Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

Etoposide combined with cytarabine and pegfilgrastim for poorly mobilizing patients with multiple myeloma and lymphoma: A prospective multicentre study.

A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.

Successful treatment pure red cell aplasia after ABO major mismatched allogeneic hematopoietic stem cell transplantation with avatrombopag and low dose rituximab.

BACKGROUND: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo-HSCT yet. STUDY DESIGN AND METHODS: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO-incompatible allo-HSCT. RESULTS: Five cases of PRCA were identified from 72 patients who underwent allo-HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+  and O+ , respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low-dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low-dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. CONCLUSION: Low-dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO-incompatible allo-HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails.

From clinical variables to multiomics analysis: a margin morphology-based gross classification system for hepatocellular carcinoma stratification.

OBJECTIVE: Selecting interventions for patients with solitary hepatocellular carcinoma (HCC) remains a challenge. Despite gross classification being proposed as a potential prognostic predictor, its widespread use has been restricted due to inadequate studies with sufficient patient numbers and the lack of established mechanisms. We sought to investigate the prognostic impacts on patients with HCC of different gross subtypes and assess their corresponding molecular landscapes. DESIGN: A prospective cohort of 400 patients who underwent hepatic resection for solitary HCC was reviewed and analysed and gross classification was assessed. Multiomics analyses were performed on tumours and non-tumour tissues from 49 patients to investigate the mechanisms underlying gross classification. Inverse probability of treatment weight (IPTW) was used to control for confounding factors. RESULTS: Overall 3-year survival rates varied significantly among the four gross subtypes (type I: 91%, type II: 80%, type III: 74.6%, type IV: 38.8%). Type IV was found to be independently associated with poor prognosis in both the entire cohort and the IPTW cohort. The four gross subtypes exhibited three distinct transcriptional modules. Particularly, type IV tumours exhibited increased angiogenesis and immune score as well as decreased metabolic pathways, together with highest frequency of TP53 mutations. Patients with type IV HCC may benefit from adjuvant intra-arterial therapy other than the other three subtypes. Accordingly, a modified trichotomous margin morphological gross classification was established. CONCLUSION: Different gross types of HCC showed significantly different prognosis and molecular characteristics. Gross classification may aid in development of precise individualised diagnosis and treatment strategies for HCC.

Evolving roles of CD38 metabolism in solid tumour microenvironment.

Given that plenty of clinical findings and reviews have already explained in detail on the progression of CD38 in multiple myeloma and haematological system tumours, here we no longer give unnecessary discussion on the above progression. Though therapeutic antibodies have been regarded as a greatest breakthrough in multiple myeloma immunotherapies due to the durable anti-tumour responses in the clinic, but the role of CD38 in the immunologic regulation and evasion of non-hematopoietic solid tumours are just initiated and controversial. Therefore, we will focus on the bio-function of CD38 enzymatic substrates or metabolites in the variety of non-hematopoietic malignancies and the potential therapeutic value of targeting the CD38-NAD+ or CD38-cADPR/ADPR signal axis. Though limited, we review some ongoing researches and clinical trials on therapeutic approaches in solid tumour as well.

FBXO6 regulates the antiviral immune responses via mediating alveolar macrophages survival.

Inducing early apoptosis in alveolar macrophages is one of the strategies influenza A virus (IAV) evolved to subvert host immunity. Correspondingly, the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 is reported to interact with virus polymerase basic protein 1-frame 2 (PB1-F2) accessory protein to counteract virus-induced apoptosis. Herein, we report that one of the F-box proteins, FBXO6, promotes proteasomal degradation of NLRX1, and thus facilitates IAV-induced alveolar macrophages apoptosis and modulates both macrophage survival and type I interferon (IFN) signaling. We observed that FBXO6-deficient mice infected with IAV exhibited decreased pulmonary viral replication, alleviated inflammatory-associated pulmonary dysfunction, and less mortality. Analysis of the lungs of IAV-infected mice revealed markedly reduced leukocyte recruitment but enhanced production of type I IFN in Fbxo6-/- mice. Furthermore, increased type I IFN production and decreased viral replication were recapitulated in FBXO6 knockdown macrophages and associated with reduced apoptosis. Through gain- and loss-of-function studies, we found lung resident macrophages but not bone marrow-derived macrophages play a key role in the differences FBXO6 signaling pathway brings in the antiviral immune response. In further investigation, we identified that FBXO6 interacted with and promoted the proteasomal degradation of NLRX1. Together, our results demonstrate that FBXO6 negatively regulates immunity against IAV infection by enhancing the degradation of NLRX1 and thus impairs the survival of alveolar macrophages and antiviral immunity of the host.

