VIC Regimen (Vemurafenib/Irinotecan/Cetuximab) Versus Bevacizumab Plus Chemotherapy as First-Line Treatment for BRAF V600E-Mutated Unresectable or Metastatic Colorectal Cancer in Asian Patients: A Prospective Cohort Study.

BACKGROUND: Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined. METHODS: In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively. CONCLUSIONS: Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.

Extracellular Matrix-Mimetic Intrinsic Versatile Coating Derived from Marine Adhesive Protein Promotes Diabetic Wound Healing through Regulating the Microenvironment.

The management of diabetic wound healing remains a severe clinical challenge due to the complicated wound microenvironments, including abnormal immune regulation, excessive reactive oxygen species (ROS), and repeated bacterial infections. Herein, we report an extracellular matrix (ECM)-mimetic coating derived from scallop byssal protein (Sbp9Δ), which can be assembled in situ within 30 min under the trigger of Ca2+ driven by strong coordination interaction. The biocompatible Sbp9Δ coating and genetically programmable LL37-fused coating exhibit outstanding antioxidant, antibacterial, and immune regulatory properties in vitro. Proof-of-concept applications demonstrate that the coating can reliably promote wound healing in animal models, including diabetic mice and rabbits, ex vivo human skins, and Staphylococcus aureus-infected diabetic mice. In-depth mechanism investigation indicates that improved wound microenvironments accelerated wound repair, including alleviated bacterial infection, lessened inflammation, appearance of abundant M2-type macrophages, removal of ROS, promoted angiogenesis, and re-epithelialization. Collectively, our investigation provides an in situ, convenient, and effective approach for diabetic wound repair.

Cadmium-Induced Physiological Responses, Biosorption and Bioaccumulation in Scenedesmus obliquus.

Cadmium ion (Cd2+) is a highly toxic metal in water, even at low concentrations. Microalgae are a promising material for heavy metal remediation. The present study investigated the effects of Cd2+ on growth, photosynthesis, antioxidant enzyme activities, cell morphology, and Cd2+ adsorption and accumulation capacity of the freshwater green alga Scenedesmus obliquus. Experiments were conducted by exposing S. obliquus to varying concentrations of Cd2+ for 96 h, assessing its tolerance and removal capacity towards Cd2+. The results showed that higher concentrations of Cd2+ (>0.5 mg L-1) reduced pigment content, inhibited algal growth and electron transfer in photosynthesis, and led to morphological changes such as mitochondrial disappearance and chloroplast deformation. In this process, S. obliquus counteracted Cd2+ toxicity by enhancing antioxidant enzyme activities, accumulating starch and high-density granules, and secreting extracellular polymeric substances. When the initial Cd2+ concentration was less than or equal to 0.5 mg L-1, S. obliquus was able to efficiently remove over 95% of Cd2+ from the environment through biosorption and bioaccumulation. However, when the initial Cd2+ concentration exceeded 0.5 mg L-1, the removal efficiency decreased slightly to about 70%, with biosorption accounting for more than 60% of this process, emerging as the predominant mechanism for Cd2+ removal. Fourier transform infrared correlation spectroscopy analysis indicated that the carboxyl and amino groups of the cell wall were the key factors in removing Cd2+. In conclusion, S. obliquus has considerable potential for the remediation of aquatic environments with Cd2+, providing algal resources for developing new microalgae-based bioremediation techniques for heavy metals.

Multi-kingdom microbial signatures in excess body weight colorectal cancer based on global metagenomic analysis.

Excess body weight (EBW) increases the risk of colorectal cancer (CRC) and is linked to lower colonoscopy compliance. Here, we extensively analyzed 981 metagenome samples from multiple cohorts to pinpoint the specific microbial signatures and their potential capability distinguishing EBW patients with CRC. The gut microbiome displayed considerable variations between EBW and lean CRC. We identify 44 and 37 distinct multi-kingdom microbial species differentiating CRC and controls in EBW and lean populations, respectively. Unique bacterial-fungal associations are also observed between EBW-CRC and lean-CRC. Our analysis revealed specific microbial functions in EBW-CRC, including D-Arginine and D-ornithine metabolism, and lipopolysaccharide biosynthesis. The best-performing classifier for EBW-CRC, comprising 12 bacterial and three fungal species, achieved an AUROC of 0.90, which was robustly validated across three independent cohorts (AUROC = 0.96, 0.94, and 0.80). Pathogenic microbial species, Anaerobutyricum hallii, Clostridioides difficile and Fusobacterium nucleatum, are EBW-CRC specific signatures. This work unearths the specific multi-kingdom microbial signatures for EBW-CRC and lean CRC, which may contribute to precision diagnosis and treatment of CRC.

