Life-threatening gastrointestinal bleeding caused by cytomegalovirus-induced duodenal ulcer in a patient with AIDS: A case report.

Background: The reasons for gastrointestinal bleeding among patients with acquired immune deficiency syndrome (AIDS) were complex. Here we present an unusual case of life-threatening gastrointestinal bleeding caused by a cytomegalovirus-induced duodenal ulcer in an AIDS patient. Case presentation: A 31-year-old male with AIDS was admitted on July 18, 2023, complaining of abdominal pain for 38 days and intermittent hematochezia for 12 days. During his hospitalization, gastrointestinal endoscopy attributed gastrointestinal bleeding to a giant duodenal ulcer. Furthermore, cytomegalovirus(CMV) infection was confirmed as the reason for the ulcer through metagenomic next-generation sequencing (mNGs), hematoxylin-eosin(HE) staining, and immunohistochemistry (IHC) staining for the biopsy tissue. The patient's gastrointestinal bleeding was stopped by interventional embolization. Following a 4-week course of anti-CMV treatment, the giant duodenal ulcer was cured. Conclusions: For AIDS patients with gastrointestinal bleeding, the CMV-induced gastrointestinal ulcer should be considered. Comprehensive mothods (mNGs, HE staining and IHC staining for biopsy tissue) were benefit for confirmed diagnosis. Beside anti-CMV treatment, the interventional embolization is a choice for hemostasis.

Patterns and Prognosis of Local Recurrence of Nasopharyngeal Carcinoma after Intensity-modulated Radiotherapy.

Objective: To investigate the patterns of local failure and prognosis in patients with locally recurrent nasopharyngeal carcinoma (rNPC) after primary intensity-modulated radiotherapy (IMRT). Methods: The data of 298 patients with locally rNPC after IMRT were retrospectively analyzed. Magnetic resonance images of the initial and recurrent tumors were reviewed and, for patients with extra-nasopharyngeal local recurrence, the gross tumor volume of local recurrence was transferred to the original IMRT plan for dosimetry analysis. Significant prognostic factors for overall survival (OS) were selected by multivariate Cox regression analysis. Results: The commonest recurrence sites were the nasopharynx (93%, 277/298) and skull base (53.7%, 160/298). Of the 21 patients with extra-nasopharyngeal recurrence (19 cases valid), 12 had in-field failures, 4 had marginal failures, and 3 had out-field failures. The ethmoid sinus (57.1%, 4/7) and nasal cavity (28.6%, 2/7) were the most frequent sites of marginal and out-field failures. After median follow-up of 37 months, the 3-year and estimated 5-year OS rates were 57.3% and 41.7%, respectively. Multivariate analysis showed that age, recurrence interval, plasma Epstein-Barr virus (EBV) DNA level, and recurrent T stage were independent prognostic factors for OS. Conclusions: Local failure after IMRT occurs most commonly in the nasopharynx and skull base. In patients with extra-nasopharyngeal recurrence, in-field failure remains the main failure pattern, and marginal and out-field failures mainly occur in the ethmoid sinus and nasal cavity. Elder age, shorter recurrence interval, detectable plasma EBV DNA, and advanced recurrent T stage are negative predictors of OS in patients with rNPC.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Hydroxycitric Acid Alleviated Lung Ischemia-Reperfusion Injury by Inhibiting Oxidative Stress and Ferroptosis through the Hif-1α Pathway.

