Ligustrazine alleviates spinal cord injury-induced neuropathic pain by inhibiting the TLR4/NF-κB signaling pathway.

OBJECTIVE: To investigate the effects of ligustrazine on neuropathic pain (NPP) in rats with sciatic nerve injury and to provide new scientific insight for broadening the clinical application of ligustrazine. METHODS: Human spinal cord cell line STR cells were transfected with TLR4-mimic or mimic negative control (mimic-NC). After transfection, the STR cells were treated with different concentrations of ligustrazine (0, 0.25, 0.5, 1, 2 µm) for 24 h or 48 h. Cell proliferation was detected by MTT assay and colony formation assay. A rat model was further constructed to evaluate mechanical and cold pain sensitivity behaviors by fiber mechanical stimulation and freezing spray. The extracellular fluids of medial prefrontal cortex (mPFC) and central amygdala (CeA) were collected by intracranial dual-site simultaneous microdialysis. The contents of glutamic acid (Glu), aspartate (Asp), glycine (Gly), and γ-aminobutyric acid (GABA) in extracellular fluids were detected by HPLC. RESULTS: Compared to the 0 µm group, ligustrazine concentration at 0.5 µm significantly decreased the relative cell viability of STR cells and promoted the cell apoptosis rate. Ligustrazine at 0.25 µm significantly reduced the colony number of STR cells (all P<0.05). Compared to the control group, 1 µM ligustrazine significantly increased the protein expression of Bax and cleaved caspase 3 in STR cells but decreased the protein expression of Bcl-2 (all P<0.001). Compared to the control group, 2 µM ligustrazine treatments significantly reduced the protein levels of TLR4 and p-Akt in STR cells (all P<0.001). However, 2 µM ligustrazine treatments did not change the protein expression of Akt (P>0.05). Compared to the control group, the level of TLR4 in STR cells transfected with TLR4-mimic was significantly increased (P<0.001). Compared to the control group, transfection of TLR4-mimic reversed the anti-proliferative and pro-apoptotic effects of ligustrazine on STR cells (all P<0.001). CONCLUSION: The analgesic effect of Ligustrazine on neuropathic pain caused by spinal cord injury may be related to its inhibition of the release of excitatory amino acid transmitters Glu and Gly through the TLR4/NF-κB pathway, regulation of the dynamic balance of excitatory and inhibitory amino acid neurotransmitters, and alleviation of the central sensitization effect caused by the excitotoxicity of Glu.

Improper toy waste handling can harm human health via seafood consumption: A comprehensive health risk assessment of heavy metals.

Toy production has been increasing over the last few decades to meet the growing demands for toys across the globe, which has inevitably worsened the problem of toy waste. Given the lack of modern waste disposal facilities, rural villagers in many developing countries often discard and incinerate toy waste in backyards or riverbanks, which may release the pollutants from toys (e.g., heavy metals), contaminate the surrounding areas, and eventually threaten the health of residents. As such, this study examined the impact of improper toy waste handling on the nearby aquaculture site by measuring the contamination level of heavy metals (As, Cd, Cu, Pb, and Zn) in the sediment and seafood (crabs, shrimps, and fish). The health risk of heavy metals via seafood consumption was assessed in different groups of people (males, females, teenagers, and seniors). Results showed that the sediment and seafood at the aquaculture site were generally not contaminated with heavy metals (contamination factor and bioaccumulation factor <1). However, consuming the seafood cultured at this site, especially for crabs, could pose a health risk to humans due to As and Cd (hazard quotient > 1), irrespective of their age and gender. This risk could not be lowered by cooking, except As by boiling. Overall, we revealed that improper toy waste handling did not cause severe heavy metal pollution in the surrounding environment, but the consumption of contaminated seafood could still threaten human health. To safeguard public health, we propose that toy waste should be appropriately treated by the authorities concerned. In addition, consuming seafood with long culture periods (e.g., crabs) should be reduced to minimize the dietary intake of heavy metals and their associated health risk.

Aggregation-Induced Emission-Active Photosensitizer-Mediated Photodynamic Therapy for Anti-Psoriasis.