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.

Effectiveness of single-dose 6 mg pegfilgrastim in mobilizing peripheral blood stem cells in allogeneic hematopoietic cell transplantation donors.

A single injection of 12 mg pegfilgrastim was used to mobilize peripheral blood progenitor cells (PBPCs) from healthy donors in some studies. The purpose of this study was to determine if 6 mg of pegfilgrastim was effective and safe for mobilizing CD34+ cells in donors for allogeneic hematopoietic stem cell transplantation. We conducted a retrospective case-matched design. A single dosage of 6 mg pegfilgrastim was used to mobilize PBPCs from 60 healthy donors. Granulocyte colony-stimulating factor (G-CSF, 10 µg/kg) was administered daily to the matched donors. Leukapheresis was scheduled to commence on day 4 of the mobilization regimen. The median yielded CD34+ cell in the pegfilgrastim group was higher than those in the G-CSF group, at 5.06 × 106/kg recipient weight. The 73.3% of donors mobilized with pegfilgrastim yielded >4 × 106 cells/kg CD34+ cells in a single apheresis procedure when compared to the 33.3% of donors mobilized with G-CSF (P < 0.001). The myeloid-derived suppressor cells (MDSC) proportion in the pegfilgrastim group was significantly higher than that in the G-CSF group (P < 0.001). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was higher in the G-CSF group than that in the pegfilgrastim group (26.7% vs. 11.7%), without statistical difference. In comparison to the G-CSF group, the pegfilgrastim group had a reduced median pain intensity numerical rating scale score (1 vs. 2). A single 6 mg dosage of pegfilgrastim is effective and safe for allogeneic PBPCs collection from healthy donors. Pegfilgrastim may decrease the incidence of aGVHD by boosting MDSCs, which need further investigation.

Multiple-day administration of fosaprepitant combined with tropisetron and olanzapine improves the prevention of nausea and vomiting in patients receiving chemotherapy prior to autologous hematopoietic stem cell transplant: a retrospective study.

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase.

Successful haploidentical transplantation using plasma exchange and post-transplantation cyclophosphamide for severe aplastic anemia patients with anti-human leukocyte antigen donor-specific antibodies.

Haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HSCT) has emerged as a novel strategy to treat patients suffering from severe aplastic anemia (SAA) who lack matched donors due to the availability and easy access to sources of donors. Anti-human leukocyte antigen donor-specific antibodies (DSAs) have been found to influence the outcome of Haplo-HSCT. Between March 2016 and March 2020, 7 SAA patients with DSAs underwent Haplo-HSCT in our center. We employed a modified protocol of post-transplantation cyclophosphamide and plasma exchange aiming to decrease the levels of DSAs. All 7 patients successfully achieved hematopoietic reconstruction. The median follow-up is 31 (range, 8 to 45) months. They survived and were transfusion-independent in the absence of clonality. No occurrence of primary or secondary graft failure has been noted among any of the patients. There was no severe acute and chronic GVHD occurred. This protocol is effective for Haplo-HSCT in SAA patients with DSAs, which provides an option for the SAA patients without other alternative donor.

Noncanonical Role of FBXO6 in Regulating Antiviral Immunity.

The evolutionarily conserved F-box family of proteins are well known for their role as the key component of SKP1-Cullin1-F-box (SCF) E3 ligase in controlling cell cycle, cell proliferation and cell death, carcinogenesis, and cancer metastasis. However, thus far, there is only limited investigation on their involvement in antiviral immunity. In contrast to the canonical function of FBXO6 associated with SCF E3 ligase complex, we report, in this study, that FBXO6 can also potently regulate the activation of IFN-I signaling during host response to viral infection by targeting the key transcription factor IFN-regulatory factor 3 (IRF3) for accelerated degradation independent of SCF in human embryonic kidney cells (HEK293T) and human lung cancer epithelial cells (A549). Structure and function delineation has further revealed that FBXO6 interacts with IAD domain of IRF3 through its FBA region to induce ubiquitination and degradation of IRF3 without the involvement of SCF. Thus, our studies have identified a general but, to our knowledge, previously unrecognized role and a novel noncanonical mechanism of FBXO6 in modulating IFN-I-mediated antiviral immune responses, which may protect the host from immunopathology of overreactive and harmful IFN-I production.