Lung ischemia-reperfusion injury (LIRI) is a prevalent occurrence in various pulmonary diseases and surgical procedures, including lung resections and transplantation. LIRI can result in systemic hypoxemia and multi-organ failure. Hydroxycitric acid (HCA), the primary acid present in the peel of Garcinia cambogia, exhibits anti-inflammatory, antioxidant, and anticancer properties. However, the effects of HCA on LIRI remain unknown. To investigate the impact of HCA on LIRI in mice, the mice were randomly divided into four groups: the control group, the I/R model group, and the I/R + low- or high-dose HCA groups. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia for 12 h followed by reoxygenation for 6 h to simulate in vitro LIRI. The results demonstrated that administration of HCA effectively attenuated lung injury, inflammation, and edema induced by ischemia reperfusion. Moreover, HCA treatment significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels while decreasing iron content and increasing superoxide dismutase (SOD) levels after ischemia-reperfusion insult. Mechanistically, HCA administration significantly inhibited Hif-1α and HO-1 upregulation both in vivo and in vitro. We found that HCA could also alleviate endothelial barrier damage in H/R-induced HUVECs in a concentration-dependent manner. In addition, overexpression of Hif-1α counteracted HCA-mediated inhibition of H/R-induced endothelial cell ferroptosis. In summary, these results indicate that HCA alleviated LIRI by inhibiting oxidative stress and ferroptosis through the Hif-1α pathway.

Are people living with HIV have a low vulnerability to omicron variant infection: results from a cross-sectional study in China.

BACKGROUND: A surge of more than 80 million Omicron variant infected cases was reported in China less than a month after the "zero COVID" strategy ended on December 7, 2022. In this circumstance, whether people living with HIV (PLWH) in China experience a similar risk is not clear. METHODS: A cross-sectional study was conducted in the Wuchang District of Wuhan between December 20, 2022, and January 18, 2023 through a self-administered online survey. PLWH and HIV-negative people aged ≥ 18 years old who volunteered for this survey were eligible. The prevalence of Omicron variant infection between PLWH and HIV-negative people was compared, and the factors associated with the Omicron variant infection among PLWH and HIV-negative people were further evaluated, respectively. RESULTS: In total, 890 PLWH and 1,364 HIV-negative adults from Wuchang District were enrolled. Among these participants, 690 PLWH (77.5%) and 1163 HIV-negative people (85.3%) reported SARS-CoV-2 infection. Gender, chronic disease conditions, and COVID-19 vaccination status significantly differed between the two groups. After adjusting gender, age, comorbidities, and COVID-19 vaccination status, the risk of SARS-CoV-2 infection among PLWH was significantly lower than among HIV-negative people (aOR 0.56, 95%CI 0.42-0.76). Multivariable logistic regression analysis showed that PLWH with older age and detectable HIV-viral load (HIV-VL) had decreased risk of SARS-CoV-2 infection (aOR 0.98, 95%CI 0.96-0.99; aOR 0.59, 95%CI 0.36-0.97). Compared with PLWH receiving one/two doses of COVID-19 vaccines, no significant differences in the risk of SARS-CoV-2 infection were observed among PLWH receiving three doses of inactivated vaccines and four doses of vaccines (three doses of inactivated vaccines plus one dose of inhaled recombinant adenovirus type 5 (AD5)-vectored vaccine). Among HIV-negative people, those receiving four doses of COVID-19 vaccines had a lower risk of SARS-CoV-2 infection than those receiving one/two doses (aOR 0.14, 95%CI 0.08-0.25). CONCLUSIONS: Our study proves that PLWH have a lower risk of Omicron variant infection than HIV-negative people. However, even PLWH with younger age and virological suppression should strengthen the prevention against SARS-CoV-2 infection. Three doses of inactivated vaccines plus one dose of inhaled recombinant AD5-vectored COVID-19 vaccine may provide better protection for HIV-negative people.

Case Report: Giant Oral Ulcers Attributed to Cytomegalovirus Infection in a Patient with AIDS.

Oral ulcers are often neglected in patients with AIDS. However, giant oral ulcers are uncommon and are usually suspected to be malignant lesions. Our study presents a case of giant ulcers in an AIDS patient that were initially suspected to be oral cancer. To assist with diagnosis, conventional microbiological tests, metagenomic next-generation sequencing, and a pathological examination were conducted on oral lesion biopsy specimens. The case was finally confirmed via hematoxylin-eosin staining and immunohistochemical staining to be a cytomegalovirus infection.

Characterization of peripheral cytokine-secreting cells responses in HIV/TB co-infection.