Hyperproliferative keratinocytes and subcutaneous inflammation contribute to the characteristic symptoms of psoriasis, including erythema, scales, or scaly plaques on the skin. These symptoms significantly affect patients' quality of life and cause severe physical and psychological distress. However, current treatment strategies have limited therapeutic effect and may lead to adverse side effects. In this study, we present the novel organic photosensitizer TBTDC [5-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-3-methylthiophene-2,4-dicarbonitrile] nanoparticles (NPs) with aggregation-induced emission (AIE) characteristics to mediate photodynamic therapy (TBTDC NP-PDT) for psoriasis treatment. We demonstrate that TBTDC NPs effectively generate reactive oxygen species upon light irradiation and lead to significant apoptosis of psoriatic keratinocytes. Furthermore, TBTDC NPs exhibit high cellular uptake in diseased keratinocytes and induce endoplasmic reticulum stress (ERS)-mediated autophagy, which can also enhance apoptosis. Importantly, TBTDC NPs show no cytotoxicity toward keratinocytes. These unique properties of TBTDC NPs enable remarkable therapeutic effects against psoriasis-like skin lesions and related inflammation in vivo. Overall, our AIE-active TBTDC NP-PDT represents a promising strategy for treating psoriasis in clinical settings.

ZnO nanoparticles induce melanoma-like lesions via recruiting dermal dendritic cells in barrier-damaged skin in mice.

ZnO nanoparticles (NPs) are used in skin treatments and cosmetics, the toxicity of long-term and continuous exposure to ZnO NPs is unknown. Mice with epidermal barrier dysfunction revealed melanoma-like lesions after continuous exposure to ZnO NPs. However, the effects of metallic NPs on the skin microenvironment and immune system remain poorly understood. Mice with epidermal barrier failure were given continuous exposure to ZnO NPs for 7 weeks. The malignant transformation of melanocytes was induced with ZnO NPs 2.5 µg/ml for 72 h exposure. The supernatant of the culture medium from dendritic cells after being exposed to 10 µg/ml ZnO NPs for 24 h was applied to melanocytes to explore the effect of recruitment of DCs. The expressure of ZnO NPs resulted in a tendency of malignant transformation of melanocytes, the recruitment of DCs induces this process by produce inflammatory factors such as TNF-α. These DC-produced inflammatory factors, which were induced by ZnO NP exposure, increased the production of matrix metalloproteinases in melanocytes and expedited the malignant transformation process. Our findings revealed that the disrupted cutaneous microenvironment by ZnO NPs penetrated directly promoted the malignant transformation of melanocytes, which process also indirectly enhanced by the TNF-αsecreted from the recruited DCs.

Integration of Bioinformatics and Machine Learning to Identify CD8+ T Cell-Related Prognostic Signature to Predict Clinical Outcomes and Treatment Response in Breast Cancer Patients.

The incidence of breast cancer (BC) continues to rise steadily, posing a significant burden on the public health systems of various countries worldwide. As a member of the tumor microenvironment (TME), CD8+ T cells inhibit cancer progression through their protective role. This study aims to investigate the role of CD8+ T cell-related genes (CTRGs) in breast cancer patients. METHODS: We assessed the abundance of CD8+ T cells in the TCGA and METABRIC datasets and obtained CTRGs through WGCNA. Subsequently, a prognostic signature (CTR score) was constructed from CTRGs screened by seven machine learning algorithms, and the relationship between the CTR score and TME, immunotherapy, and drug sensitivity was analyzed. Additionally, CTRGs' expression in different cells within TME was identified through single-cell analysis and spatial transcriptomics. Finally, the expression of CTRGs in clinical tissues was verified via RT-PCR. RESULTS: The CD8+ T cell-related prognostic signature consists of two CTRGs. In the TCGA and METABRIC datasets, the CTR score appeared to be negatively linked to the abundance of CD8+ T cells, and BC patients with higher risk score show a worse prognosis. The low CTR score group exhibits higher immune infiltration levels, closely associated with inhibiting the tumor microenvironment. Compared with the high CTR score group, the low CTR score group shows better responses to chemotherapy and immune checkpoint therapy. Single-cell analysis and spatial transcriptomics reveal the heterogeneity of two CTRGs in different cells. Compared with the adjacent tissues, CD163L1 and KLRB1 mRNA are downregulated in tumor tissues. CONCLUSIONS: This study establishes a robust CD8+ T cell-related prognostic signature, providing new insights for predicting the clinical outcomes and treatment responses of breast cancer patients.

