCl2 solution reduces the adaptability of plants and therefore makes it difficult for grass seeds to germinate normally. PAM solutions are beneficial for the development of herbaceous plants. Among the three herbaceous species, ryegrass exhibited the best degree of development and was more suitable for growth in the tailings. The ryegrass plants planted in the tailings sprayed with PAM grew the best, and the root-soil complex that formed increased the shear strength of the tailings.

Prevotella copri transplantation promotes neurorehabilitation in a mouse model of traumatic brain injury.

BACKGROUND: The gut microbiota plays a critical role in regulating brain function through the microbiome-gut-brain axis (MGBA). Dysbiosis of the gut microbiota is associated with neurological impairment in Traumatic brain injury (TBI) patients. Our previous study found that TBI results in a decrease in the abundance of Prevotella copri (P. copri). P. copri has been shown to have antioxidant effects in various diseases. Meanwhile, guanosine (GUO) is a metabolite of intestinal microbiota that can alleviate oxidative stress after TBI by activating the PI3K/Akt pathway. In this study, we investigated the effect of P. copri transplantation on TBI and its relationship with GUO-PI3K/Akt pathway. METHODS: In this study, a controlled cortical impact (CCI) model was used to induce TBI in adult male C57BL/6J mice. Subsequently, P. copri was transplanted by intragastric gavage for 7 consecutive days. To investigate the effect of the GUO-PI3K/Akt pathway in P. copri transplantation therapy, guanosine (GUO) was administered 2 h after TBI for 7 consecutive days, and PI3K inhibitor (LY294002) was administered 30 min before TBI. Various techniques were used to assess the effects of these interventions, including quantitative PCR, neurological behavior tests, metabolite analysis, ELISA, Western blot analysis, immunofluorescence, Evans blue assays, transmission electron microscopy, FITC-dextran permeability assay, gastrointestinal transit assessment, and 16 S rDNA sequencing. RESULTS: P. copri abundance was significantly reduced after TBI. P. copri transplantation alleviated motor and cognitive deficits tested by the NSS, Morris's water maze and open field test. P. copri transplantation attenuated oxidative stress and blood-brain barrier damage and reduced neuronal apoptosis after TBI. In addition, P. copri transplantation resulted in the reshaping of the intestinal flora, improved gastrointestinal motility and intestinal permeability. Metabolomics and ELISA analysis revealed a significant increase in GUO levels in feces, serum and injured brain after P. copri transplantation. Furthermore, the expression of p-PI3K and p-Akt was found to be increased after P. copri transplantation and GUO treatment. Notably, PI3K inhibitor LY294002 treatment attenuated the observed improvements. CONCLUSIONS: We demonstrate for the first time that P. copri transplantation can improve GI functions and alter gut microbiota dysbiosis after TBI. Additionally, P. copri transplantation can ameliorate neurological deficits, possibly via the GUO-PI3K/Akt signaling pathway after TBI.

Identification and characterization of three monoclonal antibodies targeting the SFTSV glycoprotein and displaying a broad spectrum recognition of SFTSV-related viruses.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne viral pathogen that causes severe fever with thrombocytopenia syndrome (SFTS). The disease was initially reported in central and eastern China, then later in Japan and South Korea, with a mortality rate of 13-30%. Currently, no vaccines or effective therapeutics are available for SFTS treatment. In this study, three monoclonal antibodies (mAbs) targeting the SFTSV envelope glycoprotein Gn were obtained using the hybridoma technique. Two mAbs recognized linear epitopes and did not neutralize SFTSV, while the mAb 40C10 can effectively neutralized SFTSV of different genotypes and also the SFTSV-related Guertu virus (GTV) and Heartland virus (HRTV) by targeting a spatial epitope of Gn. Additionally, the mAb 40C10 showed therapeutic effect in mice infected with different genotypes of SFTSV strains against death by preventing the development of lesions and by promoting virus clearance in tissues. The therapeutic effect could still be observed in mice infected with SFTSV which were administered with mAb 40C10 after infection even up to 4 days. These findings enhance our understanding of SFTSV immunogenicity and provide valuable information for designing detection methods and strategies targeting SFTSV antigens. The neutralizing mAb 40C10 possesses the potential to be further developed as a therapeutic monoclonal antibody against SFTSV and SFTSV-related viruses.