Combinatorial screening of a panel of FDA-approved drugs identifies several candidates with anti-Ebola activities.

Ebola virus (EBOV), pathogen of Ebola hemorrhagic fever (EHF), is an enveloped filamental RNA virus. Recently, the EHF crisis occurred in the Democratic Republic of the Congo again highlights the urgency for its clinical treatments. However, no Food and Drug Administration (FDA)-approved therapeutics are currently available. Drug repurposing screening is a time- and cost-effective approach for identifying anti-EBOV therapeutics. Here, by combinatorial screening using pseudovirion and minigenome replicon systems we have identified several FDA-approved drugs with significant anti-EBOV activities. These potential candidates include azithromycin, clomiphene, chloroquine, digitoxin, epigallocatechin-gallate, fluvastatin, tetrandrine and tamoxifen. Mechanistic studies revealed that fluvastatin inhibited EBOV pseudovirion entry by blocking the pathway of mevalonate biosynthesis, while the inhibitory effect of azithromycin on EBOV maybe due to its intrinsic cationic amphiphilic structure altering the homeostasis of later endosomal vesicle similar as tamoxifen. Moreover, based on structure and pathway analyses, the anti-EBOV activity has been extended to other family members of statins, such as simvastatin, and multiple other cardiac glycoside drugs, some of which exhibited even stronger activities. More importantly, in searching for drug interaction, we found various synergy between several anti-EBOV drug combinations, showing substantial and powerful synergistic against EBOV infection. In conclusion, our work illustrates a successful and productive approach to identify new mechanisms and targets for treating EBOV infection by combinatorial screening of FDA-approved drugs.

L-Theanine Attenuates Isoflurane-Induced Injury in Neural Stem Cells and Cognitive Impairment in Neonatal Mice.

The neurodevelopmental toxicity of isoflurane has been proved by many studies, which makes it essential to explore the underline mechanisms and search for protective agents to attenuate its neurotoxcity. Accumulating evidence showed that L-theanine had neuroprotective effects on injured neurons and the developing brain. The present study was designed to investigate whether L-theanine could attenuate isoflurane-induced damage in neural stem cells and cognitive impairment in young mice, and to discuss the role of protein kinase B (Akt)-glycogen synthase kinase 3ß (GSK-3ß) signaling pathway in this process. Multipotential neural stem cells (NSCs) and C57BL/6J mice were treated with either gas mixture, isoflurane, or L-theanine 30 min prior to isoflurane exposure, respectively. NSC viability was detected by CCK-8 assay. NSC proliferation and apoptosis were assessed by immunofluorescence and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, respectively. The levels of cleaved caspase-3 and phosphorylated (p)-Akt and p-GSK-3ß in NSCs were tested by Western blotting. Cognitive function of mice was tested by Morris Water Maze at postnatal day (P) 30-35. The results indicated that isoflurane exposure inhibited NSC viability and proliferation, promoted NSC apoptosis as well as increased caspase-3 activation and down-regulated the expressions of p-Akt and p-GSK-3ß in NSCs, and that isoflurane exposure on neonatal mice would induce late cognitive impairment. Pretreatment with L-theanine could attenuate isoflurane-caused damage in NSCs and cognitive deficits in young mice. Addinonally, the protective effects of L-theanine on isoflurane-injured NSCs could be reversed by Akt inhibitor Triciribine. Our data showed that pretreatment with L-theanine eliminated the NSC damage and cognitive impairment induced by isoflurane exposure, and that the neuroprotective effect of L-theanine was associated with the Akt-GSK-3ß signaling pathway.

Multi-regional sequencing reveals intratumor heterogeneity and positive selection of somatic mtDNA mutations in hepatocellular carcinoma and colorectal cancer.

