Induced Pluripotent Stem Cells Facilitate the Development and Evaluation of Cancer Vaccines.

Cancer vaccines are an approach to elicit amplified antigen-specific immune responses. Induced pluripotent stem cells (iPSCs) have potential utility for the development of universal vaccines due to their intrinsic antigenic epitopes. Concurrently, iPSCs can undergo pluripotent differentiation and are thus a stable source of both antigen-presenting cells for producing immune cell-based vaccines and tumor organoids for facilitating the exploration and adaptive assessment of tumor vaccines. This review describes the specific contributions of iPSCs to vaccine development, summarizes their diverse developmental trajectories, and discusses the obstacles to their application along with potential solutions.

Proximal femoral nail antirotation versus InterTan nail for the treatment of intertrochanteric fractures: A systematic review and meta-analysis.

PURPOSE: This meta-analysis compared the efficacy and safety of Proximal Femoral Nail Antirotation (PFNA) and InterTan Nail in the treatment of intertrochanteric fractures. Given the high incidence of femoral intertrochanteric fractures in the elderly population and its impact on quality of life, choosing the most effective and safest surgical option is crucial. PFNA and InterTan are currently two commonly used techniques, but there is a lack of systematic evaluation comparing their safety and effectiveness. This study aims to fill this knowledge gap through Meta-analysis, providing clinicians with evidence-based treatment recommendations. MATERIALS AND METHODS: A computer search was used to search for published literature on PFNA and InterTan in the treatment of intertrochanteric fractures in PubMed (Medline), Web of Science, Embase, Cochrane Library (CENTRAL), Cinahl, CBM, and CNKI.A total of 853 related literatures were retrieved, and 15 literatures were finally included. Newcastle-Ottawa-Scale and Cochrane systematic review methodologies were used to assess the quality of the literature. Meta-analysis was performed using Review Manager 5.4 software, following data extraction. RESULTS: The comparison found that during the surgical treatment of intertrochanteric fractures, the operation time, fluoroscopy time, and blood loss in the PFNA group were significantly shorter than those in the InterTan group, and the difference was statistically significant. In terms of postoperative complication rates, the InterTan group had a significant advantage over the PFNA group. Shaft fracture, varus collapse, cut out, screw migration, and pain of hip and thigh were the most likely to occur in the PFNA group, and the differences were all statistically significant. In terms of postoperative efficacy, the results of the PFNA group and the InterTan group were comparable, and there was no significant differences. CONCLUSIONS: When selecting surgical techniques for the treatment of femoral intertrochanteric fractures, it is necessary to conduct individualized assessments based on the patient's overall health status, surgical tolerance, and post-operative recovery needs. For patients who cannot tolerate long-term surgery or are in poor physical condition, PFNA may be more appropriate. While for patients who can tolerate long-term surgery or have more complex conditions, InterTan may be more suitable.

Acute pancreatitis and refractory hypercalcemia in the third trimester caused by parathyroid carcinoma.

BACKGROUND: Hypercalcemia can be a rare contributor to acute pancreatitis (AP) in pregnancy. This is primarily due to primary hyperparathyroidism (PHPT), resulting from parathyroid carcinoma. We exhibited a case report to analyze the diagnosis and treatment during the onset of hypercalcemia-induced AP. CASE PRESENTATION: A 32-year-old primigravida presented with acute pancreatitis near full-term gestation. Following a cesarean delivery, there was a reduction in serum amylase and peripancreatic exudate, but her serum calcium concentrations persistently elevated over 4.0 mmol/L. Interventions to lower the hypercalcemia were only temporarily effective, until a high serum parathyroid hormone (PTH) concentration of 1404 pg/mL was detected. Ultrasound revealed a 31 mm × 24 mm hypoechoic oval nodule in the left lower lobe of the thyroid gland. She underwent a parathyroidectomy, resulting in a dramatic decrease in serum PTH level, from preoperative levels of 2051 pg/mL to 299 pg/mL just 20 minutes after removal. Similarly, her serum calcium declined from 3.82 mmol/L to 1.73 mmol/L within 24 hours postoperatively. The final histopathology suggested parathyroid carcinoma. CONCLUSION: When refractory hypercalcemia is present, serum PTH levels should be measured to determine PHPT. Parathyroidectomy is the optimal strategy for alleviating hypercalcemia and clarifying the underlying pathology.

