Effect of Adding Electroacupuncture to Standard Triple Antiemetic Therapy on Chemotherapy-Induced Nausea and Vomiting: A Randomized Controlled Clinical Trial.

PURPOSE: We aim to determine the effectiveness of adding electroacupuncture to standard triple antiemetic therapy for treating chemotherapy-induced nausea and vomiting (CINV). METHODS: From March 2022 to December 2023, a randomized, blind, sham-controlled trial conducted across six Chinese hospitals investigated patients with breast cancer undergoing highly emetogenic chemotherapy (HEC). Patients were randomly assigned to either true electroacupuncture (n = 120) or sham electroacupuncture (n = 119) groups, with both groups receiving standard triple antiemetic therapy. The primary end point was the proportion of complete protection (no vomiting, no need for rescue treatment, and no significant nausea, as evaluated using the visual analog scale [VAS]) within 120 hours after receiving HEC. RESULTS: Among 239 randomly assigned patients, 235 (98.3%) completed the trial. In the full analysis set, compared with the sham electroacupuncture group, the true electroacupuncture group demonstrated a significant increase in the complete protection rate from 34.5% to 52.9% (P = .004). Additionally, true electroacupuncture also showed enhanced total control (4.3% v 13.4%; P = .014), no significant nausea (37.9% v 58.8%; P = .001), no nausea (4.3% v 13.4%; P = .014), and nausea VAS score = 0 mm (4.3% v 12.6%; P = .023). However, the occurrence of no vomiting in the overall stage was similar (76.7% v 73.9%; P = .622) in both groups. Post hoc exploratory analysis showed a significantly higher rate of complete protection during the delayed stage in the true electroacupuncture group compared with the sham electroacupuncture group, with no significant difference observed during the acute stage. CONCLUSION: Adding true electroacupuncture to standard triple antiemetic therapy significantly enhances the efficacy of CINV treatment in patients with breast cancer receiving HEC.

Incidence rate of osteonecrosis of jaw after cancer treated with bisphosphonates and denosumab: A systematic review and meta-analysis.

OBJECTIVES: This study aimed to assess the overall incidence of osteonecrosis of the jaw (ONJ) caused by bisphosphonates and denosumab when used for controlling bone cancer metastasis or as adjuvant therapy. SUBJECTS AND METHODS: A systematic search of the PubMed, Embase, and Cochrane Library databases and major meetings' proceedings as of July 30, 2022, identified randomized controlled trials (RCTs) and observational trials that evaluated ONJ caused by denosumab or bisphosphonates. The total incidence and risk ratio (RR) for ONJ were calculated using a random-effects model. RESULTS: A total of 42 003 patients with various solid tumors reported in 23 RCTs were included. The overall ONJ incidence in cancer patients receiving denosumab or bisphosphonates was 2.08% (95% CI 1.37-2.91; p < .01; I2  = 94.99%). Patients receiving denosumab had a higher ONJ incidence than those receiving bisphosphonates (RR 1.64, 95% CI 1.10-2.44; p < .05; I2  = 65.4%). Subgroup analyses showed that prostate cancer patients receiving denosumab and receiving zoledronic acid had the highest ONJ incidences, 5.0% and 3.0%, respectively. The incidence of ONJ induced by different doses was also different. CONCLUSIONS: The incidence of ONJ caused by denosumab and bisphosphonates is low, the dose of the drug and the type of cancer have certain influence on ONJ. Therefore, clinicians should use the drug reasonably to improve the quality of life of patients.

miR-92b ameliorates lipoteichoic acid induced endometritis by suppressing Wnt/ß-catenin pathway activation.