High-Throughput Screening Strategy for Electrocatalysts for Selective Catalytic Oxidation of Formaldehyde to Formic Acid.

Electrocatalytic oxidation of formaldehyde (FOR) is an effective way to prevent the damage caused by formaldehyde and produce high-value products. A screening strategy of a single-layer MnO2-supported transition metal catalyst for the selective oxidation of formaldehyde to formic acid was designed by high-throughput density functional calculation. N-MnO2@Cu and MnO2@Cu are predicted to be potential FOR electrocatalysts with potential-limiting steps (PDS) of 0.008 and -0.009 eV, respectively. Electronic structure analysis of single-atom catalysts (SACs) shows that single-layer MnO2 can regulate the spin density of loaded transition metal and thus regulate the adsorption of HCHO (Ead), and Ead is volcanically distributed with the magnetic moment descriptor -|mM - mH|. In addition, the formula quantifies Ead and |mM - mH| to construct a volcano-type descriptor α describing the PDS [ΔG(*CHO)]. Other electronic and structural properties of SACs and α are used as input features for the GBR method to construct machine learning models predicting the PDS (R2 = 0.97). This study hopes to provide some insights into FOR electrocatalysts.

Roundup® induces premature senescence of mouse granulosa cells via mitochondrial ROS-triggered NLRP3 inflammasome activation.

Roundup, a glyphosate-based herbicide widely used in agriculture, has raised concerns regarding its potential impact on human health due to the detection of its residues in human urine and serum. Granulosa cells are essential for oocyte growth and follicle development. Previous research has shown that Roundup could affect steroid synthesis, increases oxidative stress, and induces apoptosis in granulosa cells. However, little is known about the effects of Roundup on NLRP3 (nucleotide binding oligomerization domain-like receptor family pyrin-containing domain protein 3) inflammasome activation and cellular senescence in granulosa cells. Here, we provided evidence that exposure to Roundup induced premature senescence in mouse granulosa cells through the activation of NLRP3 inflammasome triggered by mitochondrial ROS. Our findings demonstrated that Roundup significantly reduced the viability of granulosa cells under in vitro culture conditions. It also disrupted mitochondrial function and induced oxidative stress in these cells. Subsequent investigations showed that NLRP3 inflammasome was activated in treated granulosa cells, as evidenced by the upregulation of inflammasome-related genes and the processing of inflammatory cytokines IL-1ß and IL-1α into their mature forms. Consequently, premature cellular senescence occurred in response to the challenge posed by Roundup. Notably, direct inhibition of NLRP3 inflammasome with MCC950 does not alleviate mitochondrial damage and oxidative stress. However, supplementation of resveratrol, which has been known to attenuate mitochondrial damage and oxidative stress, effectively mitigated the inflammatory response and the expression of senescence-related markers, and prevented the senescence in granulosa cells. These results suggested that mitochondrial function and oxidative homeostasis might play pivotal roles as upstream regulators of NLRP3 inflammasome. In summary, our findings indicated that the premature senescence of granulosa cells caused by mitochondrial ROS-triggered NLRP3 inflammasome activation might contribute to the ovarian toxicity of Roundup, in addition to its known effects on steroidogenesis and apoptosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00229-0.

TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia.

BACKGROUND: White matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor-2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored. METHODS: Controlled cortical injury was induced in both wild-type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism-related genes, while western blot was conducted to validate the findings. RESULTS: TREM2 expressed highest at 3 days post-TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities. CONCLUSIONS: We demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia.

Qilong capsule prevents myocardial ischemia/reperfusion injury by inhibiting platelet activation via the platelet CD36 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qilong capsule (QC) is developed from the traditional Chinese medicine formula Buyang Huanwu Decoction, which has been clinically used to invigorate Qi and promote blood circulation to eliminate blood stasis. Myocardial ischemia‒reperfusion injury (MIRI) can be attributed to Qi deficiency and blood stasis. However, the effects of QC on MIRI remain unclear. AIM OF THE STUDY: This study aimed to investigate the protective effect and possible mechanism of QC on platelet function in MIRI rats. MATERIALS AND METHODS: The left anterior descending artery of adult Sprague‒Dawley rats was ligated for 30 min and then reperfused for 120 min with or without QC treatment. Then, the whole blood viscosity, plasma viscosity, coagulation, platelet adhesion rate, platelet aggregation, and platelet release factors were evaluated. Platelet CD36 and its downstream signaling pathway-related proteins were detected by western blotting. Furthermore, the active components of QC and the molecular mechanism by which QC regulates platelet function were assessed via molecular docking, platelet aggregation tests in vitro and BLI analysis. RESULTS: We found that QC significantly reduced the whole blood viscosity, plasma viscosity, platelet adhesion rate, and platelet aggregation induced by ADP or AA in rats with MIRI. The inhibition of platelet activation by QC was associated with reduced levels of ß-TG, PF-4, P-selectin and PAF. Mechanistically, QC effectively attenuated the expression of platelet CD36 and thus inhibited the activation of Src, ERK5, and p38. The active components of QC apparently suppressed platelet aggregation in vitro and regulated the CD36 signaling pathway. CONCLUSIONS: QC improves MIRI-induced hemorheological disorders, which might be partly attributed to the inhibition of platelet activation via CD36-mediated platelet signaling pathways.