Pig-derived ECM-SIS provides a novel matrix gel for tumor modeling.

The absence of effective extracellular matrix to mimic the natural tumor microenvironment remains a significant obstacle in cancer research. Matrigel, abundant in various biological matrix components, is limited in its application due to its high cost. This has prompted researchers to explore alternative matrix substitutes. Here, we have investigated the effects of the extracellular matrix derived from pig small intestinal submucosa (ECM-SIS) in xenograft tumor modeling. Our results showed that the pig-derived ECM-SIS effectively promotes the establishment of xenograft tumor models, with a tumor formation rate comparable to that of Matrigel. Furthermore, we showed that the pig-derived ECM-SIS exhibited lower immune rejection and fewer infiltrating macrophages than Matrigel. Gene sequencing analysis demonstrated only a 0.5% difference in genes between pig-derived ECM-SIS and Matrigel during the process of tumor tissue formation. These differentially expressed genes primarily participate in cellular processes, biological regulation, and metabolic processes. These findings emphasize the potential of pig-derived ECM-SIS as a cost-effective option for tumor modeling in cancer research.

Dentin matrix protein 1 and HUVEC-ECM scaffold promote the differentiation of human dental pulp stem cells into endothelial lineage: implications in regenerative medicine.

Reprograming of the dental pulp somatic cells to endothelial cells is an attractive strategy for generation of new blood vessels. For tissue regeneration, vascularization of engineered constructs is crucial to improve repair mechanisms. In this study, we show that dentin matrix protein 1 (DMP1) and HUVEC-ECM scaffold enhances the differentiation potential of dental pulp stem cells (DPSCs) to an endothelial phenotype. Our results show that the differentiated DPSCs expressed endothelial markers CD31 and VE-Cadherin (CD144) at 7 and 14 days. Expression of CD31 and VE-Cadherin (CD144) were also confirmed by immunofluorescence. Furthermore, flow cytometry analysis revealed a steady increase in CD31 and VE-Cadherin (CD144) positive cells with DMP1 treatment when compared with control. In addition, integrins specific for endothelial cells were highly expressed during the differentiation process. The endothelial cell signature of differentiated DPSCs were additionally characterized for key endothelial cell markers using gene expression by RT-PCR, Western blotting, immunostaining, and RNA-seq analysis. Furthermore, the angiogenic phenotype was confirmed by tubule and capillary sprout formation. Overall, stimulation of DPSCs by DMP1 and use of HUVEC-ECM scaffold promoted their differentiation into phenotypically, transcriptionally, and functionally differentiated bonafide endothelial cells. This study is novel, physiologically relevant and different from conventional strategies.

[Mechanism of electroacupuncture for vascular dementia based on proteomics].