Background: Currently the responses of peripheral cytokine-secreting cells in the natural course of human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection haven't been fully elucidated. Methods: The function of peripheral proinflammatory, regulatory and cytotoxic cytokine-secreting cells were investigated by direct intracellular cytokine staining (ICS) and flow cytometry, additionally, the absolute numbers of different cytokine-secreting cells were measured among patients with HIV/TB co-infection (HT group), and compared them with the healthy controls (HC group), patients with TB (TB group) and patients with HIV infection (HIV group). After one week's anti-TB treatment, the changes of the percentages of cytokine-secreting cells were further evaluated in TB and HT groups. Results: Totally 26 individuals in the HC group, 51 in the TB group, 26 in the HIV group and 29 in the HT group were enrolled. The HT. HT group exhibited significantly lower absolute numbers of IFN-γ+CD4+, IFN-γ+CD8+, TNF-α+CD4+, IL17A+CD4+ T cells and TNF-α+CD14+ monocytes than the TB and HIV groups. Compared with the TB group, the percentages of CD8+ T cells secreting IFN-γ and perforin (p=0.010; p=0.043) were significantly lower among the HT group. Compared with the HIV group, the percentages of CD4+, CD8+ T cells and CD14+ monocytes secreting TNF-α (p=0.013; p=0.001; p<0.001) were significantly decreased, and the percentage of CD8+ T cells secreting IL-17A (p=0.015) was significantly increased among the HT group. Both the percentages of CD4+ T cells secreting TGF-ß (p<0.001; p=0.001), and CD4+ and CD8+ T cells secreting granzyme A (all p<0.001), were significantly higher among the HT group than among the TB group and HIV group. After one week's anti-TB treatment, an increased percentage of CD4+ T cells secreting TNF-α (p=0.003) was found in the TB group, and an increased percentage of CD8+ T cells secreting TNF-α (p=0.029) was found in the HT group. Conclusion: Significantly different functional profiles of peripheral proinflammatory, regulatory, and cytotoxic cytokine-secreting cells were observed in the natural course of HIV/TB co-infection compared to TB and HIV infection alone, even though the absolute numbers of those cells were significantly lower in HIV/TB co-infection. TNF-α-secreting CD8+ T cells may be a more sensitive marker for early evaluation of anti-TB treatment efficacy in patients with HIV/TB co-infection.

ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.

The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.

Unusual disseminated Talaromyces marneffei infection presenting with fever and diarrhea in an AIDS patient: a case report and literature review.

BACKGROUND: Gastrointestinal symptoms are not uncommon in patients infected with Talaromyces marneffei (T. marneffei). However, the reports on intestinal T. marneffei infection were rare. We report a case of disseminated T. marneffei infection with intestine involvement. CASE PRESENTATION: A 41-year-old female with acquired immune deficiency syndrome (AIDS) was admitted to our hospital for long-term fever, followed by abdominal pain and diarrhea. The colonoscopy performed in our hospital revealed ulcerative lesions in the colon and terminal ileum. Periodic acid-Schiff (PAS) staining of intestinal ulcer revealed that the small dots distributed inside and outside of the macrophages were yeast microorganisms. Further culture of bone marrow sample was confirmed T. marneffei positive. A diagnosis of disseminated T. marneffei infection was made, with intestine involvement. We also summarized the clinical characteristics, endoscopic findings and histopathological features of intestinal T. marneffei by literature review. CONCLUSION: In HIV-infected and other immunocompromised patients with gastrointestinal symptoms and/or associated abdominal imaging abnormalities, intestinal T. marneffei infection should be taken into consideration. Serious manifestations such as intestinal obstruction and intestinal perforation may occur. Early diagnosis is of great significance to prevent the deterioration of the illness and improve the prognosis. Histopathological examination and culture of intestinal lesions are helpful to improve the diagnosis of intestinal T. marneffei infection. ABBREVIATIONS: AIDS: acquired immune deficiency syndrome; ART: antiretroviral therapy; ESR: erythrocyte sedimentation rate; PPD:purified protein derivative; HE: Hematoxylin and eosin; PAS: Periodic acid-Schiff; CMV: cytomegalovirus; GMS:Gomori's methenamine silver nitrate.