Recent studies have revealed significant intratumor heterogeneity (ITH) of nuclear genome mutations and highlighted its function in tumor progression and treatment resistance. However, the ITH of somatic mitochondrial DNA (mtDNA) mutations detected in cancers remains unknown. In this study, we performed multiregional mtDNA sequencing of tumor and paratumor tissue samples from 12 hepatocellular carcinoma (HCC) and 13 colorectal cancer (CRC) patients. A substantial level of mtDNA mutations was found in paired non-HCC inflammatory tissues, suggesting that these tissues might not be mtDNA-genetically "normal." Moreover, our data indicated that the ITH of somatic mtDNA mutations was a common feature in HCC and CRC patients. In addition, we found that shared mutations which were observed in at least 2 samples in each patient exhibited a significantly higher heteroplasmic level than mutations that were private to a specific tumor region from both HCC (p = 0.039) and CRC patients (p = 0.001). The heteroplasmic level of shared mutations was positively correlated with intratumoral recurrence of mtDNA mutations. We also found that shared mutations in tumor tissues with a higher degree of pathogenicity risk exhibited a higher heteroplasmic level and intratumoral recurrence in both HCC and CRC patients. These findings suggest that some mtDNA mutations may undergo positive selection during the clonal expansion. Taken together, our analyses identified various levels of ITH of somatic mtDNA mutations in HCC and CRC patients and provided evidence supporting the positive selection working on some somatic mtDNA mutations in tumor tissues.

Ketamine inhibits human sperm function by Ca(2+)-related mechanism.

Ketamine, a dissociative anesthetic, which was widely used in human and animal medicine, has become a popular recreational drug, as it can induce hallucinatory effects. Ketamine abuse can cause serious damage to many aspects of the organism, mainly reflected in the nervous system and urinary system. It has also been reported that ketamine can impair the male genital system. However, the detailed effect of ketamine on human spermatozoa remains unclear. Thus, we investigated the in vitro effects of ketamine on human sperm functions, to elucidate the underlying mechanism. Human sperm were treated in vitro with different concentrations of ketamine (0, 0.125, 0.25, 0.5, 1 g/L). The results showed that 0.25-1 g/L ketamine inhibited sperm total motility, progressive motility and linear velocity, in a dose-dependent manner. In addition, the sperm's ability to penetrate viscous medium and the progesterone-induced acrosome reaction were significantly inhibited by ketamine. Ketamine did not affect sperm viability, capacitation and spontaneous acrosome reaction. The intracellular calcium concentration ([Ca(2+)]i), which is a central factor in the regulation of human sperm function, was decreased by ketamine (0.125-1 g/L) in a dose-dependent manner. Furthermore, the currents of the sperm-specific Ca(2+) channel, CatSper, which modulates Ca(2+) influx in sperm, were inhibited by ketamine (0.125-1 g/L) in a dose-dependent manner. Our findings suggest that ketamine induces its toxic effects on human sperm functions by reducing sperm [Ca(2+)]i through inhibition of CatSper channel.

A global molecular phylogeny and timescale of evolution for Cryptocercus woodroaches.

Cryptocercus is a genus of sub-social wood-feeding cockroaches that represents the sister group to the eusocial termites. We generated mitochondrial (12S+16S rRNA, COII), nuclear (28S rRNA) and Blattbacterium endosymbiont (16S+23S rRNA) sequence data for 8 new Chinese species, and combined these with previously available data to undertake the most extensive analysis of phylogenetic relationships within the genus to date. As expected, phylogenetic relationships among Blattabacterium strains were found to be congruent with those of their hosts. Three major clades were found to exist in Asian populations, one representing taxa from the Hengduan mountains in Southwestern China, a second including taxa from Russia, Korea, Northeastern China, and Yunnan in the Hengduan Mountains, and a third including taxa from the Qinling Mountains and Daba Mountains in Central China. A molecular dating analysis using 7 termite fossils to calibrate the molecular clock indicated that the divergence of American and Asian Cryptocercus occurred 55.09Ma (41.55-72.28Ma 95% CI), and that the radiations of American and Asian taxa occurred 28.48Ma (20.83-37.95Ma 95% CI) and 20.97Ma (15.78-27.21Ma 95% CI) respectively. Reconstruction of ancestral geographic distributions using S-DIVA suggested Cryptocercus was originally distributed across both continents, as opposed to ancestral migration of Cryptocercus from one continent to the other. The last common ancestor of Asian Cryptocercus was inferred to have existed in Central China. An examination of male chromosome numbers in Asian Cryptocercus showed that diploid numbers vary from 2n=15 to 2n=41, and indicates the presence of eight new species. Our study represents the most comprehensive phylogenetic and biogeographic study yet performed for this important group of cockroaches.

Hospitalization of elderly diabetic patients: characteristics, reasons for admission, and gender differences.