Risk of infection with arboviruses in a healthy population in Pakistan based on seroprevalence.

Infectious diseases caused by arboviruses are a public health concern in Pakistan. However, studies on data prevalence and threats posed by arboviruses are limited. This study investigated the seroprevalence of arboviruses in a healthy population in Pakistan, including severe fever with thrombocytopenia syndrome virus (SFTSV), Crimean-Congo hemorrhagic fever virus (CCHFV), Tamdy virus (TAMV), and Karshi virus (KSIV) based on a newly established luciferase immunoprecipitation system (LIPS) assays, and Zika virus (ZIKV) by enzyme-linked immunosorbent assays (ELISA). Neutralizing activities against these arboviruses were further examined from the antibody positive samples. The results showed that the seroprevalence of SFTSV, CCHFV, TAMV, KSIV, and ZIKV was 17.37%, 7.58%, 4.41%, 1.10%, and 6.48%, respectively, and neutralizing to SFTSV (1.79%), CCHFV (2.62%), and ZIKV (0.69%) were identified, as well as to the SFTSV-related Guertu virus (GTV, 0.83%). Risk factors associated with the incidence of exposure and levels of antibody response were analyzed. Moreover, co-exposure to different arboviruses was demonstrated, as thirty-seven individuals were having antibodies against multiple viruses and thirteen showed neutralizing activity. Males, individuals aged ≤40 years, and outdoor workers had a high risk of exposure to arboviruses. All these results reveal the substantial risks of infection with arboviruses in Pakistan, and indicate the threat from co-exposure to multiple arboviruses. The findings raise the need for further epidemiologic investigation in expanded regions and populations and the necessity to improve health surveillance in Pakistan.

Artificial Biosynthetic Pathway for Efficient Synthesis of Vanillin, a Feruloyl-CoA-Derived Natural Product from Eugenol.

Eugenol, the main component of essential oil from the Syzygium aromaticum clove tree, has great potential as an alternative bioresource feedstock for biosynthesis purposes. Although eugenol degradation to ferulic acid was investigated, an efficient method for directly converting eugenol to targeted natural products has not been established. Herein we identified the inherent inhibitions by simply combining the previously reported ferulic acid biosynthetic pathway and vanillin biosynthetic pathway. To overcome this, we developed a novel biosynthetic pathway for converting eugenol into vanillin, by introducing cinnamoyl-CoA reductase (CCR), which catalyzes conversion of coniferyl aldehyde to feruloyl-CoA. This approach bypasses the need for two catalysts, namely coniferyl aldehyde dehydrogenase and feruloyl-CoA synthetase, thereby eliminating inhibition while simplifying the pathway. To further improve efficiency, we enhanced CCR catalytic efficiency via directed evolution and leveraged an artificialvanillin biosensor for high-throughput screening. Switching the cofactor preference of CCR from NADP+ to NAD+ significantly improved pathway efficiency. This newly designed pathway provides an alternative strategy for efficiently biosynthesizing feruloyl-CoA-derived natural products using eugenol.

Engineering and application of LacI mutants with stringent expressions.