CHEK2 deficiency increase the response to PD-1 inhibitors by affecting the tumor immune microenvironment.

Immune checkpoint blockade (ICB) therapy has improved treatment effects in multiple cancers. Gene mutations in the DNA damage repair pathway (DDR) may cause genomic instability and may relate to the efficacy of ICB. Checkpoint kinase 2 (CHEK2) and polymerase epsilon (POLE) are important genes in the DDR. In this study, we aimed to study the impact of CHEK2 deficiency mutations on the response to ICB. We found that tumors with CHEK2 mutations had a significantly higher tumor mutational burden (TMB) compared to those with CHEK2-WT in a pancancer database. We noted that CHEK2 deficiency mutations potentiated the anti-tumor effect of anti-PD-1 therapy in MC38 and B16 tumor-bearing mice with the decrease of tumor volume and tumor weight after anti-PD-1 treatment. Mechanistically, CHEK2 deficiency tumors were with the increased cytotoxic CD8+ T-cell infiltration, especially cytotoxic CD8+ T cells, and modulated the tumor-immune microenvironment with an upregulated immune inflammatory pathway and antigen presentation pathway after anti-PD-1 treatment. Furthermore, murine models with POLE mutations confirmed that CHEK2 deficiency shaped similar mutational and immune landscapes as POLE mutations after anti-PD-1 treatment. Taken together, our results demonstrated that CHEK2 deficiency mutations may increase the response to ICB (eg. anti-PD-1) by influencing the tumor immune microenvironment. This indicated that CHEK2 deficiency mutations were a potentially predictive biomarker and CHEK2 deficiency may potentiate response to immunotherapy.

Imeglimin profoundly affects the circadian clock in mouse embryonic fibroblasts.

OBJECTIVE: Imeglimin is a novel antidiabetic drug structurally related to metformin. Metformin has been shown to modulate the circadian clock in rat fibroblasts. Accordingly, in the present study, we aimed to determine whether imeglimin can impact the circadian oscillator in mouse embryonic fibroblasts (MEFs). METHODS: MEFs carrying a Bmal1-Emerald luciferase (Bmal1-ELuc) reporter were exposed to imeglimin (0.1 or 1 mM), metformin (0.1 or 1 mM), a nicotinamide phosphoribosyltransferase inhibitor FK866, and/or vehicle. Subsequently, Bmal1-ELuc expression and clock gene mRNA expression levels were measured at 10-min intervals for 55 h and 4-h intervals for 32 h, respectively. RESULTS: Imeglimin significantly prolonged the period (from 26.3 to 30.0 h at 0.1 mM) and dose-dependently increased the amplitude (9.6-fold at 1 mM) of the Bmal1-ELuc expression rhythm; however, metformin exhibited minimal effects on these parameters. Moreover, imeglimin notably impacted the rhythmic mRNA expression of clock genes (Bmal1, Per1, and Cry1). The concurrent addition of FK866 partly inhibited the effects of imeglimin on both Bmal1-ELuc expression and clock gene mRNA expression. CONCLUSION: Collectively, these results reveal that imeglimin profoundly affects the circadian clock in MEFs. Further studies are needed to evaluate whether imeglimin treatment could exert similar effects in vivo.

Impact of Surgical Management for Relapse After Conversion Hepatectomy for Initially Unresectable Colorectal Liver Metastasis: A Retrospective Cohort Study.