Nanobody peptide conjugate: a novel CD163 based broad neutralizing strategy against porcine reproductive and respiratory syndrome virus.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent swine pathogen, which has caused adverse impact on the global swine industry for almost 30 years. However, due to the immune suppression caused by the virus and the genetic diversity in PRRSV, no virus-targeting broad neutralizing strategy has been successfully developed yet. Antiviral peptide and nanobody have attracted extensive attention with the ease in production and the efficacy in practice. In this study, four new fusion proteins named nanobody peptide conjugates (NPCs) were developed by combining PRRSV specific non-neutralizing nanobodies with CD163-derived peptides targeting the receptor binding domain (RBD) of PRRSV proteins. RESULTS: Four NPCs were successfully constructed using two nanobodies against PRRSV N and nsp9 individually, recombining with two antiviral peptides 4H7 or 8H2 from porcine CD163 respectively. All four NPCs demonstrated specific capability of binding to PRRSV and broad inhibitory effect against various lineages of PRRSV in a dose-dependent manner. NPCs interfere with the binding of the RBD of PRRSV proteins to CD163 in the PRRSV pre-attachment stage by CD163 epitope peptides in the assistance of Nb components. NPCs also suppress viral replication during the stage of post-attachment, and the inhibitory effects depend on the antiviral functions of Nb parts in NPCs, including the interference in long viral RNA synthesis, NF-κB and IFN-ß activation. Moreover, an interaction was predicted between aa K31 and T32 sites of neutralizing domain 4H7 of NPC-N/nsp9-4H7 and the motif 171NLRLTG176 of PRRSV GP2a. The motif 28SSS30 of neutralizing domain 8H2 of NPC-N/nsp9-8H2 could also form hydrogens to bind with the motif 152NAFLP156 of PRRSV GP3. The study provides valuable insights into the structural characteristics and potential functional implications of the RBD of PRRSV proteins. Finally, as indicated in a mouse model, NPC intranasally inoculated in vivo for 12-24 h sustains the significant neutralizing activity against PRRSV. These findings inspire the potential of NPC as a preventive measure to reduce the transmission risk in the host population against respiratory infectious agents like PRRSV. CONCLUSION: The aim of the current study was to develop a peptide based bioactive compound to neutralize various PRRSV strains. The new antiviral NPC (nanobody peptide conjugate) consists of a specific nanobody targeting the viral protein and a neutralizing CD163 epitope peptide for virus blocking and provides significant antiviral activity. The study will greatly promote the antiviral drug R&D against PRRSV and enlighten a new strategy against other viral diseases.

Case report: Magnetic resonance imaging findings of patients with diffuse uterine leiomyomatosis.

Background: Diffuse uterine leiomyomatosis (DUL) is a seldom-seen condition, with only a handful of cases of magnetic resonance imaging (MRI) findings documented. In clinical settings, it is often mistaken for multiple uterine leiomyomas due to a lack of adequate recognition of DUL. Objective: This study shows two instances of DUL, underscoring their MRI findings to improve preoperative diagnostic precision. Conclusion: For patients exhibiting multiple uterine leiomyomas with masses present in the parametrial and abdominal cavities, consideration should be given to diagnosing DUL with DPL. The discoveries outlined in this paper furnish insights that can assist in directing treatment choices.

Summary of evidence on prevention and management of bladder dysfunction in patients after radical hysterectomy.

AIM: To retrieve, analyse and summarize the relevant evidence on the prevention and management of bladder dysfunction in patients with cervical ancer after radical hysterectomy. DESIGN: Overview of systematic reviews. METHODS: 11 databases were searched for relevant studies from top to bottom according to the '6S' model of evidence-based resources. Two independent reviewers selected the articles, extracted the data and appraised the quality of the included reviews based on different types of evaluation tools. RESULTS: A total of 13 studies were identified, including four clinical consultants, four guidelines, four systematic reviews and one randomized controlled trial. 29 best evidence were summarized from five aspects, including definition, risk factors, assessment, prevention and management.

