High Mortality Worldwide Research Articles

A Review of Major Patents on Potential Malaria Vaccine Targets.

Malaria is a parasitic infection that is a great public health concern and is responsible for high mortality rates worldwide. Different strategies have been employed to improve disease control, demonstrating the ineffectiveness of controlling vectors, and parasite resistance to antimalarial drugs requires the development of an effective preventive vaccine. There are countless challenges to the development of such a vaccine directly related to the parasite's complex life cycle. After more than four decades of basic research and clinical trials, the World Health Organization (WHO) has recommended the pre-erythrocytic Plasmodium falciparum (RTS, S) malaria vaccine for widespread use among children living in malaria-endemic areas. However, there is a consensus that major improvements are needed to develop a vaccine with a greater epidemiological impact in endemic areas. This review discusses novel strategies for malaria vaccine design taking the target stages within the parasite cycle into account. The design of the multi-component vaccine shows considerable potential, especially as it involves transmission-blocking vaccines (TBVs) that eliminate the parasite's replication towards sporozoite stage parasites during a blood meal of female anopheline mosquitoes. Significant improvements have been made but additional efforts to achieve an efficient vaccine are required to improve control measures. Different strategies have been employed, thus demonstrating the ineffectiveness in controlling vectors, and parasite resistance to antimalarial drugs requires the development of a preventive vaccine. Despite having a vaccine in an advanced stage of development, such as the RTS, S malaria vaccine, the search for an effective vaccine against malaria is far from over. This review discusses novel strategies for malaria vaccine design taking into account the target stages within the parasite's life cycle.

Abstract WP234: Mitochondria Therapy Mitigates Neuroinflammation And Provides Neuroprotection Against Ischemic Stroke In Mice

Background: Ischemic stroke is the second prevalent life-threat problem associated with long-lasting neurological disabilities and a high mortality rate worldwide. Despite this, therapeutic options remain limited. Recently, mitochondria transplantation therapy has emerged as a potential approach for increasing brain protection. This study aimed to investigate the protective role of mitochondria transplantation against ischemic stroke-induced behavioral deficits and molecular alterations in a photothrombotic stroke model. Methods: Ischemic stroke was induced by a Rose Bengal photothrombosis method in young adult C57BL/6 mice. Repeated doses of isolated liver mitochondria (100μg/mouse) were administrated intranasally at 1 h, 3 h, 24 h, and 48 h post-stroke. After 72 h, mice were tested for behavioral outcomes and euthanized, and tissues were harvested to measure infarct volume, brain edema, and molecular analysis. Results: Mitochondria-treated mice showed a significant improvement in behavioral outcomes, reduction in infarct size, and brain edema compared to the vehicle-treated group. Additionally, mitochondria significantly inhibited the protein expression of NOD-like receptor protein-3, phospho-nuclear factor kappa-B, cleaved-interleukin-1β, apoptosis-associated speck-like protein, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule-1 proteins. Furthermore, mitochondria treatment showed a lower expression of nitrotyrosine, and 4-hydroxynonenal and higher expression of endothelial nitric oxide synthase and sulfotransferase-4A1 proteins, oxidative stress markers ( Table 1 ). Conclusion: Taken together, these data indicate that mitochondria reveal neuroprotection through the attenuation of inflammation against stroke. Further investigations into the role of neuroprotection of mitochondria transplantation are needed to determine whether it can be an effective therapy for stroke patients.

Exploration of the Risk Factors of Anemia in Patients with Tuberculous Meningitis in South China.