BACKGROUND: For patients with initially unresectable colorectal liver metastasis (IU-CRLM) receiving conversion therapy, disease relapse after conversion hepatectomy is common. However, few studies have focused on the assessment and management of relapse following conversion hepatectomy for IU-CRLM. METHODS: In the retrospective cohort study, 255 patients with IU-CRLM received conversion therapy and underwent subsequent R0 resection. The treatment effects of repeated liver-directed treatment (RLDT) versus non-RLDT for liver relapse were examined. Survival analysis was evaluated with the use of Cox proportional hazards methods. The importance of RLDT was further confirmed in the propensity score matching (PSM) and subgroup analyses. RESULTS: The 5-year overall survival (OS) rate after conversion hepatectomy was 34.9%. Liver relapse was observed in 208 patients. Of these patients, 106 underwent RLDT (65 underwent repeated hepatectomy and the remainder underwent ablation treatment), while 102 received only palliative chemotherapy. The relapse patients who underwent RLDT had a significantly longer OS than those who did not (hazard ratio (HR): 0.382, 95% CI: 0.259-0.563; P<0.001). In a multivariable analysis, RLDT was independently associated to prolonged survival (HR: 0.309, 95%CI: 0.181-0.529; P<0.001). In the PSM and subgroup analyses, RLDT consistently showed evidence of prolonging OS significantly. CONCLUSION: For IU-CRLM patients with liver relapse following conversion hepatectomy, the RLDT is essential for cure and prolonged survival. To avoid missing the opportunity for RLDT, intensive disease surveillance should be proposed.

Prevalence of mental disorders among middle school students in Shaoxing, China.

BACKGROUND: In China, adolescents account for about a quarter of those treated for mental disorders each year, and adolescent mental health issues have become a social hotspot. Although several epidemiological surveys of mental disorders have been conducted in China, no study has yet focused on the prevalence of mental disorders among adolescents in a certain region of Zhejiang. METHODS: In the first stage, 8219 middle school students aged 12-18 years in a city of Zhejiang Province (Shaoxing) were screened with the mental health screening checklist. In the second stage, participants who screened positive were tested with the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Then, the prevalence of mental disorders were calculated. RESULTS: The overall prevalence in this population was 12.4%, with prevalence rates exceeding 20% in both the 17- and 18-year-old age groups. The most common mental disorders were obsessive-compulsive disorder (OCD) (9.1%) and major depressive disorder (MDD) (8.9%). CONCLUSIONS: Mental disorders are common among middle school students, and girls are at higher risk than boys. As the most prevalent mental disorders, OCD and MDD should receive timely attention, especially for upper grade students.

Molecular complexation properties of Cd2+ by algal organic matter from Scenedesmus obliquus.

A detailed understanding the metals binding with algal organic matter (AOM) is essential to gain a deeper insight into the toxicity and migration of metals in algae cell. However, the molecular complexation mechanism of the metals binding with AOM remains unclear. In this study, cadmium ion (Cd2+) binding properties of AOMs from Scenedesmus obliquus, which included extracellular organic matter (EOM) and intracellular organic matter (IOM), were screened. When Cd2+ < 0.5 mg/L, the accumulation of Cd2+ could reach 40%, while Cd2+ > 0.5 mg/L, the accumulation of Cd2+ was only about 10%. EOM decreased gradually (from 8.51 to 3.98 mg/L), while IOM increased gradually (from 9.62 to 21.00 mg/L). The spectral characteristics revealed that IOM was richer in peptides/proteins and had more hydrophilic than EOM. Both EOM and IOM contained three protein-like components (containing tryptophan and tyrosine) and one humic-like component, and their contents in IOM were higher than that in EOM. The tryptophan protein-like substances changed greatly during Cd2+ binding, and that the tryptophan protein-like substances complexed to Cd2+ before tyrosine protein-like substances in IOM was identified. Moreover, the functional groups of N-H, O-H, and CO in AOM played an important role, and the N-H group was priority to interacts with Cd2+ in the complexing process. More functional groups (such as C-O and C-N) were involved in the metals complexing in EOM than in IOM. It could be concluded that Cd2+ stress promoted the secretion of AOM in Scenedesmus obliquus, and proteins in AOM could complex Cd2+ and alleviate its toxicity to algal cell. These findings provided deep insights into the interaction mechanism of AOM with Cd2+ in aquatic environments.