Endometritis is one of the important reasons for the low fecundity of dairy cows, which has brought huge economic losses to the dairy industry. Emerging evidence suggests that miR-92b is a novel therapeutic molecule that plays a crucial role in many inflammatory diseases. However, its mechanism in lipoteichoic acid (LTA) induced endometritis remains unclear. In the present study, we explored the mechanism of miR-92b on LTA-induced endometritis in vivo and in vitro. The result displayed that the expression of miR-92b was reduced in LTA induced mouse endometritis and bovine endometrial epithelial cell lines (BEND). Overexpression miR-92b significantly alleviated mouse uterine injury and reduced the protein levels of TNF-α, IL-1ß and the MPO activity. The reporter assay of luciferase showed that miR-92b directly targeted the transmembrane receptor Frizzled-10 (FZD10), a transmembrane-type Wnt receptor. Molecular experiments were further performed to explore the mechanism of miR-92b in protecting LTA induced endometritis. The results of in vitro suggested that miR-92b mimic decreased the protein levels of Wnt3a and ß-catenin in LTA stimulated BEND, which were abolished by overexpression of FZD10. As expected, miR-92b mimic decreased the expression levels of TNF-α and IL-1ß, while overexpression of FZD10 promoted the production of these pro-inflammatory cytokines. Collectively, the above findings indicated that miR-92b might be an effective strategy for treatment of LTA induced endometritis.

Meta-analysis of quality of life in patients with cancer treated with antibody-drug conjugates in randomized controlled trials.

Purpose: To evaluate the patient-reported outcomes of patients treated with commercially approved antibody-drug conjugates (ADC) reported in randomized controlled trials (RCT) published up to September 2023. Methods: A meta-analysis of 6430 patients from 12 randomized controlled trials was conducted. Results: No significant change was observed between the groups from baseline to end of treatment and end of follow-up, with a standardized mean difference of -0.08 (95% CI: -0.27-0.12) and 0.01 (95% CI: -0.11-0.12), respectively. Treatment with ADCs delayed the deterioration of patients' clinical condition compared with treatment with non-ADCs, with a hazard ratio of 0.78 (95% CI: 0.67-0.92). Conclusion: ADCs have a good correlation with delay of clinical deterioration in patients with cancer.

The MGF300-2R protein of African swine fever virus is associated with viral pathogenicity by promoting the autophagic degradation of IKKα and IKKß through the recruitment of TOLLIP.

The multigene family genes (MGFs) in the left variable region (LVR) of the African swine fever virus (ASFV) genome have been reported to be involved in viral replication in primary porcine alveolar macrophages (PAMs) and virulence in pigs. However, the exact functions of key MGFs in the LVR that regulate the replication and virulence of ASFV remain unclear. In this study, we identified the MGF300-2R gene to be critical for viral replication in PAMs by deleting different sets of MGFs in the LVR from the highly virulent strain ASFV HLJ/18 (ASFV-WT). The ASFV mutant lacking the MGF300-2R gene (Del2R) showed a 1-log reduction in viral titer, and induced higher IL-1ß and TNF-α production in PAMs than did ASFV-WT. Mechanistically, the MGF300-2R protein was found to interact with and degrade IKKα and IKKß via the selective autophagy pathway. Furthermore, we showed that MGF300-2R promoted the K27-linked polyubiquitination of IKKα and IKKß, which subsequently served as a recognition signal for the cargo receptor TOLLIP-mediated selective autophagic degradation. Importantly, Del2R exhibited a significant reduction in both replication and virulence compared with ASFV-WT in pigs, likely due to the increased IL-1ß and TNF-α, indicating that MGF300-2R is a virulence determinant. These findings reveal that MGF300-2R suppresses host innate immune responses by mediating the degradation of IKKα and IKKß, which provides clues to paving the way for the rational design of live attenuated vaccines to control ASF.

Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis.

Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.

Uterine Tissue Metabonomics Combined with 16S rRNA Gene Sequencing To Analyze the Changes of Gut Microbiota in Mice with Endometritis and the Intervention Effect of Tau Interferon.