Central nervous system (CNS) infection has a high incidence and mortality worldwide. Tuberculous meningitis (TBM) accounts for approximately 5-6% of all extrapulmonary tuberculosis (TB), and is considered an extremely lethal form of CNS TB, which has become an important threat to human health. Anemia is a common symptom of TB, and its prevalence is generally higher in patients with TBM than in other meningitis patients and healthy individuals. Anemia can increase a person's susceptibility to common infectious diseases, including TB, by compromising the immune system. Information regarding anemia during the hospitalization of TBM is still scarce in China. This study aimed to describe in detail the prevalence of anemia in patients with TBM in Southern China and its association with the clinical forms of TB, as well as other characteristics of these patients. We conducted a retrospective analysis of patients diagnosed with TBM at two tertiary hospitals in southern China. The demographic characteristics, clinical characteristics, and laboratory results of 114 patients with TBM were collected. Multivariate logistic regression analysis was performed to explore the risk factors for anemia in patients with TBM. Electronic medical record data of adult patients diagnosed with TBM from January 2004 to December 2019 were reviewed. Among 134 patients with TBM, 20 were excluded and 114 were analyzed, of whom 33 had anemic, the prevalence rate of anemia was 28.9%. Among patients with anemia, 51.5% had hypochromic microcytic anemia, 33.3% had normochromic normocytic anemia, and 15.2% had macrocytic anemia. Fever duration, TBM grade III and ESR were found to be independent predictors of anemia. Anemia was highly prevalent in patients with TBM, mainly hypochromic microcytic anemia. Besides, Fever duration, TBM grade III and ESR are predictors of anemia in patients with TBM.

Nurses' Knowledge of First Aid Management of Burn Patients at the Peshawar Burn and Plastic Surgery Center

A burn is an injury to the skin and tissues caused by chemical, electricity, radiation or heat. Burn injuries cause a relatively high morbidity and mortality rates worldwide. Objective: to assess first aid knowledge of nurses working in burn centers. Methods: A descriptive cross-sectional design with a sample size of 84 using an appropriate sampling technique was used in the study. The study was conducted in July 2022 and he August at the Peshawar Burn and Plastic Surgery Center. The instrument used for data collection was his 10-item self-structured questionnaire with a Chronbach alpha reliability of 0.87. SPSS version 24.0 was used to calculate frequencies and percentages for categorical variables. Results: Overall, 56% of participants reported having a good knowledge of burns, while 32% of participants reported being average, and 12% of participants reported first aid for burn patients reported low knowledge. Conclusions: This study concluded that nurses working in burn and plastic surgery departments have good knowledge of first aid administration

Remodeling liver microenvironment by L-arginine loaded hollow polydopamine nanoparticles for liver cirrhosis treatment

Liver cirrhosis is a liver disease with a high mortality rate worldwide, and antifibrotic drugs are commonly used clinically to alleviate the symptoms, but there are still many challenges. Many studies have shown that excessive reactive oxygen species (ROS) in the microenvironment of liver lesions is an important factor leading to the development of liver cirrhosis. Herein, a nanomedicine-mediated antioxidant therapy was utilized to remodel liver microenvironment and hence reverse the process of cirrhosis from the root. Firstly, L-arginine (L-Arg) loaded and pPB peptide modified PEGylated hollow polydopamine (HPDA) nanoparticles (L-Arg@HPDA-PEG-pPB, L@HPp) were prepared successfully. The in vitro and in vivo experiment showed that L@HPp significantly inhibited oxidative stress and inflammatory reaction, reduced the activation of hepatic stellate cells (HSCs), inhibited the pro-fibrosis molecular pathway, and reduced the deposition of extracellular matrix (ECM), thereby effectively inhibiting liver fibrosis. The pPB peptide modification increased the targeting effect to HSCs. In addition, the oxidative microenvironment in liver cirrhosis promoted the transformation of the loaded L-Arg to nitric oxide (NO), and the latter one caused vascular dilation and further relieved portal hypertension, a typical complication of liver cirrhosis. Therefore, L@HPp had a good prospect of clinical application in the treatment of liver cirrhosis and its complications.