OBJECTIVE: To explore the potential mechanism of electroacupuncture (EA) for vascular dementia (VD) using tandem mass tag (TMT) quantitative proteomics technology. METHODS: Among 80 male SPF SD rats, 78 rats which met the selection criteria through the Morris water maze test were selected and randomly divided into a sham surgery group (18 rats) and a surgery group (60 rats). VD model was established by four-vessel occlusion (4-VO) method in the surgery group, and 36 rats with successful modeling were randomly assigned to a model group (18 rats) and an EA group (18 rats). Each group was further divided into three subgroups based on intervention duration, with each subgroup containing 6 rats. Seven days after model establishment, the EA group received EA intervention at left and right "Sishencong" (EX-HN 1) and bilateral "Fengchi" (GB 20), with continuous wave at a frequency of 2 Hz and current intensity of 1 mA, daily for 30 min, with subgroups receiving EA for 7, 14, or 21 d respectively. Cognitive function before and after interventions was assessed using Morris water maze. Proteomic analysis was conducted on the optimal EA subgroup and corresponding sham surgery and model subgroups, identifying differentially expressed proteins and analyzing them through bioinformatics. Differentially expressed target proteins was performed using parallel reaction monitoring (PRM) and Western blot techniques. RESULTS: Compared to the sham surgery group, the model group exhibited prolonged escape latency and reduced number of platform crossings (P<0.01); compared with model group, the EA group showed reductions in escape latency and increased platform crossings after 7, 14, and 21 days of intervention (P<0.01, P<0.05). Compared to the 7 and 14-day intervention, the rats in the EA group of 21-day intervention showed the most significant improvements in reductions of escape latency and increased platform crossings (P<0.01, P<0.05), and was selected for further proteomic, PRM analyses, and Western blot validation. Compared to the sham surgery group, the model group displayed 71 differentially expressed proteins, with 50 up-regulated and 21 down-regulated proteins; compared to the model group, the EA group had 54 differentially expressed proteins, with 30 up-regulated and 24 down-regulated proteins. Functional enrichment and clustering analyses indicated that these proteins were primarily associated with cellular processes, metabolic processes, phagocytosis recognition, immune response, and regulation of extracellular matrix, etc. Enrichment was observed in the mammalian target of rapamycin (mTOR) signaling pathway and neurotrophic factors signaling pathways, involving glycogen synthase kinase 3ß (GSK3ß) and mitogen-activated protein kinase kinase 2 (Map2k2), with PRM and Western blot findings consistent with the proteomic results. Which meant that compared with the model group, the protein expression of GSK3ß and Map2k2 of hippocampus was increased in the EA group (P<0.01, P<0.05). CONCLUSION: EA at "Sishencong" (EX-HN 1) and "Fengchi" (GB 20) could improve cognitive function in VD rats, with the mechanism involving multiple targets and pathways, potentially related to GSK3ß, Map2k2 proteins, and the mTOR and neurotrophic factor signaling pathways.

Link between mutations in ACVRL1 and PLA2G4A genes and chronic intestinal ulcers: A case report and review of literature.

BACKGROUND: Genetic factors of chronic intestinal ulcers are increasingly garnering attention. We present a case of chronic intestinal ulcers and bleeding associated with mutations of the activin A receptor type II-like 1 (ACVRL1) and phospholipase A2 group IVA (PLA2G4A) genes and review the available relevant literature. CASE SUMMARY: A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain, diarrhea, and dark stools. At the onset 6 years ago, the patient had received treatment at a local hospital for abdominal pain persisting for 7 d, under the diagnosis of diffuse peritonitis, acute gangrenous appendicitis with perforation, adhesive intestinal obstruction, and pelvic abscess. The surgical treatment included exploratory laparotomy, appendectomy, intestinal adhesiolysis, and pelvic abscess removal. The patient's condition improved and he was discharged. However, the recurrent episodes of abdominal pain and passage of black stools started again one year after discharge. On the basis of these features and results of subsequent colonoscopy, the clinical diagnosis was established as inflammatory bowel disease (IBD). Accordingly, aminosalicylic acid, immunotherapy, and related symptomatic treatment were administered, but the symptoms of the patient did not improve significantly. Further investigations revealed mutations in the ACVRL1 and PLA2G4A genes. ACVRL1 and PLA2G4A are involved in angiogenesis and coagulation, respectively. This suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A genes. Oral Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical symptoms. CONCLUSION: Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in IBD. Orally administered Kangfuxin liquid may have therapeutic potential.

Synergistic targeting of TrxR1 and ATM/AKT pathway in human colon cancer cells.

Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.

Deep learning model to predict lupus nephritis renal flare based on dynamic multivariable time-series data.

