Physiological and transcriptomic analyses provide preliminary insights into the autotoxicity of Lilium brownii.

Lilium brownii F. E. Brown ex Miellez var. viridulum Baker (Longya lily) is a variety of Lilium brownii F.E. Br. ex Miellez. We used HS-SPME and GC-MS to screened the tissues of L. brownii roots, stems, bulbs, and leaves and obtained 2,4-DTBP as an autotoxic substance for subsequent analysis. 2,4-DTBP was highly autotoxic in some treatment groups. Based on changes in physiological indicators, we carried out transcriptomic analysis to investigate the mechanisms of autotoxicity of substances on L. brownii and obtained 188,505 Unigenes. GO and KEGG enrichment analyses showed that L. brownii responded differently to different concentrations and treatment times of 2,4-DTBP. We observed significant changes in genes associated with ROS, phytohormones, and MAPK signaling cascades. 2,4-DTBP affects chloroplasts, the integrity of the respiratory electron transport chain, and ribosomes, causing L. brownii autotoxicity. Our findings provide a practical genomic resource for future research on L. brownii autotoxicity and evidence for the mechanism of action of autotoxic substances.

Effects of Supplementing Tributyrin on Meat Quality Characteristics of Foreshank Muscle of Weaned Small-Tailed Han Sheep Lambs.

This experiment aimed to evaluate the effects of supplementing tributyrin (TB) on the meat quality characteristics of foreshank muscle of weaned lambs. A total of 30 healthy weaned Small-Tailed Han female lambs with body weights ranging from 23.4 to 31.6 kg were selected and randomly divided into five groups, and each group consisted of 6 lambs. The control group was fed a basic total mixed ration, while other groups were fed the same ration supplemented with 0.5, 1.0, 2.0, and 4.0 g/kg TB, respectively. The experiment lasted 75 d, including 15 d of adaptation. Foreshank muscle obtained at the same position from each lamb was used for chemical analysis and sensory evaluation. The results showed that supplementing TB increased the muscle contents of ether extract (p = 0.029), calcium (p = 0.030), phosphorus (p = 0.007), and intermuscular fat length (p = 0.022). Besides, TB increased the muscle pH (p = 0.001) and redness (p < 0.001) but reduced the lightness (p < 0.001), drip loss (p = 0.029), cooking loss (p < 0.001), shear force (p = 0.001), hardness (p < 0.001), cohesiveness (p < 0.001), springiness (p < 0.001), gumminess (p < 0.001), and chewiness (p < 0.001). In addition, TB increased the muscle content of inosine-5'-phosphate (p = 0.004). Most importantly, TB increased the muscle contents of essential amino acids (p < 0.001). Furthermore, TB increased the saturated fatty acids level in the muscle (p < 0.001) while decreasing the unsaturated fatty acids content (p < 0.001). In conclusion, supplementing TB could influence the meat quality of foreshank muscle of weaned lambs by modifying the amino acid and fatty acid levels.

Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery.

Epigenetic dysregulation has been reported in multiple cancers including leukemias. Nonetheless, the roles of the epigenetic reader Tudor domains in leukemia progression and therapy remain unexplored. Here, we conducted a Tudor domain-focused CRISPR screen and identified SGF29, a component of SAGA/ATAC acetyltransferase complexes, as a crucial factor for H3K9 acetylation, ribosomal gene expression, and leukemogenesis. To facilitate drug development, we integrated the CRISPR tiling scan with compound docking and molecular dynamics simulation, presenting a generally applicable strategy called CRISPR-Scan Assisted Drug Discovery (CRISPR-SADD). Using this approach, we identified a lead inhibitor that selectively targets SGF29's Tudor domain and demonstrates efficacy against leukemia. Furthermore, we propose that the structural genetics approach used in our study can be widely applied to diverse fields for de novo drug discovery.

METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation.