Integrating Transcriptomics and Metabolomics to Explore the Novel Pathway of Fusobacterium nucleatum Invading Colon Cancer Cells

Colorectal cancer (CRC) is a malignancy with a very high incidence and mortality rate worldwide. Fusobacterium nucleatum bacteria and their metabolites play a role in inducing and promoting CRC; however, no studies on the exchange of information between Fusobacterium nucleatum extracellular vesicles (Fnevs) and CRC cells have been reported. Our research shows that Fusobacterium nucleatum ATCC25586 secretes extracellular vesicles carrying active substances from parental bacteria which are endocytosed by colon cancer cells. Moreover, Fnevs promote the proliferation, migration, and invasion of CRC cells and inhibit apoptosis; they also improve the ability of CRC cells to resist oxidative stress and SOD enzyme activity. The genes differentially expressed after transcriptome sequencing are mostly involved in the positive regulation of tumor cell proliferation. After detecting differential metabolites using liquid chromatography-tandem mass spectrometry, Fnevs were found to promote cell proliferation by regulating amino acid biosynthesis in CRC cells and metabolic pathways such as central carbon metabolism, protein digestion, and uptake in cancer. In summary, this study not only found new evidence of the synergistic effect of pathogenic bacteria and colon cancer tumor cells, but also provides a new direction for the early diagnosis and targeted treatment of colon cancer.

Changes of energy metabolism in failing heart and its regulation by SIRT3.

Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.

Gamma-Aminobutyric Acid Type A Receptor Subunit Pi is a potential chemoresistance regulator in colorectal cancer.

Colorectal cancer (CRC) is one of the cancers with high morbidity and mortality worldwide. Chemotherapy is commonly used for metastatic or more advanced CRC. The mechanism of CRC chemoresistance is still under active investigation. Therefore, we identify and validate differentially expressed genes (DEGs) between oxaliplatin/5-FU resistant and sensitive CRC cells. Three datasets of colorectal cancer patients (GSE28691, GSE81006, and GSE77932) from the Gene Expression Omnibus (GEO) database were analyzed and volcano plots for DEGs were generated using the GEO2R tool. The intersection of three GEO datasets showed that GABRP was significantly upregulated in chemo-resistant CRC cells or patients with an adjusted p-value less than 0.01. The potential protein-protein interaction (PPI) network with GABRP was analyzed by the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) website. The PPI network predicted ANKRD66, CLINT1, HAP1, PLCL1, GABARPAP, GABARAPL1, NSF, GABARAPL2, TRAK2, and CLIC3 had a high likelihood to interact with GABRP. Especially, GABARAP, GABARAPL1, ANKRD66, CLINT1, and CLIC3 were enriched as the most possibly associated proteins with GABRP among the networks. GABRP was significantly more expressed in both oxaliplatin/5-FU resistant CRC cells than in those counterpart sensitive CRC cells using quantitative PCR (qPCR) analysis. Consistently, TCGA, Oncomine, andHuman Protein Atlas (HPA) databases confirmed that higher expression of GABRP was robustly foundin CRC patients than those inothervarious cancer types or normal colon tissues. We identify GABRP as a promising drug target to mediate oxaliplatin or 5-FU resistance in CRC. It provided the theoretical basis and potential clinical value for CRC patients.

Malignant cancer may increase the risk of all-cause in-hospital mortality in patients with acute myocardial infarction: a multicenter retrospective study of two large public databases