OBJECTIVES: To develop an interpretable deep learning model of lupus nephritis (LN) relapse prediction based on dynamic multivariable time-series data. DESIGN: A single-centre, retrospective cohort study in China. SETTING: A Chinese central tertiary hospital. PARTICIPANTS: The cohort study consisted of 1694 LN patients who had been registered in the Nanjing Glomerulonephritis Registry at the National Clinical Research Center of Kidney Diseases, Jinling Hospital from January 1985 to December 2010. METHODS: We developed a deep learning algorithm to predict LN relapse that consists of 59 features, including demographic, clinical, immunological, pathological and therapeutic characteristics that were collected for baseline analysis. A total of 32 227 data points were collected by the sliding window method and randomly divided into training (80%), validation (10%) and testing sets (10%). We developed a deep learning algorithm-based interpretable multivariable long short-term memory model for LN relapse risk prediction considering censored time-series data based on a cohort of 1694 LN patients. A mixture attention mechanism was deployed to capture variable interactions at different time points for estimating the temporal importance of the variables. Model performance was assessed according to C-index (concordance index). RESULTS: The median follow-up time since remission was 4.1 (IQR, 1.7-6.7) years. The interpretable deep learning model based on dynamic multivariable time-series data achieved the best performance, with a C-index of 0.897, among models using only variables at the point of remission or time-variant variables. The importance of urinary protein, serum albumin and serum C3 showed time dependency in the model, that is, their contributions to the risk prediction increased over time. CONCLUSIONS: Deep learning algorithms can effectively learn through time-series data to develop a predictive model for LN relapse. The model provides accurate predictions of LN relapse for different renal disease stages, which could be used in clinical practice to guide physicians on the management of LN patients.

Substantial decline of organ preservation fluid contamination following adoption of ischemia-free liver transplantation: a post-hoc analysis.

INTRODUCTION: Preservation fluid (PF) contaminations are common in conventional liver transplantation (CLT) and presumably originate from organ or PF exposures to the external environment in a non-strict sterile manner. Such exposures and PF contamination may be avoided in ischaemia-free liver transplantation (IFLT) because of the strict sterile surgical procedures. In this study, the authors evaluated the impact of IFLT on organ PF contamination. METHODS: A post-hoc analysis using data from the first randomized controlled trial of IFLT was performed to compare the incidence, pathogenic spectrum of PF contamination, and incidence of early recipient infection between IFLT and CLT. Multivariable logistic regression was used to explore risk factors for PF contamination. RESULTS: Of the 68 cases recruited in the trial, 64 were included in this post-hoc analysis. The incidence of culture-positive PF was 9.4% (3/32) in the IFLT group versus 78.1% (25/32) in the CLT group ( P <0.001). Three microorganisms were isolated from PF in the IFLT group, while 43 were isolated in the CLT group. The recipient infection rate within postoperative day 14 was 3.1% (1/32) in the IFLT group vs 15.6% (5/32) in the CLT group, although this difference did not reach statistical significance ( P =0.196). Multivariate analysis revealed that adopting IFLT is an independent protective factor for culture-positive PF. CONCLUSION: PF contamination is substantially decreased in IFLT, and IFLT application is an independent protective factor for PF contamination. Using rigorous sterile measures and effective antibiotic therapy during IFLT may decrease PF contamination.

Combination of TrxR1 inhibitor and lenvatinib triggers ROS-dependent cell death in human lung cancer cells.

Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo. To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.

Harmonizing florbetapir and PiB PET measurements of cortical Aß plaque burden using multiple regions-of-interest and machine learning techniques: An alternative to the Centiloid approach.

INTRODUCTION: Machine learning (ML) can optimize amyloid (Aß) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aß (mcAß) than Centiloid. METHODS: PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aß and actual PiB mcAß in the training set were used to train ML models generating synthetic PiB mcAß. The correlation coefficient (R) between the synthetic/actual PiB mcAß in the testing set was assessed. RESULTS: In the testing set, the synthetic/actual PiB mcAß correlation R = 0.985 (R2  = 0.970) using artificial neural network was significantly higher (p ≤ 6.6e-4) than the FBP/PiB correlation R = 0.927 (R2  = 0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p = 9.677e-05 /0.045/0.0017). DISCUSSION: ML improved mcAß comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.

CD6 triggers actomyosin cytoskeleton remodeling after binding to its receptor complex.