BACKGROUND: Understanding the differences in characteristics, gender, and common causes for admission in hospitalized elderly diabetic patients provides a theoretical basis for their successful management. This study explored the reasons and gender differences in hospitalizations of elderly patients with diabetes mellitus. METHODS: Patients aged ≥60 years who had received a diagnosis of diabetes by the time of discharge, from 1 January 2011 to 1 January 2014, were retrospectively enrolled. Hospitalization data of the patients were collected, and reasons for hospitalization were analyzed based on chief complaints and principle diagnosis. RESULTS: The most frequent reasons stated for admission were related to the chronic complications of diabetes (42.1 %), seconded by hyperglycemia (26.4 %) and infection (15.7 %). Ketonuria, ketonemia, or diabetic ketoacidosis was more commonly seen in women than men, whereas diabetic nephropathy and neoplasms were more frequently found in men than women. Regarding infection as a cause of hospitalization, the 4 main types were respiratory tract (44.5 %), urinary tract (20.3 %), gastrointestinal (14.8 %), and skin and soft tissue (10.9 %). Respiratory tract infection was significantly more common in men (61.4 %) than women (31 %, P = 0.001), whereas urinary tract infection was more frequent in women (29.6 %) than men (8.8 %, P = 0.004). CONCLUSION: The most frequent reasons for hospital admission in elderly diabetic patients were chronic complications of diabetes, hyperglycemia, and infection. Men and women differed in reasons for hospital admission.

NAF-1 antagonizes starvation-induced autophagy through AMPK signaling pathway in cardiomyocytes.

NAF-1 (nutrient-deprivation autophagy factor-1), an autophagy-related gene-related (ATG) protein, has been implicated in the autophagic pro-survival response. However, its role in autophagy has not been examined in the cardiomyocytes. In this study, we found that nutritional stress (NS) induced by glucose deprivation strongly induced autophagy in cultured neonatal rat cardiomyocytes, which was associated with NAF-1 down-regulation in cardiomyocytes under NS conditions. Furthermore, we demonstrate that ectopic expression of NAF-1 was sufficient to inhibit autophagy in cardiomyocytes under glucose deprivation conditions. Moreover, results of the co-immunoprecipitation assay indicate that NAF-1 antagonized autophagy by promoting the interaction between Beclin1 and Bcl-2 in NS-induced cardiomyocytes. Importantly, our results indicate that overexpression of NAF-1 significantly inhibited AMPK activity and protected cardiomyocytes from NS-induced cell death. Taken together, these data show that ectopic expression of NAF-1 antagonizes the degree of autophagy in cardiomyocytes and enhances cell survival during starvation conditions.

[Effect of three-dimensional acellular fibrotic lung matrices on fibroblast-to-myofibroblast differentiation].

OBJECTIVE: To explore the effect of three-dimensional (3D) and two-dimensional (2D) acellular fibrotic lung matrices on fibroblast-to-myofibroblast differentiation. METHODS: Twenty adult SD rats were randomly divided into control group and idiopathic pulmonary fibrosis (IPF) group. The pulmonary fibrosis was induced by Bleomycin. Normal and fibrotic decellularized lungs were made, then sections with 500 µm (3D) and 10 µm (2D) thick were cut by a standard Vibratome. The lung fibroblasts were isolated from the lungs of SD rats at postnatal day 1, which were seeded dropwise into different slices (2D/3D normal and fibrotic scaffolds), then cultured for 72 hours in vitro. The protein expression of alpha smooth muscle actin (α-SMA) was measured by immunofluorescence staining and western blot. RESULTS: There was no spatial structure both in 2D normal scaffold and fibrotic scaffold. The spatial structure was different between 3D normal scaffold and fibrotic scaffold. The relative expression amount of α-SMA in 2D normal and fibrotic scaffold group and none scaffold group were (4.64 ± 0.36, 4.86 ± 0.37, 4.67 ± 0.35, respectively), there were no difference among them (P>0.05). In 3D fibrotic scaffold group, the relative expression amount of α-SMA was significantly increased compared with those in 3D normal scaffold group and 2D fibrotic scaffold group (6.29 ± 0.85 vs 4.85 ± 0.56, 4.86 ± 0.37, both P<0.05). CONCLUSION: 3D acellular fibrotic lung scaffold can promote fibroblast-to-myofibroblast differentiation.