BackgroundAcute myocardial infarction (AMI) and cancer are diseases with high morbidity and mortality worldwide, bringing a serious economic burden, and they share some risk factors. The purpose of this study was to determine the effect of cancer on the all-cause in-hospital mortality of patients with AMI.MethodsThis multicenter retrospective study analyzed patients with AMI from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and eICU Collaborative Research Database (eICU-CRD) in the United States. Patients were divided into two groups based on whether they had concomitant malignant cancer: cancer and noncancer groups. The outcome was all-cause in-hospital mortality. The association between the two groups and their outcomes were analyzed using Kaplan–Meier and Cox proportional-hazards regression models. Propensity score matching (PSM) and propensity score based inverse probability of treatment weighting (IPTW) were used to further adjust for confounding variables to verify the stability of the results.ResultsThe study included 3,034 and 5,968 patients with AMI from the MIMIC-IV database and the eICU-CRD, respectively. Kaplan–Meier survival curves indicated that the probability of in-hospital survival was lower in patients with cancer than in those without cancer. After adjusting for potential confounding variables using multivariable Cox proportional hazards regression, the risk of all-cause in-hospital mortality was significantly higher in the cancer than the noncancer group, and the HR (95% CI) values for the cancer group were 1.56(1.22,1.98) and 1.35(1.01,1.79) in the MIMIC-IV database and the eICU-CRD, respectively. The same results were obtained after using PSM and IPTW, which further verified the results.ConclusionsAmong the patients with AMI, the all-cause in-hospital mortality risk of those with cancer was higher than those without cancer. Therefore, when treating such patients, comprehensive considerations should be made from a multidisciplinary perspective involving cardiology and oncology, with the treatment plan adjusted accordingly.

The role of major immune cells in myocardial infarction.

Myocardial infarction (MI) is a cardiovascular disease (CVD) with high morbidity and mortality worldwide, often leading to adverse cardiac remodeling and heart failure, which is a serious threat to human life and health. The immune system makes an important contribution to the maintenance of normal cardiac function. In the disease process of MI, necrotic cardiomyocytes release signals that activate nonspecific immunity and trigger the action of specific immunity. Complex immune cells play an important role in all stages of MI progression by removing necrotic cardiomyocytes and tissue and promoting the healing of damaged tissue cells. With the development of biomaterials, cardiac patches have become an emerging method of repairing MI, and the development of engineered cardiac patches through the construction of multiple animal models of MI can help treat MI. This review introduces immune cells involved in the development of MI, summarizes the commonly used animal models of MI and the newly developed cardiac patch, so as to provide scientific reference for the accurate diagnosis and effective treatment of MI.

Daurisoline suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting MEK1/2 kinase.

Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancers and has a high mortality rate worldwide. The 5-year survival rate of ESCC patients in developing countries is <20%. Hence, there is an urgent need for developing new and effective treatments that are based on newly-discovered emerging molecules and pathways to prevent ESCC occurrence and recurrence. We investigated the effects of Daurisoline, a bis-benzylisoquinoline alkaloid extracted from the rhizome of menisperum dauricum, on ESCC cell proliferation and elucidated the molecular mechanisms underlying its functions. To explore the effects of Daurisoline on ESCC growth in vitro and in vivo, cell proliferation assays and anchorage-independent growth assays were performed and a patient-derived xenograft (PDX) model was established. Subsequently, phosphoproteomics, molecular docking analysis, pull down assays, mutation experiments and in vitro kinase assay were performed to explore the mechanism of Daurisoline's function on ESCC. Daurisoline inhibited ESCC proliferation in vitro and reduced ESCC PDX exnograft growth in vivo by reducing ERK1/2 phosphorylation. Furthermore, it directly bound to MEK1 (at Asn78 and Lys97) and MEK2 (at Asp194 and Asp212) kinases to inactivate the ERK1/2 signaling pathway. Our results suggest that Daurisoline is a dual inhibitor of MEK1 and MEK2 and suppresses ESCC growth both in vitro and in vivo by inactivating the ERK1/2 signaling pathway. This is first report on the use of MEK inhibitor for ESCC and highlights its potential applications for ESCC treatment and prevention.

Role of adrenergic receptors in shock.

Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)-hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets.

Investigation of drug-related problems in patients hospitalized in chest disease wards: A randomized controlled trial.