The T cell marker CD6 regulates both T cells and target cells during inflammatory responses by interacting with its receptors. However, only a few receptors binding to the extracellular domains of CD6 have been identified, and cellular events induced by CD6 engagement with its receptors in target cells remain poorly understood. In this study, we identified CD44 as a novel CD6 receptor by proximity labeling and confirmed the new CD6-CD44 interaction by biochemical and biophysical approaches. CD44 and the other 2 known CD6 receptors, CD166 and CDCP1, were distributed diffusely on resting retinal pigment epithelium (RPE) cells but clustered together to form a receptor complex upon CD6 binding. CD6 stimulation induced dramatic remodeling of the actomyosin cytoskeleton in RPE cells mediated by activation of RhoA, and Rho-associated kinase signaling, resulting in increased myosin II phosphorylation. Such actomyosin activation triggered the disassembly of tight junctions responsible for RPE barrier integrity in a process that required all components of the tripartite CD6 receptor complex. These data provided new insights into the mechanisms by which CD6 mediates T cell-driven disruption of tissue barriers during inflammation.

Acute-on-chronic liver failure induced by antiviral therapy for chronic hepatitis C: A case report.

BACKGROUND: There have been no reports of acute-on-chronic liver failure (ACLF) during treatment of chronic hepatitis C (CHC) with direct-acting antivirals (DAAs). CASE SUMMARY: We report a 50-year-old male patient with CHC. The patient sought medical attention from the Department of Infectious Diseases at our hospital due to severe yellowing of the skin and sclera, which developed 3 mo previously and attended two consecutive hospitals without finding the cause of liver damage. It was not until 1 mo ago that he was diagnosed with CHC at our hospital. After discharge, he was treated with DAAs. During treatment, ACLF occurred, and timely measures such as liver protection, enzyme lowering, anti-infective treatment, and suppression of inflammatory storms were implemented to control the condition. CONCLUSION: DAA drugs significantly improve the cure rate of CHC. However, when patients have factors such as autoimmune attack, coinfection, or unclear hepatitis C virus genotype, close monitoring is required during DAA treatment.

A Metamaterial Computational Multi-Sensor of Grip-Strength Properties with Point-of-Care Human-Computer Interaction.

Grip strength is a biomarker of frailty and an evaluation indicator of brain health, cardiovascular morbidity, and psychological health. Yet, the development of a reliable, interactive, and point-of-care device for comprehensive multi-sensing of hand grip status is challenging. Here, a relation between soft buckling metamaterial deformations and built piezoelectric voltage signals is uncovered to achieve multiple sensing of maximal grip force, grip speed, grip impulse, and endurance indicators. A metamaterial computational sensor design is established by hyperelastic model that governs the mechanical characterization, machine learning models for computational sensing, and graphical user interface to provide visual cues. A exemplify grip measurement for left and right hands of seven elderly campus workers is conducted. By taking indicators of grip status as input parameters, human-computer interactive games are incorporated into the computational sensor to improve the user compliance with measurement protocols. Two elderly female schizophrenic patients are participated in the real-time interactive point-of-care grip assessment and training for potentially sarcopenia screening. The attractive features of this advanced intelligent metamaterial computational sensing system are crucial to establish a point-of-care biomechanical platform and advancing the human-computer interactive healthcare, ultimately contributing to a global health ecosystem.

Combination therapy with HSP90 inhibitors and piperlongumine promotes ROS-mediated ER stress in colon cancer cells.

Colon cancer is a major cause of cancer-related death. Despite recent improvements in the treatment of colon cancer, new strategies to improve the overall survival of patients are urgently needed. Heat shock protein 90 (HSP90) is widely recognized as a promising target for treating various cancers, including colon cancer. However, no HSP90 inhibitor has been approved for clinical use due to limited efficacy. In this study, we evaluated the antitumor activities of HSP90 inhibitors in combination with piperlongumine in colon cancer cells. We show that combination treatment with HSP90 inhibitors and piperlongumine displayed strong synergistic interaction in colon cancer cells. These agents synergize by promoting ER stress, JNK activation, and DNA damage. This process is fueled by oxidative stress, which is caused by the accumulation of reactive oxygen species. These studies nominated piperlongumine as a promising agent for HSP90 inhibitor-based combination therapy against colon cancer.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg-1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) ß-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.