Endometritis is a common cow disease characterized by inflammation of endometrium, which leads to infertility or low fertility of cows and brings huge economic losses to the dairy industry. Tau interferon (IFN-τ) has many important biological functions, including an anti-inflammatory effect. The present study aimed to survey the effects of IFN-τ administration on gut microflora and body metabolism in mice with endometritis and to explore the potential relationship. The results indicated that IFN-τ obviously alleviated the damage and ultrastructural changes of mouse endometrium induced by Escherichia coli and enhanced tight junction protein's expression level. Through analysis by 16S rRNA gene sequencing, we found that IFN-τ, especially at 12 h, could regulate the composition of gut microbiota associated with Pediococcus, Staphylococcus, and Enterorhabdus in E. coli-induced mouse endometritis. Through histometabonomics, it was found that endometritis was related to 11 different metabolites and 4 potential metabolic pathways. These metabolites and metabolic pathways were major participants in metabolic pathways, cysteine and methionine metabolism, arachidonic acid metabolism, and pyrimidine metabolism. Correlation analysis of gut microbiota with uterine tissue metabolomics showed that changes in metabolic pathways might be affected by gut microbiota, such as Enterorhabdus in mouse endometritis. The above results indicated that the anti-inflammatory mechanism of IFN-τ might be reduction of the abundance of Enterorhabdus in the gut microbiota, affecting the expression level of important metabolites in uterine tissue and thus playing an anti-inflammatory role. IMPORTANCE The change in intestinal flora has been the focus of many disease studies in recent years, but the pathogenetic effect of interferon on endometritis is still unclear. The results of this study showed that IFN-τ alleviated the damage in mouse endometritis induced by E. coli and improved the endometrial tissue barrier. Its functional mechanism may be reduction of the abundance of Enterorhabdus in the intestinal microbiota, affecting the expression level of important metabolites in uterine tissue and thus playing an anti-inflammatory role.

The association between HER2-low expression and prognosis of breast cancer: a systematic review and meta-analysis.

Background: The use of antibody-drug conjugates for the treatment of advanced-stage human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer (BC) has shown prominent curative effects, which has led to increased academic interest. However, the role of HER2-low expression in the prognosis of BC remains controversial. Methods: We conducted a systematic search of the PubMed, Embase, and Cochrane library databases and several oncology conferences until 20 September 2022. We used fixed- and random-effects models to calculate odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and pathological complete response (pCR) rates. Results: Overall, 26 studies encompassing 677,248 patients were included in the meta-analysis. Patients with HER2-low BC showed significantly better OS than those with HER2-zero BC in the overall population (HR = 0.90; 95% CI: 0.85-0.97) and hormone receptor-positive population (HR = 0.98; 95% CI: 0.96-0.99), whereas no significant difference was observed in the OS of the hormone receptor-negative population (p > 0.05). In addition, there was no significant difference in the DFS of the overall and hormone receptor-negative population (p > 0.05), but better DFS than those with HER2-zero BC in the hormone receptor-negative population (HR = 0.96; 95% CI: 0.94-0.99). There was also no significant difference in the PFS of the overall population, hormone receptor-positive, and hormone receptor-negative population (p > 0.05). Patients with HER2-low BC had a lower pCR rate after neoadjuvant treatment than those with HER2-zero BC. Conclusions: Compared to patients with HER2-zero BC, those with HER2-low BC had better OS in the overall population and hormone receptor-positive population, DFS in hormone receptor-positive population and lower pCR in the overall population. The biological differences between HER2-low and HER2-zero BCs, particularly in hormone receptor-positive patients, and the relationship between HER2-low expression status and prognosis need to be explored further.

Incidence of antibody-drug conjugates-related pneumonitis in patients with solid tumors: A systematic review and meta-analysis.