Objective: According to the World Health Organization (WHO), chest diseases are among the 10 diseases that cause the highest mortality worldwide. Drug-related problems (DRPs), readmission, and antimicrobial resistance are critical problems in chest disease wards. Active involvement of clinical pharmacists (CPs) who are focused on reducing the risks of potential problems is needed. The aim of this study is to investigate the effects of pharmaceutical care (PC) services on the pulmonology service. Method: A randomized controlled trial at a university hospital in Istanbul was conducted between June 2020 and December 2021. The participants were randomized into the control group (CG) and intervention group (IG). In the CG, CPs identified and classified the DRPs according to Pharmaceutical Care Network Europe v9.0 (PCNE) and provided solutions to DRPs for the IG. The effect of PC services was evaluated by the number and classification of DRPs, and readmissions within 30days were compared between the two groups. Results: Out of 168 patients, 82 were assigned to the IG. The average number of medicines administered per patient in the CG and IG was 14.45 ± 7.59 and 15.5 ± 6.18, respectively. In the CG and IG, the numbers of patients with DRPs were 62 and 46, respectively. The total number of DRPs was 160 for CG and 76 for IG. A statistically significant difference was found in favor of the IG, in terms of the number of patients with DRPs, the total number of DRPs, and readmission within 30 days (p < 0.05). Conclusion: In this study, CP recommendations were highly accepted by the healthcare team. Pharmaceutical care services provided by CPs would decrease possible DRPs and led to positive therapeutic outcomes. Cognitive clinical pharmacy services have beneficial effects on health care, and these services should be expanded in all settings where patients and pharmacists are present.

Immunoprofiling of Equine Plasma against Deinagkistrodon acutus in Taiwan: Key to Understanding Differential Neutralization Potency in Immunized Horses.

Snakebite envenoming is a public health issue linked to high mortality and morbidity rates worldwide. Although antivenom has been the mainstay treatment for envenomed victims receiving medical care, the diverse therapeutic efficacy of the produced antivenom is a major limitation. Deinagkistrodon acutus is a venomous snake that poses significant concern of risks to human life in Taiwan, and successful production of antivenom against D. acutus envenoming remains a considerable challenge. Among groups of horses subjected to immunization schedules, few or none subsequently meet the quality required for further scale-up harvesting. The determinants underlying the variable immune responses of horses to D. acutus venom are currently unknown. In this study, we assessed the immunoprofiles of high-potency and low-potency horse plasma against D. acutus venom and explored the conspicuous differences between these two groups. Based on the results of liquid chromatography with tandem mass spectrometry (LC-MS/MS), acutolysin A was identified as the major component of venom proteins that immunoreacted differentially with the two plasma samples. Our findings indicate underlying differences in antivenoms with variable neutralization efficacies, and may provide valuable insights for improvement of antivenom production in the future.

Application and practice of trimodal prehabilitation model in preoperative management of patients with lung cancer undergoing video-assisted thoracoscopic surgery.

Lung cancer is one of the malignant tumors with high mortality worldwide. To date, the most effective treatment of non-small cell lung cancer (NSCLC) is still surgical resection. Video-assisted thoracoscopic surgery has become the main surgical approach. Tumor patients are the high-risk perioperative population. At present, how to optimize perioperative management measures to improve the patient's body function and promote the rehabilitation after video-assisted thoracoscopic surgery is a hot research topic for medical staff. In this study, 148 patients with lung cancer were selected as the research object, to analyze and discuss the application value of trimodal prehabilitation model in preoperative management of patients with lung cancer undergoing video-assisted thoracoscopic surgery.