Faecalibacterium prausnitzii Abrogates Intestinal Toxicity and Promotes Tumor Immunity to Increase the Efficacy of Dual CTLA4 and PD-1 Checkpoint Blockade.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy and Faecalibacterium prausnitzii (F. prausnitzii) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of F. prausnitzii. In vivo, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. F. prausnitzii administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, F. prausnitzii enhanced the antitumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. F. prausnitzii abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that F. prausnitzii administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the antitumor activity of immunotherapy. SIGNIFICANCE: F. prausnitzii alleviates colitis while enhancing the tumor-suppressive effects of immune checkpoint blockade, indicating that supplementation with F. prausnitzii could be a treatment strategy to mitigate immunotherapy toxicity in patients with cancer.

Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer.

Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.

L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy.

Lenvatinib is an oral tyrosine kinase inhibitor that acts on multiple receptors involved in angiogenesis. Lenvatinib is a standard agent for the treatment of several types of advanced cancers; however, it frequently causes muscle-related adverse reactions. Our previous study revealed that lenvatinib treatment reduced carnitine content and the expression of carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle of rats. Therefore, this study aimed to evaluate the effects of L-carnitine on myotoxic and anti-angiogenic actions of lenvatinib. Co-administration of L-carnitine in rats treated with lenvatinib for 2 weeks completely prevented the decrease in carnitine content and expression levels of carnitine-related and OXPHOS proteins, including carnitine/organic cation transporter 2, in the skeletal muscle. Moreover, L-carnitine counteracted lenvatinib-induced protein synthesis inhibition, mitochondrial dysfunction, and cell toxicity in C2C12 myocytes. In contrast, L-carnitine had no influence on either lenvatinib-induced inhibition of vascular endothelial growth factor receptor 2 phosphorylation in human umbilical vein endothelial cells or angiogenesis in endothelial tube formation and mouse aortic ring assays. These results suggest that L-carnitine supplementation could prevent lenvatinib-induced muscle toxicity without diminishing its antineoplastic activity, although further clinical studies are needed to validate these findings.

Evaluation of Cd2+ stress on Synechocystis sp. PCC6803 based on single-cell elemental accumulation and algal toxicological response.

With the development of single cell analysis techniques, the concept of precision toxicology has been proposed in recent years. Due to the heterogeneity of cells, we need to perform toxicological assessments on individual cells. Microalgae, one kind of important primary producers, play as a major pathway by which heavy metals enter the food chain and thus accumulate/transfer to higher trophic levels. Herein, the biosorption of Cd (Ex-Cd) and bioaccumulation of Cd (In-Cd) for Synechocystis sp. PCC 6803 were investigated by online 3D droplet microfluidic device combined with inductively coupled plasma mass spectrometry detection. Meanwhile, the algal toxicological responses of the algae cell to Cd2+ exposure under different concentration (50, 100, and 150 µg L - 1) and time (15 min, 24, 48 and 96 h) were studied. Combining single-cell analysis with toxicological indicators, the toxicity mechanism of Cd2+to algal was discussed. The single cell analysis results revealed heterogeneity in cellular uptake of Cd2+. The proportion of Cd-containing cells and Cd content in single algal cells all reached the maximum at 24 h. The uptake of Cd2+ occurred within 15 min under all tested exposure concentrations and a large part of Cd2+ were adsorbed on the algal cells surface. The Pearson correlation analysis showed that cell density, chlorophyll a and carotenoids were significantly negatively correlated with Cd accumulation, whereas ROS level and SOD activity were significantly positively correlated with Cd accumulation. It suggested that Cd2+accumulated intracellular would show toxic effects on the algal cells and oxidative stress is the main mechanism of Cd toxicity to algal cells. This work promotes our understanding of the toxicological responses of microalgae under Cd stress at single cells level.

Electrochemical Micro-Immunosensor of Cubic AuPt Dendritic Nanocrystals/Ti3C2-MXenes for Exosomes Detection.