Adverse pregnancy outcomes among pregnant women living with HIV in Hubei province, China: prevalence and risk factors.

Mother-to-child transmission of Human Immunodeficiency Virus (HIV) has been greatly reduced with the advance of intervention technology. However, adverse pregnancy outcomes (APOs) are still common, and little is known about the driving forces of APOs among pregnant women living with HIV in China. Between January 2004 and December 2020, a total of 638 pregnancies among pregnant women living with HIV were enrolled in this study, 84 (13.2%) pregnancies with 87 APOs were reported. Preterm birth (3.8%), ectopic pregnancy (3.4%), spontaneous abortion (2.0%), and embryo arrest (1.7%) were the most common APOs in pregnant women living with HIV. Exposure to antiretroviral drugs (ARVs) during the first trimester (RR = 4.077, 95% CI: 0.521, 1.484, P<0.001) and the first CD4+ T lymphocyte count (CD4 count)≤ 350/µl (RR = 2.227, 95% CI: 0.063, 0.991, P = 0.026) were risk factors of APOs. The age≤ 30 years (RR = -2.513, 95% CI: -1.067, -0.132, P = 0.012) was associated with the decreasing of APOs. Encouraging people to initiate combination antiretroviral therapy and reach a high CD4 count level before pregnancy would be helpful to prevent APOs. Pregnant women exposed to ARVs in the first trimester needed more attention for APOs.

The Role of CD4+CD8+ T Cells in HIV Infection With Tuberculosis.

Background: Tuberculosis (TB) is an important opportunistic infection in acquired immunodeficiency diseases (AIDS). Although the frequency of CD4+CD8+ double-positive (DP) T cells has been observed to increase in pathological conditions, their role (phenotypic and functional) is poorly described, especially in human immunodeficiency virus (HIV) infection with TB (HIV/TB (HT) coinfection). Methods: The percentage and phenotypic and functional properties of peripheral blood DP T cells in patients with HT coinfection in comparison to uninfected controls and to patients with HIV or TB mono-infection were analyzed by direct intracellular cytokine staining (ICS). Results: Total and CD4lowCD8high DP T cells were significantly increased in patients with both HIV and TB mono-infection, especially in patients with HT coinfection. Compared with healthy controls (HCs), the percentage of DP T cells expressing chemokine receptor 5 (CCR5) in patients with HT coinfection was significantly higher. Compared with HCs and patients with TB, a lower percentage of tumor necrosis factor α (TNF-α) secreting DP T cells and a higher percentage of granzyme A-secreting DP T cells were observed in patients with HIV mono-infection and HT coinfection, respectively. In addition, DP T cells expressed more cytolytic markers (granzyme A and perforin) than CD4+ T cells, but similarly to CD8+ T cells in patients with HT coinfection. Conclusions: Our data suggested that HT coinfection resulted in a marked increase in DP T cells, especially the CD4lowCD8high subpopulation. DP T cells may be susceptible to HT coinfection, and have the same cytotoxic function as CD8+ T cells.

A comparative study on ultrasound-guided elite, Mammotome, and core needle biopsy for diagnosing malignant breast masses.

Introduction: The present study aims to clarify the advantages and disadvantages of elite biopsy, to provide a reference for selecting the puncture method. Material and methods: A total of 802 patients with a BI-RADS grade ≥ 4, as evaluated by the molybdenum target, and measurable lesions revealed by colour Doppler ultrasound, who were admitted at our department from January 2017 to January 2018, were enrolled in the present study. These patients were randomly divided into three groups: elite, Mammotome and core needle biopsy groups. The pathological underestimation rate, diagnostic accordance rate, haematoma incidence rate, and costs of these three biopsy methods were compared. Results: The difference in diagnostic accordance rates between the elite biopsy group and core needle biopsy group was statistically significant (98.9% vs. 94.7%, p = 0.003), as well as between the Mammotome biopsy group and core needle biopsy group (99.6% vs. 94.7%, p < 0.001). The difference in pathological underestimation rates between the elite biopsy group and core needle biopsy group was statistically significant (7.2% vs. 37.3%, p < 0.001), as well as between the Mammotome biopsy group and core needle biopsy group (1.6% vs. 7.2%, p < 0.001). The difference between the Mammotome biopsy group and elite biopsy group was not statistically significant. The incidence of haematoma in the Mommotome, elite, and core needle groups was 15.9%, 13%, and 21.7%, respectively (13% vs. 21.7%, p = 0.021). Conclusions: Elite biopsy has a low rate of pathological underestimation and low incidence of haematoma, can improve the breast conserving rate, and has an affordable cost. As a biopsy method with high accuracy, safety, and economy, elite biopsy can be widely used in clinics.