Significant Changes in Cytoplasmic Amino Acid Composition Occur in the Transition between Mid-Exponential and Stationary Phases of Growth of Staphylococcus aureus: An Example of Adaptive Homeostasis in Response to Nutrient Limitations

The bacterial pathogen Staphylococcus aureus causes a wide range of infections that result in high morbidity and mortality rates worldwide. S. aureus is known for its capacity to survive harsh environments between hosts and certain strains are very efficient as opportunistic pathogens. It is important to understand their capacities for metabolic adaptation in response to changing environmental conditions. This investigation aimed to explore the alterations in the amino acid compositions of the cytoplasm as nutrients became limiting during the growth of S. aureus. Cells were grown under optimal growth conditions and harvested at the mid-exponential and stationary phases of growth and then extracted for the analyses of amino acids in the cytoplasm. The analyses revealed that the stationary phase cells had a significantly higher concentration of total cytoplasmic amino acids compared with cells at the mid-exponential phase and displayed substantial alterations in amino acid composition. Aspartic acid was the major amino acid in the stationary phase cells, whereas glutamic acid was the most abundant in the mid-exponential cells. The glutamic acid was reduced by 47% of its original value when the growth was extended to the stationary phase. Interestingly, certain amino acids were either absent or present depending on the phase of growth. These outcomes are in line with the premise that bacterial cells of S. aureus transition into a different form of metabolic homeostasis in the shift between the exponential and stationary phases of growth, as nutrients become depleted and waste products accumulate in the external medium. The ability of S. aureus to continually and promptly adapt to differences within growth phases may represent an essential strategy assisting its virulence as a successful opportunistic pathogen to establish infections. An understanding of the switch mechanisms controlling these obvious alterations in amino acids through the growth/life cycle of this virulent pathogen may provide novel clinical strategies to battle infection.

An anoikis-based signature for predicting prognosis in hepatocellular carcinoma with machine learning.

Background: Hepatocellular carcinoma (HCC) is a common malignancy with high mortality worldwide. Despite advancements in diagnosis and treatment in recent years, there is still an urgent unmet need to explore the underlying mechanisms and novel prognostic markers. Anoikis has received considerable attention because of its involvement in the progression of human malignancies. However, the potential mechanism of anoikis-related genes (ANRGs) involvement in HCC progression remains unclear. Methods: We use comprehensive bioinformatics analyses to determine the expression profile of ANRGs and their prognostic implications in HCC. Next, a risk score model was established by least absolute shrinkage and selection operator (Lasso) Cox regression analysis. Then, the prognostic value of the risk score in HCC and its correlation with clinical characteristics of HCC patients were further explored. Additionally, machine learning was utilized to identify the outstanding ANRGs to the risk score. Finally, the protein expression of DAP3 was examined on a tissue microarray (TMA), and the potential mechanisms of DAP3 in HCC was explored. Results: ANRGs were dysregulated in HCC, with a low frequency of somatic mutations and associated with prognosis of HCC patients. Then, nine ANRGs were selected to construct a risk score signature based on the LASSO model. The signature presented a strong ability of risk stratification and prediction for overall survival in HCC patients.Additionally, high risk scores were closely correlated with unfavorable clinical features such as advanced pathological stage, poor histological differentiation and vascular invasion. Moreover, The XGBoost algorithm verified that DAP3 was an important risk score contributor. Further immunohistochemistry determined the elevated expression of DAP3 in HCC tissues compared with nontumor tissues. Finally, functional analyses showed that DAP3 may promote HCC progression through multiple cancer-related pathways and suppress immune infiltration. Conclusion: In conclusion, the anoikis-based signature can be utilized as a novel prognostic biomarker for HCC, and DAP3 may play an important role in the development and progression of HCC.

Rngtt governs biliary-derived liver regeneration initiation by transcriptional regulation of mTORC1 and Dnmt1 in zebrafish.