Prevalence and genotype distribution of HPV infection from Hangzhou of Zhejiang Province pre- and during COVID-19 pandemic.

Limited data exist on HPV prevalence and genotyping during the COVID-19 pandemic. A total of 130,243 samples from 129, 652 women and 591 men who visited the First People's Hospital of Linping District between 2016 and 2022 were recruited. HPV genotypes were detected by polymerase chain reaction (PCR) amplification and nucleic acid molecular hybridization. Then the prevalence characteristics of HPV genotypes and trends in HPV infection rates from 2016 to 2022 were analyzed. Results showed that among the study population, the overall prevalence of HPV infection was 15.29%, with 11.25% having single HPV infections and 4.04% having multiple HPV infections, consistent with previous findings. HPV genotypes exhibited similar distribution patterns in both male and female groups, with HPV16, HPV52, HPV58, HPV18, and HPV39 being the most prevalent. Age-related analysis unveiled a bimodal pattern in HPV prevalence, with peaks in infection rates observed in individuals below 20 and those aged 61-65 years. Comparing the pre- and during COVID-19 periods revealed significant disparities in HPV infections, with variations in specific HPV genotypes, including 16, 18, 35, 45, 52, 58, 59, and 68. This study provides valuable insights into the prevalence, distribution, and epidemiological characteristics of HPV infections in a large population. It also highlights the potential impact of the COVID-19 pandemic on HPV trends.

Intermittent Catheterization Continuity Care on Bladder Function Recovery and Quality of Life in Patients After Radical Hysterectomy for Cervical Cancer: A Quasi-Experimental Study.

Background: Bladder dysfunction is a common complication following radical hysterectomy, affecting patients' QOL. Exploring interventions, particularly IC continuity care, is crucial for identifying strategies to enhance postoperative outcomes. This study aimed to assess the impact of continuous intermittent catheterization (IC) care on bladder function recovery and quality of life (QOL) in patients undergoing radical hysterectomy for cervical cancer. Methods: The primary outcome measured was the time to bladder function recovery, with secondary outcomes comprising EORTC QLQ-C30 assessments at 3 and 6 months post-surgery, as well as EORTC QLQ-CX24 evaluations. Meanwhile, urinary complications, readmissions, and outpatient follow-up were also compared. Results: Among the 128 participants, with 64 in each group, indwelling catheterization durations were similar. However, the IC continuity care group exhibited significantly shorter IC duration and bladder recovery time. This group demonstrated superior QOL, lower occurrence rates post-IC, reduced urethral injuries, and higher readmission and outpatient follow-up rates. Conclusion: This study underscores continuous IC care emerges as a beneficial intervention, facilitating accelerated bladder function recovery and improved QOL in patients following radical hysterectomy for cervical cancer.

Retinal ganglion cell type-specific expression of synuclein family members revealed by scRNA-sequencing.

Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive analysis of the single-cell transcriptome in healthy and injured retinas to investigate their expression patterns and roles. We observed the expression of all synuclein family members in retinal ganglion cells (RGCs), which remained consistent across species (human, mouse, and chicken). We unveiled differential expression of Snca across distinct clusters (highly expressed in most), while Sncb and Sncg displayed uniform expression across all clusters. Further, we observed a decreased expression in RGCs following traumatic axonal injury. However, the proportion of α-Syn-positive RGCs in all RGCs and α-Syn-positive intrinsically photosensitive retinal ganglion cells (ipRGCs) in all ipRGCs remained unaltered. Lastly, we identified changes in communication patterns preceding cell death, with particular significance in the pleiotrophin-nucleolin (Ptn-Ncl) and neural cell adhesion molecule signaling pathways, where communication differences were pronounced between cells with varying expression levels of Snca. Our study employs an innovative approach using scRNA-seq to characterize synuclein expression in health retinal cells, specifically focusing on RGC subtypes, advances our knowledge of retinal physiology and pathology.