Optimal transcriptional regulatory circuits are expected to exhibit stringent control, maintaining silence in the absence of inducers while exhibiting a broad induction dynamic range upon the addition of effectors. In the Plac /LacI pair, the promoter of the lac operon in Escherichia coli is characterized by its leakiness, attributed to the moderate affinity of LacI for its operator target. In response to this limitation, the LacI regulatory protein underwent engineering to enhance its regulatory properties. The M7 mutant, carrying I79T and N246S mutations, resulted in the lac promoter displaying approximately 95% less leaky expression and a broader induction dynamic range compared to the wild-type LacI. An in-depth analysis of each mutation revealed distinct regulatory profiles. In contrast to the wild-type LacI, the M7 mutant exhibited a tighter binding to the operator sequence, as evidenced by surface plasmon resonance studies. Leveraging the capabilities of the M7 mutant, a high-value sugar biosensor was constructed. This biosensor facilitated the selection of mutant galactosidases with approximately a seven-fold improvement in specific activity for transgalactosylation. Consequently, this advancement enabled enhanced biosynthesis of galacto-oligosaccharides (GOS).

In Vivo Pharmacokinetic Study of Polygonatum cyrtonema Polysaccharide DPC1 after Oral and Intraperitoneal Administration.

(1) Background: Polygonatum cyrtonema is a medicinal plant, and its polysaccharides are used for immunomodulation and the treatment of hyperglycemia. Investigation of the tissue distribution and pharmacokinetics of P. cyrtonema polysaccharide can further elucidate its pharmacological mechanisms. (2) Methods: A fluorescence-labeling approach using rhodamine B (RhB) as a fluorescent molecular probe was used for the quantitative assessment of the polysaccharide from dried P. cyrtonema (DPC1) samples, and the pharmacokinetics and tissue distribution of DPC1 were evaluated in mice after intraperitoneal or oral administration. (3) Results: DPC1 was successfully labeled with RhB, showing degrees of fluorescence labeling at 0.453% and 0.568% as determined by the ultraviolet and enzyme marker methods, respectively. DPC1-RhB was rapidly absorbed into the bloodstream after oral and intraperitoneal administration. Pharmacokinetic characteristics showed that oral administration and intraperitoneal administration were consistent with the features of a two-compartment model. (4) Conclusion: After administration, DPC1-RhB was primarily distributed in the tissues of the heart, spleen, and lung, indicating that the drug has a targeted effect on these tissues. Overall, the findings provide a comprehensive reference for the in vivo distribution of DPC1, together with a foundation for further elucidation of its pharmacological mechanisms and the development and application of DPC1 formulations.

Hypoxic Exosomal circPLEKHM1-Mediated Crosstalk between Tumor Cells and Macrophages Drives Lung Cancer Metastasis.

Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell-derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non-small cell lung cancer (NSCLC) cells, a hypoxia-induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1-eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1-targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA-mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.

Predictive value of hyponatremia for short-term mortality in supratentorial spontaneous intracerebral hemorrhage: a single center study.

Background: Hyponatremia is a common electrolyte disturbance in patients with neurological disease; however, its predictive role for outcome in patients with supratentorial spontaneous intracerebral hemorrhage (sICH) is controversial. This study aims to explore the association between hyponatremia within 7 days after bleeding and 90-day mortality in patients with supratentorial sICH. Methods: A retrospective analysis was conducted at our institution. Patients with sICH meeting the inclusion criteria were enrolled in this study. Multivariate regression analyses were performed to determine the predictive value of hyponatremia (serum sodium <135 mmol/L) for 90-day mortality and functional outcome. Subgroup analysis was performed based on the degree and duration of hyponatremia and therapeutic strategies. The Spearman correlation test was performed to explore the relationship between hyponatremia severity and duration with variables in a multivariate regression model. Kaplan-Meier curve was depicted to reveal the relationship between hyponatremia and mortality. The receiver operating characteristic (ROC) curve was plotted to show the diagnostic effect of the minimum concentration of serum sodium (sodiummin) on 90-day mortality. Results: A total of 960 patients were enrolled, 19.6% (188) of whom were patients with hyponatremia and 26.0% (250) had 90-day mortality. The incidence of hyponatremia was roughly 2.5 times in non-survivors compared with survivors (34.8% vs. 14.2%). Multivariate regression analysis revealed that hyponatremia was the independent predictor of 90-day mortality (OR 2.763, 95%CI 1.836-4.157) and adverse outcome (OR 3.579, 95%CI 2.332-6.780). Subgroup analysis indicated an increased trend in mortality risk with both duration (more or less than 48 h) and severity of hyponatremia (mild, moderate, and severe) and confirmed the predictive value of hyponatremia for mortality in patients undergoing surgical intervention (external ventricular drainage, craniotomy, and decompressive craniectomy; all p < 0.05). The Spearman correlation test indicated no moderate or strong relationship between hyponatremia severity and duration with other variables in the multivariate model (all |rs| < 0.4). The ROC curve suggested the moderate diagnostic performance of sodiummin for mortality in both general patients and subgroups of therapeutic method patients (AUC from 0.6475 to 0.7384). Conclusion: Hyponatremia occurring in the first 7 days after bleeding is an independent predictor of 90-day morality and adverse outcome. Rigorous electrolyte scrutiny in patients treated surgically is required.