Exosomes are extracellular vesicles that exist in body circulation as intercellular message transmitters. Although the potential of tumor-derived exosomes for non-invasive cancer diagnosis is promising, the rapid detection and effective capture of exosomes remains challenging. Herein, a portable electrochemical aptasensor of cubic AuPt dendritic nanocrystals (AuPt DNs)/Ti3C2 assisted in signal amplification, and aptamer CD63 modified graphene oxide (GO) was immobilized on a screen-printed carbon electrode (SPCE) as the substrate materials for the direct capture and detection of colorectal carcinoma exosomes. Cubic AuPt DNs/Ti3C2 was synthesized according to a simple hydrothermal procedure, and the AuPt DNs/Ti3C2-Apt hybrid demonstrated an efficient recognition of exosomes. Under optimal conditions, a detection limit of down to 20 exosomes µL-1 was achieved with the linear range from 100 exosomes µL-1 to 5.0 × 105 exosomes µL-1. The proposed immunosensor could be suitable for the analysis of exosomes and has clinical value in the early diagnosis of cancer.

The association of serum vitamin D level and neonatal respiratory distress syndrome.

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a critical disease in premature infants. Vitamin D plays an important role in promoting the development of fetal lung structure and the formation of pulmonary surfactants. This study aimed to investigate the correlation between the serum 25(OH)D3 level in the cord blood of premature infants and the prognosis of NRDS. METHODS: This retrospective study recruited 82 preterm infants (gestational age 28-36 weeks) diagnosed with NRDS as the NRDS group, and 82 non-NRDS preterm infants as the control group, respectively. The diagnostic efficiency of 25(OH)D3 on NRDS was revealed by receiver operating characteristics curve (ROC) analysis. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the 25(OH)D3 level in the serum of the cord blood in preterm neonates. The NRDS risk indicators were identified by the multivariate logistic regression analysis. RESULTS: Cord blood 25(OH)D3 levels were significantly lower in NRDS preterm infants than control group infants. 25(OH)D3 levels in cord blood can be used to predict NRDS in preterm infants. In addition, 25(OH)D3 levels in cord blood were positively correlated with Apgar score (1 min/5 min) and negatively correlated with oxygen support/CPAP duration in preterm infants with NRDS. 25(OH)D3 in cord blood <57.69 nmol/L (24 ng/ml), gestational age <31 weeks, birth weight <1.86 kg, Apgar score (1 min) <7 and Apgar score (5 min) < 8 were independent risk factors for NRDS. CONCLUSION: 25(OH)D3 level is an independent risk factor for NRDS in preterm infants.

Hsa_Circ_0005044 Promotes Osteo/Odontogenic Differentiation of Dental Pulp Stem Cell Via Modulating miR-296-3p/FOSL1.

Circular RNAs (circRNAs) are a form of RNAs that lack coding potential. The role of such circRNAs in dental pulp stem cell (DPSC) osteo/odontogenic differentiation remains to be determined. In this study, circRNA expression profiles in DPSC osteo/odontogenic differentiation process were analyzed by RNA-seq. qRT-PCR was used to confirm the differential expression of circ_0005044, miR-296-3p, and FOSL1 in DPSC osteogenic differentiation process. Circ_0005044, miR-296-3p, and FOSL1 were knocked down or overexpressed. Osteoblastic activity and associated mineral activity were monitored via alkaline phosphatase (ALP) and alizarin red S (ARS) staining. Interactions between miR-296-3p, circ_0005044, and FOSL1 were assessed through luciferase reporter assays. Finally, an in vivo system was used to confirm the relevance of circ_0005044 to osteoblastic differentiation. As results, we detected significant circ_0005044 and FOSL1 upregulation in DPSC osteo/odontogenic differentiation process, as well as concomitant miR-296-3p downregulation. When knocking down circ_0005044 or overexpressed miR-296-3p, this significantly inhibited osteogenesis. Luciferase reporter assay confirmed that miR-296-3p was capable of binding to conserved sequences in the wild-type forms of both the circ_0005044 and FOSL1. Furthermore, knocking down circ_0005044 in vivo significantly attenuated bone formation. Therefore, the circ_0005044/miR-2964-3p/FOSL1 axis regulates DPSC osteo/odontogenic differentiation, which may provide potential molecular targets for dental-pulp complex regeneration.

Investigation of toxic effect of mercury on Microcystis aeruginosa: Correlation between intracellular mercury content at single cells level and algae physiological responses.