In cases of end-stage liver diseases, the proliferation of existing hepatocytes is compromised, a feature of human chronic liver disease, in which most hepatocytes are dysfunctional. So far, liver transplantation represents the only curative therapeutic solution for advanced liver diseases, and the shortage of donor organs leads to high morbidity and mortality worldwide. The promising treatment is to prompt the biliary epithelial cells (BECs) transdifferentiation. However, the critical factors governing the initiation of BEC-derived liver regeneration are largely unknown. The zebrafish has advantages in large-scale genetic screens to identify the critical factors involved in liver regeneration. Here, we combined N-ethyl-N-nitrosourea screen, positional cloning, transgenic lines, antibody staining, and in situ hybridization methods and identified a liver regeneration defect mutant ( lrd ) using the zebrafish extensive liver injury model. Through positional cloning and genomic sequencing, we mapped the mutation site to rngtt . Loss of rngtt leads to the defects of BEC dedifferentiation, bipotential progenitor cell activation, and cell proliferation in the initiation stage of liver regeneration. The transdifferentiation from BECs to hepatocytes did not occur even at the late stage of liver regeneration. Mechanically, Rngtt transcriptionally regulates the attachment of mRNA cap to mTOR complex 1 (mTORC1) components and dnmt1 to maintain the activation of mTORC1 and DNA methylation in BECs after severe liver injury and prompt BEC to hepatocyte conversion. Furthermore, rptor and dnmt1 mutants displayed the same liver regeneration defects as rngtt mutation. In conclusion, our results suggest Rngtt is a new factor that initiates BEC-derived liver regeneration.

A Zinc- and Calcium-Rich Lysosomal Nanoreactor Rescues Monocyte/Macrophage Dysfunction under Sepsis.

Sepsis is a dysregulation of the immune response to pathogens and has high morbidity and mortality worldwide. However, the unclear mapping and course of dysregulated immune cells currently hinders the development of advanced therapeutic strategies to treat sepsis. Here, evidence is provided using single-cell RNA sequencing from peripheral blood mononuclear cells in sepsis that pathogens attacking monocytes/macrophages disrupt their immune function. The results reveal an enormous decline in monocytes/macrophages in sepsis and chart the evolution of their impaired phagocytosis (Pha) capabilities. Inspired by these findings, nanoparticles, named "Alpha-MOFs," are developed that target dysfunctional monocytes/macrophages to actively (A) lift (L) Pha by the release of lysosome-sensitive ions from a mineralized metal-organic framework (MOF). Alpha-MOFs have good stability and biosafety in peripheral blood and efficiently targeted monocytes/macrophages. They also release calcium and zinc ions into monocyte/macrophage lysosomes to promote the Pha and degradation of bacteria. Taken together, these results suggest that Alpha-MOFs rescue monocytes/macrophages dysfunction and effectively improve their survival rate during sepsis.

Effect of vaccination on clinical outcomes in COVID-19 positive chronic kidney disease patients on haemodialysis

Introduction: Coronavirus disease 2019 (COVID-19) resulted in high mortality worldwide, with significantly higher mortality among patients with comorbidities including chronic kidney disease (CKD). Vaccines were developed against COVID-19 and it was given emergency approval because of the associated high mortality. There are only few studies on the efficacy of vaccine in CKD patients on haemodialysis. Effect of vaccination on clinical outcomes in COVID-19 positive CKD patients on haemodialysis was studied. Materials and methods: In this retrospective study on CKD patients on haemodialysis with confirmed COVID-19 infection, comparison was done on the clinical outcomes between the vaccinated and unvaccinated population. Results: Of the 104 patients, 74 patients were vaccinated against COVID-19 and 30 were unvaccinated. The study population received either covishield (50) or covaxin (24) which were the approved vaccines in India at that time. Among the vaccinated group 15 (20%) needed invasive mechanical ventilation and 16 (53%) in the unvaccinated group (P value 0.001). There were 16 (22%) deaths in the vaccinated group and 15 (50%) in the unvaccinated group with a significantly higher mortality in the unvaccinated group (P value 0.005). 11 (21%) patients on covishiled and 4 (18%) on covaxin needed invasive mechanical ventilation and there were 12 (24%) deaths in the covishield group and 4 (18%) in covaxin group. Conclusion: Severity of disease and mortality is less in vaccinated CKD patients on haemodialysis compared to unvaccinated reiterating the importance of vaccination against COVID-19 in high risk patients.