BACKGROUND: While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. METHODS: Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. RESULTS: METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). CONCLUSIONS: Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.

Clinical efficacy and biomarker analysis of neoadjuvant camrelizumab plus chemotherapy for early-stage triple-negative breast cancer: a experimental single-arm phase II clinical trial pilot study.

BACKGROUND: Triple-negative breast cancer (TNBC) is associated with a dismal prognosis. Immune checkpoint inhibitors have shown promising antitumor activity in neoadjuvant settings. This single-arm, phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy as the neoadjuvant therapy (NAT) in early TNBC. METHODS: Patients received eight cycles of camrelizumab plus nonplatinum-based chemotherapy. The primary endpoint was total pathological complete response (pCR). Secondary endpoints included the breast pathological complete response (bpCR), adverse events (AEs). Multiomics biomarkers were assessed as exploratory objective. RESULTS: Twenty of 23 TNBC patients receiving NAT underwent surgery, with the total pCR rate of 65% (13/20) and bpCR rate of 70% (14/20). Grade ≥3 treatment-related AEs were observed in 14 (60.9%) patients, with the most common AE being neutropenia (65.2%). Tumor immune microenvironment was analyzed between pCR and non-pCR samples before and after the NAT. Gene expression profiling showed a higher immune infiltration in pCR patients than non-pCR patients in pre-NAT samples. Through establishment of a predictive model for the NAT efficacy, TAP1 and IRF4 were identified as the potential predictive biomarkers for response to the NAT. Gene set enrichment analysis revealed the glycolysis and hypoxia pathways were significantly activated in non-pCR patients before the NAT, and this hypoxia was aggravated after the NAT. CONCLUSION: Camrelizumab plus nonplatinum-based chemotherapy shows a promising pCR rate in early-stage TNBC, with an acceptable safety profile. TAP1 and IRF4 may serve as potential predictive biomarkers for response to the NAT. Aggravated hypoxia and activated glycolysis after the NAT may be associated with the treatment resistance.

Benefits of tributyrin on growth performance, gastrointestinal tract development, ruminal bacteria and volatile fatty acid formation of weaned Small-Tailed Han lambs.

This study aimed to determine the effects of tributyrin on growth performance, gastrointestinal tract development, ruminal bacteria and volatile fatty acid (VFA) formation. Thirty healthy weaned Small-Tailed Han female lambs at 3 months old with BW 27.5 ± 4.1 kg (mean ± SD) were randomly assigned to five groups of six lambs each, and each group received tributyrin at 0, 0.5, 1.0, 2.0 and 4.0 g/kg in feed. Weights were measured before the start and end of the study. After 15 d adaptation, DMI, feed, faeces and urine were recorded every week. Lambs were sacrificed at d 75. Compared to lambs fed no tributyrin, lambs fed 4.0 g/kg tributyrin had higher average daily BW gain (P = 0.04) and DMI (P < 0.01). Tributyrin reduced nitrogen (P < 0.01), Ca (P < 0.01) and P (P < 0.01) losses derived from faeces and urine. The mostly important, tributyrin increased dorsal sac thickness (P < 0.01), papillae length (P = 0.04) and width (P < 0.01), ventral sac papillae length (P < 0.01) and width (P < 0.01), caudodorsal blind sac thickness (P = 0.02), papillae length (P < 0.01) and width (P < 0.01). Furthermore, tributyrin increased thicknesses of both the duodenum (P < 0.01) and ileum (P = 0.01), and villus heights of the duodenum (P = 0.01), ileum (P < 0.01), jejunum (P < 0.01) and caecum (P = 0.02), but tributyrin decreased duodenal (P < 0.01) and caecal crypt depths (P < 0.01). Tributyrin reduced rumen pH (P < 0.01) while promoting total VFA concentration (P < 0.01). Tributyrin improved the structure of rumen bacteria by enhancing Clostridium (P = 0.04), Butyrivibrio (P < 0.01), Streptococcus (P = 0.04), Prevotella (P = 0.04), Ruminobacter (P = 0.02) and Fibrobacter (P = 0.03). In conclusion, tributyrin could stimulate gastrointestinal tract development by enhancing colonization of rumen VFA-producing bacteria, and dietary supplementation of tributyrin at 4.0 g/kg of DM was recommended for the weaned lambs.