BACKGROUND: Antibody-drug conjugates (ADCs) have demonstrated significant efficacy in treating solid tumors. However, the occurrence of ADC drug-associated pneumonitis can limit the use of ADCs or have severe consequences, and we know comparatively little about this. METHODS: PubMed, EMBASE, and the Cochrane library were exhaustively searched for articles and conference abstracts published before September 30, 2022. Two authors independently extracted data from the included studies. A random-effects model was used to conduct a meta-analysis of the relevant outcomes. Forest plots reflected the incidence rates from each study, and binomial methods were used to calculate the 95 % confidence interval. RESULTS: This meta-analysis included 7732 patients from 39 studies and evaluated the incidence of ADCs drug-associated pneumonitis which have received market approval for the treatment of solid tumors. The total incidence of solid tumors for all-grade pneumonitis was 5.86 % (95 % CI, 3.54-8.66 %) and for grade ≥3 was 0.68 % (95 % CI, 0.18-1.38 %). The incidence of all-grade pneumonitis was 5.08 % (95 % CI, 2.76-7.96 %) and for grade ≥3 was 0.57 % (95 % CI, 0.10-1.29 %) with ADC monotherapy. The incidence of all-grade and grade ≥3 pneumonitis in trastuzumab deruxtecan (T-DXd) was 13.58 % (95 % CI, 9.43-18.29 %) and 2.19 % (95 % CI, 0.94-3.81 %), respectively, the highest in ADC therapy. Total incidence of all-grade pneumonitis was 10.58 % (95 % CI, 4.34-18.81 %) and for grade ≥3 pneumonitis was 1.29 % (95 % CI, 0.22-2.92 %) with ADC combination therapy. The incidence of pneumonitis was higher with combination therapy than with monotherapy in both all-grade and grade ≥3 groups, but there was no statistical significance (P = .138 and P = .281, respectively). The incidence of ADC-associated pneumonitis in non-small cell lung cancer (NSCLC) was 22.18 % (95 % CI, 2.14-52.61 %), the highest among solid tumors. The 11 included studies reported 21 pneumonitis-related deaths. CONCLUSIONS: Our findings will assist clinicians in choosing the optimal therapeutic options for patients with solid tumors treated with ADCs.

Two-step anaerobic digestion of rice straw with nanobubble water.

Lignocellulose usually requires pretreatment to improve biogas production. To enhance lignocellulose biodegradability and improve anaerobic digestion (AD) efficiency, different types (N2, CO2, and O2) of nanobubble water (NW) were applied in this study as soaking agent and AD accelerant to increase the biogas yield of rice straw. The results showed that the cumulative methane yields of treating with NW in two-step AD increased by 11.0%-21.4% compared with untreated straw. The maximum cumulative methane yield was 313.9±1.7 mL/gVS in straw treated with CO2-NW as soaking agent and AD accelerant (PCO2-MCO2). The application of CO2-NW and O2-NW as AD accelerants increased bacterial diversity and relative abundance of Methanosaeta. This study suggested that using NW could enhance soaking pretreatment and methane production of rice straw in two-step AD; however, combined treatment with inoculum and NW or microbubble water in the pretreatment needs to compare in future.

Association between high body mass index and prognosis of patients with early-stage breast cancer: A systematic review and meta-analysis.

Background: A high body mass index (BMI) can indicate overweight or obesity and is a crucial risk factor for breast cancer survivors. However, the association between high BMI and prognosis in early-stage breast cancer (EBC) remains unclear. We aimed to assess the effects of high BMI on the prognosis of patients with EBC. Methods: The PubMed, Embase, and Cochrane Library databases and proceedings of major oncological conferences related to the effects of BMI on the prognosis of breast cancer were searched up to November 2021. Fixed- and random-effects models were used for meta-analyses. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were extracted from the included literature. Results: Twenty retrospective cohort studies with 33,836 patients with EBC were included. Overweight patients had worse DFS (HR: 1.16, 95% CI: 1.05-1.27, P = 0.002) and OS (HR: 1.20; 95% CI: 1.09-1.33, P < 0.001). Obesity also had adverse effects on DFS (HR: 1.17, 95% CI: 1.07-1.29, P = 0.001) and OS (HR: 1.30, 95% CI: 1.17-1.45, P < 0.001). Likewise, patients with high BMI had worse DFS (HR: 1.16, 95% CI: 1.08-1.26, P < 0.001) and OS (HR: 1.25, 95% CI: 1.14-1.39, P < 0.001). In subgroup analyses, overweight had adverse effects on DFS (HR: 1.11, 95% CI: 1.04-1.18, P = 0.001) and OS (HR: 1.18, 95% CI: 1.11-1.26, P < 0.001) in multivariate analyses, whereas the relationship that overweight had negative effects on DFS (HR: 1.21, 95% CI: 0.99-1.48, P = 0.058) and OS (HR: 1.39, 95% CI: 0.92-2.10, P = 0.123) was not statistically significant in univariate analysis. By contrast, obesity had adverse effects on DFS (HR: 1.21, 95% CI: 1.06-1.38, P = 0.004 and HR: 1.14, 95% CI: 1.08-1.22, P < 0.001) and OS (HR: 1.33, 95% CI: 1.15-1.54, P < 0.001 and HR: 1.23, 95% CI: 1.15-1.31, P < 0.001) in univariate and multivariate analyses, respectively. Conclusions: Compared with normal weight, increased body weight (overweight, obesity, and high BMI) led to worse DFS and OS in patients with EBC. Once validated, these results should be considered in the development of prevention programs.