Comparison of Ciprofol-Based and Propofol-Based Total Intravenous Anesthesia on Microvascular Decompression of Facial Nerve with Neurophysiological Monitoring: A Randomized Non-Inferiority Trial.

Purpose: Ciprofol is a recently developed short-acting gamma-aminobutyric acid receptor agonist with a higher potency than that of propofol. As a new sedative drug, there are few clinical studies on ciprofol. We sought to examine the safety and efficacy of ciprofol use for general anesthesia in neurosurgical individuals undergoing neurosurgical surgery with intraoperative neurophysiological monitoring (IONM). Patients and Methods: This single-center, non-inferiority, single-blind, randomized controlled trial was conducted from September 13, 2022 to September 22, 2023. 120 patients undergoing elective microvascular decompression surgery (MVD) with IONM were randomly assigned to receive either ciprofol or propofol. The primary outcome of this study was the amplitude of intraoperative compound muscle action potential decline, and the secondary outcome included the indexes related to neurophysiological monitoring and anesthesia outcomes. Results: The mean values of the primary outcome in the ciprofol group and the propofol group were 64.7±44.1 and 53.4±35.4, respectively. Furthermore, the 95% confidence interval of the difference was -25.78 to 3.12, with the upper limit of the difference being lower than the non-inferiority boundary of 6.6. Ciprofol could achieve non-inferior effectiveness in comparison with propofol in IONM of MVD. The result during anesthesia induction showed that the magnitude of the blood pressure drop and the incidence of injection pain in the ciprofol group were significantly lower than those in the propofol group (P<0.05). The sedative drug and norepinephrine consumption in the ciprofol group was significantly lower than that in the propofol group (P<0.05). Conclusion: Ciprofol is not inferior to propofol in the effectiveness and safety of IONM and the surgical outcome. Concurrently, ciprofol is more conducive to reducing injection pain and improving hemodynamic stability, which may be more suitable for IONM-related surgery, and has a broad application prospect.

PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

MiR-34a promotes mitochondrial pathway of apoptosis in human salivary gland epithelial cells by activating NF-κB signaling.

To investigate the potential molecular mechanism of miR-34a in Sjögren's syndrome (SS). Transmission electron microscopy was used to observe the salivary gland tissues of mild and severe SS patients. SS mouse model was constructed and injected with miR-34a antagonist. HSGE cells were transfected with miR-34a mimic. Starbase predicted miR-34a binding sites and validated them with dual-luciferase reporter assays. Immunohistochemistry, HE staining, CCK-8, TUNEL assay, flow cytometry, immunofluorescence and Western Blot were used to investigate the effects of miR-34a on NF-κB signaling and mitochondrial pathway of apoptosis in HSGE cells. Severe SS patients showed obvious mitochondrial damage and apoptosis in salivary glands. MiR-34a was overexpressed and NF-κB signaling is activated in salivary glands of severe SS patients. Inhibition of miR-34a alleviated salivary gland injury in SS mice, as well as inhibited the activation of NF-κB signaling and mitochondrial pathway of apoptosis. In conclusion, miR-34a promoted NF-κB signaling by targeting IκBα, thereby causing mitochondrial pathway apoptosis and aggravating SS-induced salivary gland damage.

A critical event frequent lead to reversible spinal cord injury during vertebral column resection surgery.