A Comparative Study of Skin Changes in Different Species of Mice in Chronic Photoaging Models.

This study aimed to design a novel mouse model of chronic photoaging. We used three different species of mice (C57BL/6J, ICR, and KM) to create a chronic photoaging model of the skin. The irradiation time was gradually increased for 40 consecutive days. The skins of the mice were removed on day 41 and subjected to staining to observe them for morphological changes. Immunohistochemistry was used to detect tumor necrosis factor-α (TNF-α) and p53 expression; superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as well. Compared with C57BL/J mice, which showed hyperpigmentation, the irradiated skin of ICR and KM mice showed more obvious skin thickening and photoaging changes of the collagen and elastic fibers. KM mice had higher levels of inflammation, oxidative stress, and senescent cells. Compared with the 5-month-old KM mice, the photoaging changes of the 9-month-old KM mice were more pronounced, the SOD values were lower, and the MDA values were higher. In summary, KM mice have higher levels of abnormal elastic fibers, inflammation, cellular senescence, and oxidative stress than ICR mice, and are more suitable for studies related to chronic skin photoaging. C57BL/6J mice were found to be suitable for studies related to skin pigmentation due to photoaging.

Development of a prediction model for the risk of 30-day unplanned readmission in older patients with heart failure: A multicenter retrospective study.

BACKGROUND AND AIM: Heart failure (HF) imposes significant global health costs due to its high incidence, readmission, and mortality rate. Accurate assessment of readmission risk and precise interventions have become important measures to improve health for patients with HF. Therefore, this study aimed to develop a machine learning (ML) model to predict 30-day unplanned readmissions in older patients with HF. METHODS AND RESULTS: This study collected data on hospitalized older patients with HF from the medical data platform of Chongqing Medical University from January 1, 2012, to December 31, 2021. A total of 5 candidate algorithms were selected from 15 ML algorithms with excellent performance, which was evaluated by area under the operating characteristic curve (AUC) and accuracy. Then, the 5 candidate algorithms were hyperparameter tuned by 5-fold cross-validation grid search, and performance was evaluated by AUC, accuracy, sensitivity, specificity, and recall. Finally, an optimal ML model was constructed, and the predictive results were explained using the SHapley Additive exPlanations (SHAP) framework. A total of 14,843 older patients with HF were consecutively enrolled. CatBoost model was selected as the best prediction model, and AUC was 0.732, with 0.712 accuracy, 0.619 sensitivity, and 0.722 specificity. NT.proBNP, length of stay (LOS), triglycerides, blood phosphorus, blood potassium, and lactate dehydrogenase had the greatest effect on 30-day unplanned readmission in older patients with HF, according to SHAP results. CONCLUSIONS: The study developed a CatBoost model to predict the risk of unplanned 30-day special-cause readmission in older patients with HF, which showed more significant performance compared with the traditional logistic regression model.

Epidemiological characteristics of respiratory viruses in hospitalized children during the COVID-19 pandemic in southwestern China.