[Application of porous tantalum Jumbo cup in revision of hip arthroplasty].

OBJECTIVE: To investigate the clinical effect of porous tantalum Jumbo cup on acetabular reconstruction in revision of total hip arthroplasty. METHODS: From September 2014 to December 2017, 18 patients(18 hips) with acetabular defect were reconstructed by porous tantalum Jumbo cup technology, including 6 males and 12 females;the age ranged from 54 to 76 years old with an average of(63.8±15.3) years. There were 6 cases of paprosky typeⅡA, 8 cases of typeⅡB, 2 cases of typeⅡC and 2 cases of type Ⅲ a. Harris score and visual analogue scale (VAS) were performed before and after operation. Imaging examination was performed to evaluate the position of hip rotation center and prosthesis, and to judge whether acetabular loosening, displacement and complications existed. RESULTS: All cases were followed up for 13 to 49 months, with an average of 20.6 months. Harris score increased from 54.6±4.7 to 86.5±3.2 one year after operation(P<0.01), and VAS score decreased from 6.8±0.7 to 0.8±0.6 one year after operation (P<0.01). The transverse coordinate of hip rotation center was (3.52±0.72) cm before operation and (3.47±0.54) cm after operation (P>0.05). The longitudinal coordinate of hip rotation center was improved from (3.02±0.84) cm before operation to (2.35±0.53) cm after operation (P<0.01). During the follow-up period, the Jumbo cup was well fixed without loosening and displacement, the acetabular cup had bone ingrowth in varying degrees, and no light transmission line and osteolysis around the acetabular cup were found. No complications such as infection and nerve injury occurred. CONCLUSION: The method of reconstructing acetabular bone defect with porous tantalum Jumbo cup is simple and easy, the early stability of acetabulum is good, and the short-term follow-up effect is good.

Choice of operative method for pancreaticojejunostomy and a multivariable study of pancreatic leakage in pancreaticoduodenectomy.

BACKGROUND: As one of the major abdominal operations, pancreaticoduodenectomy (PD) involves many organs. The operation is complex, and the scope of the operation is large, which can cause significant trauma in patients. The operation has a high rate of complications. Pancreatic leakage is the main complication after PD. When pancreatic leakage occurs after PD, it can often lead to abdominal bleeding and infection, threatening the lives of patients. One study found that pancreatic leakage was affected by many factors including the choice of pancreaticojejunostomy method which can be well controlled. AIM: To investigate the choice of operative methods for pancreaticojejunostomy and to conduct a multivariate study of pancreatic leakage in PD. METHODS: A total of 420 patients undergoing PD in our hospital from January 2014 to March 2019 were enrolled and divided into group A (n = 198) and group B (n = 222) according to the pancreatointestinal anastomosis method adopted during the operation. Duct-to-mucosa pancreatojejunostomy was performed in group A and bundled pancreaticojejunostomy was performed in group B. The operation time, intraoperative blood loss, and pancreatic leakage of the two groups were assessed. The occurrence of pancreatic leakage after the operation in different patients was analyzed. RESULTS: The differences in operative time and intraoperative bleeding between groups A and B were not significant (P > 0.05). In group A, the time of pancreatojejunostomy was 26.03 ± 4.40 min and pancreatic duct diameter was 3.90 ± 1.10 mm. These measurements were significantly higher than those in group B (P < 0.05). The differences in the occurrence of pancreatic leakage, abdominal infection, abdominal hemorrhage and gastric retention between group A and group B were not significant (P > 0.05). The rates of pancreatic leakage in patients with preoperative albumin < 30 g/L, preoperative jaundice time ≥ 8 wk, and pancreatic duct diameter < 3 mm, were 23.33%, 33.96%, and 19.01%, respectively. These were significantly higher than those in patients with preoperative albumin ≥ 30 g/L, preoperative jaundice time < 8 wk, and pancreatic duct diameter ≥ 3 cm (P < 0.05). Logistic regression analysis showed that preoperative albumin < 30 g/L, preoperative jaundice time ≥ 8 wk, and pancreatic duct diameter < 3 mm were risk factors for pancreatic leakage after PD (odds ratio = 2.038, 2.416 and 2.670, P < 0.05). CONCLUSION: The pancreatointestinal anastomosis method during PD has no significant effect on the occurrence of pancreatic leakage. The main risk factors for pancreatic leakage include preoperative albumin, preoperative jaundice time, and pancreatic duct diameter.