OBJECTIVE: To report a "critical phase" (between osteotomy completion and correction beginning) that will frequently lead to the reversible intraoperative neurophysiological monitoring (IOM) change during posterior vertebral column resection (PVCR) surgery. METHODS: The study sample consisted of 120 patients with severe spine deformity who underwent PVCR and deformity correction surgeries. Those patients were recruited consecutively from 2010 to 2018 January in our spine center. The detailed IOM data (the amplitude of MEP & SEP) and its corresponding surgical points were collected prospectively. Early and long-term postoperative neurologic outcomes were assessed for the following functions: motor, sensory, and pain at immediate postoperative and 1-year post-operation in this cases series. RESULTS: A total of 105 (105/120) patients presented varying degrees of IOM reduction in the critical phase; the mean IOM amplitude retention vs rescue rate was 27% ± 11.2 versus 58% ± 16.9, P < 0.01 (MEP) & 34% ± 8.3 versus 66% ± 12.4 P < 0.01 (SEP). Patients with postoperative spinal deficits often had a significantly longer IOM-alerting duration than the patients without (p < 0.01, Mann-Whitney U-test), and IOM-alerting duration greater than 39.5 min was identified as an independent predictor of the risk of postoperative spinal deficits. CONCLUSIONS: The reversible IOM events probably often appear in the critical phase during PVCR surgery. The new postoperative spinal deficits are possible for patients without satisfied IOM recovery or alerting duration greater than 39.5 min. Timely and suitable surgical interventions are useful for rescuing the IOM alerts.

The change of symptom clusters in gastric cancer patients during the perioperative period: a longitudinal study.

AIM AND OBJECTIVES: The purpose of this study was to describe the number, type and trajectory of symptom clusters during the perioperative period in patients with gastric cancer at four different time points. The study also aimed to identify the changes and consistency of these symptom clusters over time. DESIGN: This was a longitudinal study. METHODS: This study was conducted in a tertiary cancer hospital with 205 patients with gastric cancer. The M.D. Anderson Symptom Inventory Gastrointestinal Cancer Module was used to assess the incidence and severity of symptom clusters. Exploratory factor analysis was used to extract symptom clusters. RESULTS: The study identified four symptom clusters in patients with gastric cancer during the perioperative period: gastrointestinal symptom cluster, physical symptom cluster, psychological symptom cluster, and sleep disturbance symptom cluster. These clusters were observed across two to four time points. CONCLUSION: The findings of this study provide scientific evidence for medical staff and researchers to better understand the symptoms of patients with gastrointestinal cancer during the perioperative period. These findings can help develop individualized interventions for managing symptoms. RELEVANCE TO CLINICAL PRACTICE: Gastric cancer patients suffered from various symptom clusters, which lasted from one day before surgery to one month after surgery. They should be given careful consideration by clinical staff.

Calcium-sensing receptor-mediated macrophage polarization improves myocardial remodeling in spontaneously hypertensive rats.

Chronic inflammation is a key element in the progression of essential hypertension (EH). Calcium plays a key role in inflammation, so its receptor, the calcium-sensing receptor (CaSR), is an essential mediator of the inflammatory process. Compelling evidence suggests that CaSR mediates inflammation in tissues and immune cells, where it mediates their activity and chemotaxis. Macrophages (Mφs) play a major role in the inflammatory response process. This study provided convincing evidence that R568, a positive regulator of CaSR, was effective in lowering blood pressure in spontaneously hypertensive rats (SHRs), improving cardiac function by alleviating cardiac hypertrophy and fibrosis. R568 can increase the content of CaSR and M2 macrophages (M2Mφs, exert an anti-inflammatory effect) in myocardial tissue, reduce M1 macrophages (M1Mφs), which have a pro-inflammatory effect in this process. In contrast, NPS2143, a negative state regulator of CaSR, exerted the opposite effect in all of the above experiments. Following this study, R568 increased CaSR content in SHR myocardial tissue, lowered blood pressure, promoted macrophages to M2Mφs and improved myocardial fibrosis, but interestingly, both M1Mφs and M2Mφs were increased in the peritoneal cavity of SHRs, the number of M2Mφs remained lower than M1Mφs. In vitro, R568 increased CaSR content in RAW264.7 cells (a macrophage cell line), regulating intracellular Ca2+ ([Ca2+]i) inhibited NOD-like receptor family protein 3 (NLRP3) inflammasome activation and ultimately prevented its conversion to M1Mφs. The results showed that a decrease in CaSR in hypertensive rats causes further development of hypertension and cardiac damage. EH myocardial remodeling can be improved by CaSR overexpression by suppressing NLRP3 inflammasome activation and macrophage polarization toward M1Mφs and increasing M2Mφs.