Background: Multinational studies have reported that the implementation of nonpharmaceutical interventions (NPIs) to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission coincided with the decline of other respiratory viruses, such as influenza viruses and respiratory syncytial virus. Objective: To investigate the prevalence of common respiratory viruses during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Respiratory specimens of children with lower respiratory tract infections (LRTIs) hospitalized at the Children's Hospital of Chongqing Medical University from January 1, 2018 to December 31, 2021 were collected. Seven common pathogens, including respiratory syncytial virus (RSV), adenovirus (ADV), influenza virus A and B (Flu A, Flu B), and parainfluenza virus types 1-3 (PIV1-3), were detected by a multiplex direct immunofluorescence assay (DFA). Demographic data and laboratory test results were analyzed. Results: 1) A total of 31,113 children with LRTIs were enrolled, including 8141 in 2018, 8681 in 2019, 6252 in 2020, and 8059 in 2021.The overall detection rates decreased in 2020 and 2021 (P < 0.001). The detection rates of RSV, ADV, Flu A, PIV-1, and PIV-3 decreased when NPIs were active from February to August 2020, with Flu A decreasing most predominantly, from 2.7% to 0.3% (P < 0.05). The detection rates of RSV and PIV-1 resurged and even surpassed the historical level of 2018-2019, while Flu A continued decreasing when NPIs were lifted (P < 0.05). 2) Seasonal patterns of Flu A completely disappeared in 2020 and 2021. The Flu B epidemic was observed until October 2021 after a long period of low detection in 2020. RSV decreased sharply after January 2020 and stayed in a nearly dormant state during the next seven months. Nevertheless, the detection rates of RSV were abnormally higher than 10% in the summer of 2021. PIV-3 decreased significantly after the COVID-19 pandemic; however, it atypically surged from August to November 2020. Conclusion: The NPIs implemented during the COVID-19 pandemic affected the prevalence and seasonal patterns of certain viruses such as RSV, PIV-3, and influenza viruses. We recommend continuous surveillance of the epidemiological and evolutionary dynamics of multiple respiratory pathogens, especially when NPIs are no longer necessary.

Global research status and trends of bronchiectasis in children from 2003 to 2022: A 20-year bibliometric analysis.

Background: This study aims to analyze the research hotspots, evolution, and developing trends in pediatric bronchiectasis over the past 20 years using bibliometric analysis and visualization tools to identify potential new research directions. Methods: Publications related to bronchiectasis in children were retrieved from the Web of Science Core Collection (WoSCC) database from 2003 to 2022. Knowledge maps were performed through VOSviewer1.6.18 and CiteSpace6.1 R2. Results: A total of 2,133 publications were searched, while only 1,351 original articles written in English between 2003 and 2022 were incorporated. After removing duplicates, we finally included 1,350 articles published by 6,593 authors from 1,865 institutions in 80 countries/regions in 384 different academic journals with an average citation frequency of 24.91 times. The number of publications shows an extremely obvious binomial growth trend. The majority of publications originated from the United States, Australia, and England. The institutes in Australia, especially Charles Darwin University, published the most articles associated with pediatric bronchiectasis. In addition, Pediatric Pulmonology was the most published journal. In terms of authors, Chang AB was the most productive author, while Gangell CL had the highest average citation frequency. The five keywords that have appeared most frequently during the last two decades were "children," "cystic fibrosis," "bronchiectasis," "ct," and "pulmonary-function." According to keyword analysis, early diagnosis and intervention and optimal long-term pediatric-specific management were the most concerned topics for researchers. Conclusion: This bibliometric analysis indicates that bronchiectasis in children has drawn increasing attention in the last two decades as its recognition continues to rise, providing scholars in the field with significant information on current topical issues and research frontiers.

Dynamic changes in the migratory microbial components of colon tissue during different periods of sepsis in an LPS-induced rat model.