Fabrication of stainless-steel microfibers with amorphous-nanosized microstructure with enhanced mechanical properties.

Metallic glasses (MG) have attracted much attention due to their superior hardness and good corrosion resistance. However, designing new MG compositions is still a big challenge, and their integration into different systems is limited when they are in the shape of bulk materials. Here, we present a new method for the fabrication of MG in the form of microfibers which could greatly help them to be integrated within different systems. The newly proposed technique has the ability to form MG structure from commercially available alloy compositions thanks to its significantly improved quenching rate(~ 108 K.s-1). In this technique, individual melt droplets are ejected on a rotating wheel forming a thin film which are ruptured upon solidification leading to the formation of MG microfibers. In this regard, we have fabricated microfibers from a commercial DIN 1.4401 stainless-steel which could form a completely amorphous structure confirmed by DSC, XRD, and HRTEM. The fabricated MG microfibers show an increased hardness for more than two-fold from 3.5 ± 0.17 GPa for the as-received stainless-steel to 7.77 ± 0.60 GPa for the amorphous microfibers. Subsequent heat-treatment of the microfibers resulted in a nanocrystalline structure with the presence of amorphous regions when the hardness increases even further to 13.5 ± 2.0 GPa. We propose that confinement of both shear transformation zones and dislocations in the heat-treated MG microfibers plays a major role in enhancing strength.

Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: ß-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A1; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

Immune checkpoint inhibitors plus neoadjuvant chemotherapy in early triple-negative breast cancer: a systematic review and meta-analysis.

PURPOSE: Some studies have shown that Immune checkpoint inhibitors (ICIs) have a favorable efficacy in advanced triple negative breast cancer (TNBC) patients, but the results are controversial in neoadjuvant chemotherapy (NACT) stage. The purpose of this study is to evaluate the efficacy and safety after NACT plus ICIs in early TNBC patients. METHODS: After searching PubMed, EMBASE, the Cochrane library and several mainly oncology conferences up to 30 January 2021 systematically, and define randomized controlled trials (RCTs) exploring the efficacy and safety of programmed death protein-1/programmed cell death-Ligand 1(PD-1/PD-L1) inhibitors plus neoadjuvant chemotherapy in TNBC patients. The primary endpoint was the pathological complete response (pCR) in intention-to-treat populations (ITT), and the secondary endpoints were event-free survival (EFS) and safety analysis in the ITT populations. RESULTS: Six RCTs (N = 2142) were included in our meta-analysis; NACT plus ICIs increased pCR rates compared with NACT in intention-to-treat (ITT) populations (OR: 1.91; 95% CI: 1.32-2.78, P < 0.001). The pCR rate also increased in both PD-L1 positive (OR: 1.65; 95% CI: 1.26-2.16, P < 0.001) and PD-L1 negative patients (OR: 1.56; 95% CI: 1.04-2.33, P = 0.03), especially in PD-L1 positive patients. The benefit was also observed in nodal-positive populations (OR: 2.52; 95% CI: 1.69-3.77, P < 0.001) and Eastern Cooperative Oncology Group performance-status score (ECOG PS) 0 subgroup (OR: 1.90; 95% CI: 1.42-2.53, P < 0.001). Three RCTs (N = 1615) reported EFS and the results showed that adding PD-1/PD-L1 inhibitors increased EFS (HR 0.65, 95% CI 0.50-0.83, P = 0.0007) in ITT populations with a short follow-up time. In the safety analysis of 2205 patients with early TNBC from five eligible studies, NACT plus ICIs had a higher risk of grade 3-4 diarrhea (OR: 2.54; 95% CI: 1.21-5.32; P = 0.01), any grade of adverse effects(AEs)including vomiting (OR: 1.37; 95% CI: 1.00-1.86; P = 0.05), hyperthyroidism (OR: 6.04; 95% CI: 2.39-15.29; P < 0.001), and hypothyroidism (OR: 5.04; 95% CI: 3.02-8.39; P < 0.001). CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve pCR rates and EFS, and with an increased incidence of some immune-related AEs compared with chemotherapy alone. NACT plus ICIs might be an option in patients with in PD-L1 positive and high-risk populations with positive nodal disease early TNBC.

HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity.

HIV-1-negative factor (Nef) protein antagonizes serine incorporator 5 (SERINC5) by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identify cyclin K (CycK) and cyclin-dependent kinase 13 (CDK13) as a Nef-associated kinase complex. CycK/CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counteractivity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we generate chimeric proteins between CD8 and SERINC5 to study their response to Nef. Nef not only downregulates but, importantly, also binds to this chimera in an S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.

MARCH8 Inhibits Ebola Virus Glycoprotein, Human Immunodeficiency Virus Type 1 Envelope Glycoprotein, and Avian Influenza Virus H5N1 Hemagglutinin Maturation.

Membrane-associated RING-CH-type 8 (MARCH8) strongly blocks human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) incorporation into virions by downregulating its cell surface expression, but the mechanism is still unclear. We now report that MARCH8 also blocks the Ebola virus (EBOV) glycoprotein (GP) incorporation via surface downregulation. To understand how these viral fusion proteins are downregulated, we investigated the effects of MARCH8 on EBOV GP maturation and externalization via the conventional secretion pathway. MARCH8 interacted with EBOV GP and furin when detected by immunoprecipitation and retained the GP/furin complex in the Golgi when their location was tracked by a bimolecular fluorescence complementation (BiFC) assay. MARCH8 did not reduce the GP expression or affect the GP modification by high-mannose N-glycans in the endoplasmic reticulum (ER), but it inhibited the formation of complex N-glycans on the GP in the Golgi. Additionally, the GP O-glycosylation and furin-mediated proteolytic cleavage were also inhibited. Moreover, we identified a novel furin cleavage site on EBOV GP and found that only those fully glycosylated GPs were processed by furin and incorporated into virions. Furthermore, the GP shedding and secretion were all blocked by MARCH8. MARCH8 also blocked the furin-mediated cleavage of HIV-1 Env (gp160) and the highly pathogenic avian influenza virus H5N1 hemagglutinin (HA). We conclude that MARCH8 has a very broad antiviral activity by prohibiting different viral fusion proteins from glycosylation and proteolytic cleavage in the Golgi, which inhibits their transport from the Golgi to the plasma membrane and incorporation into virions.IMPORTANCE Enveloped viruses express three classes of fusion proteins that are required for their entry into host cells via mediating virus and cell membrane fusion. Class I fusion proteins are produced from influenza viruses, retroviruses, Ebola viruses, and coronaviruses. They are first synthesized as a type I transmembrane polypeptide precursor that is subsequently glycosylated and oligomerized. Most of these precursors are cleaved en route to the plasma membrane by a cellular protease furin in the late secretory pathway, generating the trimeric N-terminal receptor-binding and C-terminal fusion subunits. Here, we show that a cellular protein, MARCH8, specifically inhibits the furin-mediated cleavage of EBOV GP, HIV-1 Env, and H5N1 HA. Further analyses uncovered that MARCH8 blocked the EBOV GP glycosylation in the Golgi and inhibited its transport from the Golgi to the plasma membrane. Thus, MARCH8 has a very broad antiviral activity by specifically inactivating different viral fusion proteins.