Simultaneous or Prior Activation of Intrahepatic Type I Interferon Signaling Leads to Hepatitis B Virus Persistence in a Mouse Model.

It remains controversial how interferon (IFN) response contributes to hepatitis B virus (HBV) control and pathogenesis. A previous study identified that hydrodynamic injection (HI) of type I IFN (IFN-I) inducer polyinosinic-poly(C) [poly(I·C)] leads to HBV clearance in a chronic HBV mouse model. However, recent studies have suggested that premature IFN-I activation in the liver may facilitate HBV persistence. In the present study, we investigated how the early IFN-I response induces an immunosuppressive signaling cascade and thus causes HBV persistence. We performed HI of the plasmid adeno-associated virus (pAAV)/HBV1.2 into adult BALB/c mice to establish an adult acute HBV replication model. Activation of the IFN-I signaling pathway following poly(I·C) stimulation or murine cytomegalovirus (MCMV) infection resulted in subsequent HBV persistence. HI of poly(I·C) with the pAAV/HBV1.2 plasmid resulted in not only the production of IFN-I and the anti-inflammatory cytokine interleukin-10 (IL-10) but also the expansion of intrahepatic regulatory T cells (Tregs), Kupffer cells (KCs), and myeloid-derived suppressor cells (MDSCs), all of which impaired the T cell response. However, when poly(I·C) was injected at day 14 after the HBV plasmid injection, it significantly enhanced HBV-specific T cell responses. In addition, interferon-alpha/beta receptor (IFNAR) blockade rescued T cell response by downregulating IL-10 expression and decreasing Treg and KC expansion. Consistently, Treg depletion or IL-10 blockade also controlled HBV replication. IMPORTANCE IFN-I plays a double-edged sword role during chronic HBV infection. Here, we identified that application of IFN-I at different time points causes contrast outcomes. Activation of the IFN-I pathway before HBV replication induces an immunosuppressive signaling cascade in the liver and consequently caused HBV persistence, while IFN-I activation post HBV infection enhances HBV-specific T cell responses and thus promotes HBV clearance. This result provided an important clue to the mechanism of HBV persistence in adult individuals.