Preparation of Ag@3D-TiO2 Scaffolds and Determination of its Antimicrobial Properties and Osteogenesis-promoting Ability.

OBJECTIVES: The micro-nano structure of 3D-printed porous titanium (Ti) alloy with excellent performance in avoiding stress shielding and promoting bone tissue differentiation provides a new opportunity for the development of bone implants, but it necessitates higher requirements for bone tissue differentiation and the antibacterial properties of bone implants in clinical practice. METHODS: This study investigated the preparation, antimicrobial properties, and osteogenesis-promoting ability of the 3D printed porous Ti alloy anodic oxidized Ag-carrying (Ag@3D-TiO2) scaffolds. The 3D printed porous Ti alloy (3D-Ti), anodized 3D printed porous Ti alloy (3D-TiO2), and Ag@3D-TiO2 scaffolds were synthesized using electron beam melting. The antimicrobial properties of the scaffolds were examined using antibacterial tests and their cytocompatibility was assessed using a cell proliferation assay and acridine orange/ethidium bromide (AO/EB) staining. In vitro cellular assays were used to investigate the effects of the scaffold microstructural features on cell activity, proliferation, and osteogenesis-related genes and proteins. In vivo animal experiments were used to evaluate the anti-inflammatory and osteogenesis-promoting abilities of the scaffolds. RESULTS: The Ag@3D-TiO2 scaffolds exhibited sustained anti-microbial activity over time, enhanced cell proliferation, facilitated osteogenic differentiation, and increased extracellular matrix mineralization. In addition, alkaline phosphatase (ALP), collagen type I (COL-I), and osteocalcin (OCN)-related genes and proteins were upregulated. In vivo animal implantation experiments, the anti-inflammatory effect of the Ag@3D-TiO2 scaffolds were observed using histology, and a large amount of fibrous connective tissue was present around it; the Ag@3D-TiO2 scaffolds were more bio-compatible with the surrounding tissues compared with 3D-Ti and 3D-TiO2; a large amount of uniformly distributed neoplastic bone tissue existed in their pores, and the chronic systemic toxicity test showed that the 3D-Ti, 3D-TiO2, and Ag@3D-TiO2 scaffolds are biologically safe. CONCLUSION: The goal of this study was to create a scaffold that exhibits antimicrobial properties and can aid bone growth, making it highly suitable for use in bone tissue engineering.

Bioinformatics and system biology approaches to determine the connection of SARS-CoV-2 infection and intrahepatic cholangiocarcinoma.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), has infected millions of individuals worldwide, which poses a severe threat to human health. COVID-19 is a systemic ailment affecting various tissues and organs, including the lungs and liver. Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver cancer, and cancer patients are particularly at high risk of SARS-CoV-2 infection. Nonetheless, few studies have investigated the impact of COVID-19 on ICC patients. METHODS: With the methods of systems biology and bioinformatics, this study explored the link between COVID-19 and ICC, and searched for potential therapeutic drugs. RESULTS: This study identified a total of 70 common differentially expressed genes (DEGs) shared by both diseases, shedding light on their shared functionalities. Enrichment analysis pinpointed metabolism and immunity as the primary areas influenced by these common genes. Subsequently, through protein-protein interaction (PPI) network analysis, we identified SCD, ACSL5, ACAT2, HSD17B4, ALDOA, ACSS1, ACADSB, CYP51A1, PSAT1, and HKDC1 as hub genes. Additionally, 44 transcription factors (TFs) and 112 microRNAs (miRNAs) were forecasted to regulate the hub genes. Most importantly, several drug candidates (Periodate-oxidized adenosine, Desipramine, Quercetin, Perfluoroheptanoic acid, Tetrandrine, Pentadecafluorooctanoic acid, Benzo[a]pyrene, SARIN, Dorzolamide, 8-Bromo-cAMP) may prove effective in treating ICC and COVID-19. CONCLUSION: This study is expected to provide valuable references and potential drugs for future research and treatment of COVID-19 and ICC.

Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm.

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.