Genotyping bovine leukemia virus in dairy cattle of Heilongjiang, northeastern China.

BACKGROUND: Bovine leukemia virus (BLV) causes enzootic bovine leukosis in cattle and leads to heavy economic losses in the husbandry industry. Heilongjiang Province, China, is rich in dairy cattle. However, its current BLV epidemiology and genotypes have still not been evaluated and confirmed. In this report, we investigated the BLV epidemiology in dairy cattle in the major regions of Heilongjiang Province via the nested PCR assay. RESULTS: A total of 730 blood samples were collected from nine different farms in six regions of Heilongjiang. The results showed that the infection rate of these regions ranged from null to 31%. With a clustering analysis of 60 published BLV env sequences, genotypes 1 and 6 were confirmed to be circulating in Heilongjiang. Importantly, a new genotype, 11, and a new subgenotype, 6E, were also identified in the Harbin and Daqing regions, respectively. An epitope analysis showed that a cluster of T-X-D-X-R-XXXX-A sequences in genotype 11 gp51 neutralizing domain 2 was unique among all currently known BLV isolates and was therefore a defining feature of this new genotype. CONCLUSIONS: BLV epidemics and genotypes were initially investigated in dairy cattle of Heilongjiang. A relatively high infection rate was found in some regions of this province. A new genotype, G11, with a highly specific motif, was identified and thus added as a new member to the current BLV genotype family. This report provides an initial reference for future investigations and subsequent control of BLV transmission and spread in this region.

The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5.

Serine incorporator 5 (SERINC5) is a recently identified restriction factor that blocks virus entry but is antagonized by three unrelated retroviral accessory proteins. The S2 protein from equine infectious anemia virus (EIAV) has been reported to reduce SERINC5 expression at steady-state levels likely via the endocytic pathway; however, the precise mechanism is still unclear. Here, we investigated how EIAV S2 protein down-regulates SERINC5 compared with down-regulation induced by Nef from HIV-1 and glycoMA proteins from murine leukemia virus (MLV). Using bimolecular fluorescence complementation (BiFC) assay and immunoprecipitation (IP), we detected an interaction between S2 and SERINC5. We found that this interaction relies on the S2 myristoylation site, indicating that it may occur on the plasma membrane. S2 internalized SERINC5 via receptor-mediated endocytosis and targeted it to endosomes and lysosomes, resulting in a ubiquitination-dependent decrease in SERINC5 expression at steady-state levels. Both BiFC and IP detected a glycoMA-SERINC5 interaction, but a Nef-SERINC5 interaction was detected only by BiFC. Moreover, S2 and glycoMA down-regulated SERINC5 more effectively than did Nef. We further show that unlike Nef, both S2 and glycoMA effectively down-regulate SERINC2 and also SERINC5 from Xenopus tropicalis (xSERINC5). Moreover, we detected expression of the equine SERINC5 (eSERINC5) protein and observed that its expression is much weaker than expression levels of SERINC5 from other species. Nonetheless, eSERINC5 had a strong antiviral activity that was effectively counteracted by S2. We conclude that HIV-1, EIAV, and MLV share a similar mechanism to antagonize viral restriction by host SERINC5.

Long non-coding RNA AGAP2-AS1 promotes the proliferation of glioma cells by sponging miR-15a/b-5p to upregulate the expression of HDGF and activating Wnt/ß-catenin signaling pathway.