Single-cell studies can help to understand individual differences and obtain atypical cellular characteristics in view of cellular heterogeneity. Herein, the accumulation of mercury (Hg) in single algae cells was studied by droplet chip-time resolved inductively coupled plasma mass spectrometry analytical system, and the relation of Hg accumulation to the physiological responses of algae cell was explored. When low concentrations of Hg2+ (5-20 µg/L) were used in the exposure experiment, the content of Hg in single cells increased in first 2 h, then decreased with further increase of exposure time to 96 h, probably due to the growth dilution effect of the algae. When exposed to 30 µg/L Hg2+, the uptake of Hg by individual cells increased over time, which was associated with increased cell membrane permeability. The exposure to Hg2+ (5-30 µg/L) inhibited the growth of algae in a concentration-dependent manner and serious growth inhibition occurred under the exposure concentration of 30 µg/L. While the exposure concentration was lower than 20 µg/L, algal cells exhibited a recover tendency due to the self-protection mechanism of algal cells. Bivariate results showed that intracellular Hg accumulation was significantly negatively correlated with cells growth in terms of OD680, photosynthetic pigments, Fv/Fm and PIabs. On the contrast, reactive oxygen species content, superoxide dismutase activity, and cell membrane permeability were significantly positively correlated with the accumulation of intracellular Hg. These results are helpful to further understand the toxic effect of Hg on algae.

Fusobacterium nucleatum stimulates cell proliferation and promotes PD-L1 expression via IFIT1-related signal in colorectal cancer.

Fusobacterium nucleatum (F. nucleatum) is enriched in colorectal cancer (CRC) tissues and a high amount of F. nucleatum was associated with an immunosuppressive tumor environment. PD-L1 is an important immune checkpoint expressed on tumor cells and promotes tumor immune escape. Whether PD-L1 is regulated by F. nucleatum is still unclear. We demonstrated that F. nucleatum promoted CRC progression and upregulated PD-L1 protein expression in CRC cell lines. Combined m6A-seq and RNA-seq identified m6A-modified IFIT1 mediating F. nucleatum induced PD-L1 upregulation. IFIT1 mRNA was modified with m6A modifications in 3'UTR and the m6A levels were altered by F. nucleatum treatment. Our results also indicated that IFIT1 served as a potential oncogene in CRC and regulated PD-L1 protein levels through altering PD-L1 ubiquitination. Clinical CRC data confirmed the correlation among F. nucleatum abundance, IFIT1 and PD-L1 expressions. Our work highlighted the function of F. nucleatum in stimulating PD-L1 expression through m6A-modified IFIT1 and provided new aspects for understanding F. nucleatum mediated immune escape.

Clinical observation of acupuncture combined with modern rehabilitation in the treatment of limb motor dysfunction after ischemic stroke: A randomized controlled trial.

BACKGROUND: Motor dysfunction is a common sequela of ischemic stroke. This study aimed to explore the effective treatment of ischemic stroke by combining acupuncture and modern rehabilitation training. METHODS: This study was a single-center, randomized controlled clinical trial conducted at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, 90 cases were finally included, divided into 45 cases each in the body acupuncture group and the head acupuncture group. INTERVENTIONS: Both groups received basic drug treatment, modern rehabilitation training, and basic life care guidance; the body acupuncture group was treated with reference to acupuncture points from the classic textbook of acupuncture and moxibustion, and the head acupuncture group was given Zhu's scalp acupuncture treatment based on the body acupuncture group. Primary outcome index: unassisted muscle strength grading scale; secondary outcome index: assessment of activities of daily living; simplified Fugl-Meyer motor function rating scale. RESULTS: The Barthel scale score, Manual Muscle Testing scale score (upper and lower limbs), and simplified Fugl-Meyer scale score (upper and lower limbs) in the 2 groups were improved (P ≤ .05), and the efficacy of the head-acupuncture group was better than that of the body-acupuncture group (P ≤ .05); there was no significant improvement in the simplified Fugl-Meyer scale (hand) score in both groups (P ≥ .05). There was no significant improvement in these scores (P ≥ .05). The difference in efficiency between the 2 groups was not statistically significant (P ≤ .05), and the apparent efficiency in the cephalic needle group was higher than that in the body needle group (P ≤ .05). CONCLUSIONS: Simultaneous treatment with Zhu's scalp acupuncture and body acupuncture combined with modern rehabilitation training can significantly improve limb motor function in patients with ischemic stroke, and its efficacy is better than that of body acupuncture alone combined with modern rehabilitation training.