Expression of caspase-3 and hypoxia inducible factor 1α in hepatocellular carcinoma complicated by hemorrhage and necrosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver. Its onset is latent, and it shows high heterogeneity and can readily experience intrahepatic metastasis or systemic metastasis, which seriously affects patients' quality of life. Numerous studies have shown that hypoxia inducible factor1α (HIF-1α) plays a significant role in the occurrence and development of tumors, as it promotes the formation of intratumoral vessels and plays a key role in their metastasis and invasion. Some studies have reported that caspase-3, which is induced by various factors, is involved in the apoptosis of tumor cells. AIM: To investigate the expression of caspase-3 and HIF-1α and their relationship to the prognosis of patients with primary HCC complicated by pathological changes of hemorrhage and necrosis. METHODS: A total of 88 patients with HCC complicated by pathological changes of hemorrhage and necrosis who were treated at our hospital from January 2017 to December 2019 were selected. The expression of caspase-3 and HIF-1α in HCC and paracancerous tissues from these patients was assessed. RESULTS: The positive expression rate of caspase-3 in HCC tissues was 27.27%, which was significantly lower than that in the paracancerous tissues (P < 0.05), while the positive expression rate of HIF-1α was 72.73%, which was significantly higher than that in the paracancerous tissues (P < 0.05). The positive expression rates for caspase-3 in tumor node metastasis (TNM) stage III and lymph node metastasis tissues were 2.78% and 2.50%, respectively, which were significantly lower than those in TNM stage I-II and non-lymph node metastasis tissues (P < 0.05). The positive expression rates of HIF-1α in TNM stage III, lymph node metastasis, and portal vein tumor thrombus tissues were 86.11%, 87.50%, and 88.00%, respectively, and these values were significantly higher than those in TNM stage I-II, non-lymph node metastasis, and portal vein tumor thrombus tissues (P < 0.05). The expression of caspase-3 and HIF-1α in HCC tissues were negatively correlated (r s = - 0.426, P < 0.05). The median overall survival time of HCC patients was 18.90 mo (95% CI: 17.20-19.91). The results of the Cox proportional risk regression model analysis showed that TNM stage, portal vein tumor thrombus, lymph node metastasis, caspase-3 expression, and HIF-1α expression were the factors influencing patient prognosis (P < 0.05). CONCLUSION: The expression of caspase-3 decreases and HIF-1α increases in HCC tissues complicated by pathological changes of hemorrhage and necrosis, and these are related to clinicopathological features and prognosis.

Natural Killer Cells Regulate the Maturation of Liver Sinusoidal Endothelial Cells Thereby Promoting Intrahepatic T-Cell Responses in a Mouse Model.

Functional maturation of liver sinusoidal endothelial cells (LSECs) plays an important role in intrahepatic T-cell activation and control of viral infections. Natural killer (NK) cells have been reported to prompt the maturation of antigen-presenting cells (APCs), especially for dendritic cells (DCs), but the interaction between NK cells and LSECs is elusive. Here, we investigated whether and how NK cells are involved in regulating LSEC maturation and if this has a role in controlling hepatitis B virus (HBV) infection in a mouse model. A chronic HBV replication mouse model was established by hydrodynamic injection (HI) of 6 µg adeno-associated virus plasmid (pAAV)/HBV 1.2. The nucleotide-binding oligomerization domain-containing protein 1 (NOD1) ligand diaminopemelic acid (DAP) was imported into liver by HI at day 14 after plasmid injection. We found that HI of DAP recruited conventional NK cells (cNK) into the liver and promoted tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) production of NK cells in a chemokine (C-X-C motif) receptor 3 (CXCR3)-dependent manner. Importantly, the maturation of LSECs and the anti-HBV effects of DAP were impaired in CXCR3-/- mice; this possibly was associated with the decreased number of intrahepatic cNK cells. Consistently, depleting cNK cells but not liver-resident NK cells also impaired the maturation and antigen-presenting function of LSECs, which reduced intrahepatic HBV-specific T-cell responses and thus inhibited HBV clearance both in wild-type and in Rag1-/- mice. Moreover, TNF-α or IFN-γ stimulation as well as coculture with intrahepatic NK cells partly promoted LSEC phenotypic and functional maturation in vitro. Conclusion: NOD1-triggered NK cell activation may lead to the enhancement of intrahepatic T-cell responses by promoting maturation of LSECs through soluble cytokines and cell-cell contact, thereby controlling HBV replication and expression.

Epidemiological characteristics of hepatic echinococcosis, concurrent cerebral echinococcosis, and pulmonary echinococcosis in Ganzi County, Sichuan Province, China.