Glioma is a kind of malignant brain tumor which damages the central nervous system of adults. Recent years, the molecular mechanism involved in the initiation and progression of glioma has been widely reported. Long non-coding RNAs (lncRNAs) have been proved to be significant modulators in the biological processes of glioma. In this study, we found that lncRNA AGAP2-AS1 was differentially expressed in glioma tissue samples and cell lines. Kaplan-Meier method was used to analyze the correlation between AGAP2-AS1 expression and the overall survival of glioma patients. Higher expression of AGAP2-AS1 was correlated with the lower overall survival of glioma patients. Functionally, AGAP2-AS1 knockdown inhibited glioma cell proliferation and accelerated glioma cell apoptosis. Mechanistically, AGAP2-AS1 upregulated HDGF by sponging miR-15a/b-5p. The function of AGAP2-AS1-miR-15a/b-5p-HDGF axis was confirmed by performing rescue assays. Experimental results suggested that miR-15a/b-5p and HDGF involved in AGAP2-AS1-mediated glioma cell proliferation. Moreover, AGAP2-AS1 and HDGF were found to activate Wnt/ß-catenin signaling pathway in glioma cell lines. In summary, this study demonstrated that AGAP2-AS1 promoted glioma cell proliferation by sponging miR-15a/b-5p to upregulate the expression of HDGF.

Murine Leukemia Virus Glycosylated Gag Reduces Murine SERINC5 Protein Expression at Steady-State Levels via the Endosome/Lysosome Pathway to Counteract SERINC5 Antiretroviral Activity.

Glycosylated Gag (glycoGag) is an accessory protein expressed by most gammaretroviruses, including murine leukemia virus (MLV). MLV glycoGag not only enhances MLV replication and disease progression but also increases human immunodeficiency virus type 1 (HIV-1) infectivity as Nef does. Recently, SERINC5 (Ser5) was identified as the target for Nef, and the glycoGag Nef-like activity has been attributed to the Ser5 antagonism. Here, we investigated how glycoGag antagonizes Ser5 using MLV glycoMA and murine Ser5 proteins. We confirm previous observations that glycoMA relocalizes Ser5 from plasma membrane to perinuclear punctated compartments and the important role of its Y36XXL39 motif in this process. We find that glycoMA decreases Ser5 expression at steady-state levels and identify two other glycoGag crucial residues, P31 and R63, for the Ser5 downregulation. The glycoMA and Ser5 interaction is detected in live cells using a bimolecular fluorescence complementation assay. Ser5 is internalized via receptor-mediated endocytosis and relocalized to Rab5+ early, Rab7+ late, and Rab11+ recycling endosomes by glycoMA. Although glycoMA is not polyubiquitinated, the Ser5 downregulation requires Ser5 polyubiquitination via the K48- and K63-linkage, resulting in Ser5 destruction in lysosomes. Although P31, Y36, L39, and R63 are not required for glycoMA interaction with Ser5, they are required for Ser5 relocalization to lysosomes for destruction. In addition, although murine Ser1, Ser2, and Ser3 exhibit very poor antiviral activity, they are also targeted by glycoMA for lysosomal destruction. We conclude that glycoGag has a broad activity to downregulate SERINC proteins via the cellular endosome/lysosome pathway, which promotes viral replication.IMPORTANCE MLV glycoGag not only enhances MLV replication but also increases HIV-1 infectivity similarly as Nef. Recent studies have discovered that both glycoGag and Nef antagonize a novel host restriction factor Ser5 and promote viral replication. Compared to Nef, the glycoGag antagonism of Ser5 is still poorly understood. MLV glycoGag is a transmembrane version of the structural Gag protein with an extra 88-amino-acid leader region that determines its activity. We now show that glycoGag interacts with Ser5 in live cells and internalizes Ser5 via receptor-mediated endocytosis. Ser5 is polyubiquitinated and relocalized to endosomes and lysosomes for massive destruction. In addition to the previously identified tyrosine-based sorting signal, we find two more important residues for Ser5 relocalization and downregulation. We also find that the Ser5 sensitivity to glycoGag is conserved in the SERINC family. Together, our findings highlight the important role of endosome/lysosome pathway in the enhancement of viral replication by viral proteins.