Connectome-based predictive modeling of Internet addiction symptomatology.

Internet addiction symptomatology (IAS) is characterized by persistent and involuntary patterns of compulsive Internet use, leading to significant impairments in both physical and mental well-being. Here, a connectome-based predictive modeling approach was applied to decode IAS from whole-brain resting-state functional connectivity in healthy population. The findings showed that IAS could be predicted by the functional connectivity between prefrontal cortex with the cerebellum and limbic lobe and connections of the occipital lobe with the limbic lobe and insula lobe. The identified edges associated with IAS exhibit generalizability in predicting IAS within an independent sample. Furthermore, we found that the unique contributing network, which predicted IAS in contrast to the prediction networks of alcohol use disorder symptomatology (the range of symptoms and behaviors associated with alcohol use disorder), prominently comprised connections involving the occipital lobe and other lobes. The current data-driven approach provides the first evidence of the predictive brain features of IAS based on the organization of intrinsic brain networks, thus advancing our understanding of the neurobiological basis of Internet addiction disorder (IAD) susceptibility, and may have implications for the timely intervention of people potentially at risk of IAD.

Dual antiplatelet therapy after intravenous thrombolysis for patients with minor ischemic stroke：A meta-analysis.

OBJECTIVE: Intravenous thrombolysis (IVT) has been shown to effectively decrease both the disability rate and mortality associated with acute ischemic stroke, however, there is also a risk of vascular re-occlusion. Antiplatelet therapy can mitigate this risk. Nevertheless, there are no relevant guidelines recommending whether the administration of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel can be performed following thrombolysis. The aim of this study was to conduct a meta-analysis utilizing multiple studies in order to assess the effectiveness and safety of DAPT after IVT in cases of acute mild ischemic stroke (AMIS). METHODS: A comprehensive search on English literature published was performed on databases including PubMed, Embase, Web of Science, and Cochrane up until September 1, 2023. All cases were ischemic stroke patients who underwent IVT within a 4.5-hour timeframe and had a National Institutes of Health Stroke Scale (NIHSS) score of ≤5 (or 3) upon admission. The primary efficacy endpoint is the 90-day Modified Rankin Scale (mRS) Score (MRS score 0-1), while the primary safety endpoint encompassed the occurrence of symptomatic intracranial hemorrhage (SICH) and 90-day mortality. The study's secondary objective is the recurrence of any type of stroke (hemorrhagic and ischemic) within a 90-day period. The included studies underwent an evaluation of bias risk using the Newcastle Ottawa scale. Risk ratios (RRs) and CIs were calculated using a random effects model, and the findings and heterogeneity among the included studies were visually presented on a forest plot. (There was a protocol registration (PROSPERO):). RESULTS: Out of the 1081 studies that were obtained, only 3 met the criteria and were included in the meta-analysis (657 patients in total). The findings indicate that, there was a significant difference in the mRS of 0-1 between single antiplatelet therapy (SAPT) with only aspirin or clopidogrel and DAPT with aspirin and clopidogrel ((RR,1.11[95%CI,0.99-1.24];P=0.07;I2=55%), and no significant difference in stroke recurrence after 90 days or 1 year ((RR,0.94[95%CI,0.41-2.16];P=0.89;I2=30%); Regarding safety evaluation, the results showed no significant difference in the SICH (RR,0.65[95%CI,0.11-3.97];P=0.64;I2=0%) and the incidence of mortality (RR,0.97[95%CI,0.19-4.96];P=0.97;I2=0%) between the two groups. CONCLUSIONS: For patients with acute mild ischemic stroke (AMIS), in conjunction with DAPT after IVT can improve the 90-day prognosis, without increasing the risk of intracranial hemorrhage and 90-day mortality. However, it cannot reduce the risk of stroke recurrence.