Human echinococcosis has become a major public health problem in most parts of the world. The objective of this article was to study the demographics of patients with hepatic echinococcosis in Ganzi County to elucidate the main risk factors, as well as to report the concurrent prevalence of cerebral echinococcosis and pulmonary echinococcosis.We recruited 195 patients with hepatic echinococcosis from the Datongma area of Ganzi County from January 2018 to November 2018. The patients' demographics, living environments, supported medical resources, knowledge of echinococcosis prevention and control, and hygienic practices were investigated and analyzed. The prevalence of cerebral echinococcosis and pulmonary echinococcosis were also investigated.The data were analyzed to identify risk factors for human echinococcosis. Our analysis showed that the herding Tibetan population within the 20 to 60 age group, and females, in particular, were at the highest risk of human echinococcosis infection. Having stray dogs around habitations and intimate activities with dogs and livestock were also behavioral risk factors. People with poor health literacy and low educational qualifications had possible risks of infection. In terms of hygiene, not using tap water as the drinking water source and lack of medical staff were significantly correlated with echinococcosis prevalence. Four patients were diagnosed with cerebral echinococcosis. Among them, 1 patient had both cerebral echinococcosis and pulmonary echinococcosis.Possible high-risk factors for echinococcosis were being female, herding population, in the 20 to 60 age group, having stray dogs around habitations, having activities with dogs and livestock, having poor health literacy, having low educational qualifications, and not using tap water as a drinking water source. The detection rate for brain echinococcosis in patients with hepatic echinococcosis was high (2.05%). Effective preventive strategies should be implemented in epidemic areas. Head CT scans should be applied for early detection of cerebral echinococcosis to carry out the treatment.

Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid-Dependent Immunodominant Response.

The tumor-associated antigen mucin 1 (MUC1) has been pursued as an attractive target for cancer immunotherapy, but the poor immunogenicity of the endogenous antigen hinders the development of vaccines capable of inducing effective anti-MUC1 immunodominant responses. Herein, we prepared synthetic anti-MUC1 vaccines in which the hydrophilic MUC1 antigen was N-terminally conjugated to one or two palmitoyl lipid chains (to form amphiphilic Pam-MUC1 or Pam2 -MUC1). These amphiphilic lipid-tailed MUC1 antigens were self-assembled into liposomes containing the NKT cell agonist αGalCer as an adjuvant. The lipid-conjugated antigens reshaped the physical and morphological properties of liposomal vaccines. Promising results showed that the anti-MUC1 IgG antibody titers induced by the Pam2 -MUC1 vaccine were more than 30- and 190-fold higher than those induced by the Pam-MUC1 vaccine and the MUC1 vaccine without lipid tails, respectively. Similarly, vaccines with the TLR1/2 agonist Pam3 CSK4 as an adjuvant also induced conjugated lipid-dependent immunological responses. Moreover, vaccines with the αGalCer adjuvant induced significantly higher titers of IgG antibodies than vaccines with the Pam3 CSK4 adjuvant. Therefore, the non-covalent assembly of the amphiphilic lipo-MUC1 antigen and the NKT cell agonist αGalCer as a glycolipid adjuvant represent a synthetically simple but immunologically effective approach for the development of anti-MUC1 cancer vaccines.

Swertia mussotii extracts induce mitochondria-dependent apoptosis in gastric cancer cells.

Swertia mussotii (Gentianaceae) is a traditional Chinese medicinal plant grown in the Qinghai-Tibet Plateau. Three fractions from S. mussotii extract, named SWF50, SWF 70 and SWF100, were screened for in vitro anti-proliferative activity on two gastric cancer cell lines, MGC-803 and BGC-823 cells using MTT assay. Our results demonstrated that SMF70 showed an anti-proliferative effect in MGC-803 cells and SMF100 showed an anti-proliferative effect in BGC-823 cells in vitro. Moreover, both two fractions induced apoptosis via depolymerization of cytoskeletal filaments, increased cytoplasmic levels of ROS and Ca2+ and disrupted mitochondrial transmembrane potential. In addition, flow cytometry analysis indicated that both two fractions could induce cell apoptosis and arrest the cell cycle at S phase. Our results indicate that SMF70 induces apoptosis of MGC-803 cells and SMF100 induces apoptosis of BGC-823 cells via a mitochondrial-dependent pathway. Meanwhile, we also investigated antitumor effect of SMF70 in vivo, and exhibited effective tumor growth inhibition. Our findings demonstrate that S. mussotii extracts could be a potential new alternative therapeutic agent gastric cancer.