Previous studies have shown that bacterial translocation may play an important role in worsening gastrointestinal injury during sepsis. However, the dynamics of specific microbiota components in intestinal tissues at different sepsis stages remain unclear. Rats receiving intraperitoneal lipopolysaccharide (LPS) were sacrificed at 12 h and 48 h post-injection. Routine blood, serum cytokines, and microbiota in colon tissue, colonic contents, and lung tissue at different time points were assessed. Migratory microbial components in colonic tissue at 12 h and 48 h post-LPS were identified using source tracking, characteristic component identification, and abundance difference analyses. Colonic tissue microbiota changed dynamically over time after LPS injection, involving translocation of microbial components from colon contents and lung tissue at different time points. Bacteria migrating to colon tissue at 12 h sepsis were mainly from colonic contents, while those at 48 h were predominantly from the lung tissue. The migratory microbial components in colon tissue were widely associated with blood indicators and colonizing genus abundance and microbiota functionality in colon tissue. In this study, the temporal dynamics of bacterial translocation from various sources into colon tissues at different sepsis progression stages were characterized for the first time, and the species composition of these migrating microbes was delineated. These bacterial migrants may contribute to the pathophysiological processes in sepsis through direct interactions or indirectly by modulating colonic microbiota community structure and function.

Activin B-activated Cdc42 signaling plays a key role in regulating adipose-derived mesenchymal stem cells-mediated skin wound healing.

BACKGROUND: In our previous study, activin B in combination with ADSCs enhances skin wound healing. However, the underlying molecular mechanisms are not well studied. Cdc42 is recognized to play a critical role in the regulation of stem cells. METHODS: Pull-down assay was performed to investigate the activity of Cdc42. The dominant-negative mutant of Cdc42 (Cdc42N17) was used to explore the role of Cdc42 in activin B-induced ADSCs migration, proliferation, and secretion in vitro. Cdc42N17-transfected ADSCs were injected into a full-thickness excisional wound model to explore their efficiency in wound healing in vivo. The wound healing efficacy was evaluated by the wound closure rates and histological examination. The neovascularization and wound contraction were detected by immunohistochemistry staining of CD31 and α-SMA. Finally, the underlying mechanisms were explored by RNA sequencing. RESULTS: Cdc42N17 inhibited ADSCs migration, proliferation, and secretion induced by activin B. Furthermore, Cdc42N17-transfected ADSCs inhibited the wound closure rate and suppressed the expression of CD31 and α-SMA induced by activin B in vivo. The RNA sequencing showed that the differentially expressed genes in Cdc42N17-transfected ADSCs versus ADSCs were associated with cell migration, proliferation, and adhesion. Further study revealed that the Cdc42-Erk-Srf pathway was required for activin B-induced proliferation in ADSCs. CONCLUSIONS: Our study indicates that Cdc42 plays a crucial role in ADSCs-mediated skin wound healing induced by activin B.

Continuous ZnO nanoparticle exposure induces melanoma-like skin lesions in epidermal barrier dysfunction model mice through anti-apoptotic effects mediated by the oxidative stress-activated NF-κB pathway.

BACKGROUND: Increasing interest in the hazardous properties of zinc oxide nanoparticles (ZnO NPs), commonly used as ultraviolet filters in sunscreen, has driven efforts to study the percutaneous application of ZnO NPs to diseased skin; however, in-depth studies of toxic effects on melanocytes under conditions of epidermal barrier dysfunction remain lacking. METHODS: Epidermal barrier dysfunction model mice were continuously exposed to a ZnO NP-containing suspension for 14 and 49 consecutive days in vivo. Melanoma-like change and molecular mechanisms were also verified in human epidermal melanocytes treated with 5.0 µg/ml ZnO NPs for 72 h in vitro. RESULTS: ZnO NP application for 14 and 49 consecutive days induced melanoma-like skin lesions, supported by pigmented appearance, markedly increased number of melanocytes in the epidermis and dermis, increased cells with irregular nuclei in the epidermis, recruited dendritic cells in the dermis and dysregulated expression of melanoma-associated gene Fkbp51, Trim63 and Tsp 1. ZnO NPs increased oxidative injury, inhibited apoptosis, and increased nuclear factor kappa B (NF-κB) p65 and Bcl-2 expression in melanocytes of skin with epidermal barrier dysfunction after continuously treated for 14 and 49 days. Exposure to 5.0 µg/ml ZnO NPs for 72 h increased cell viability, decreased apoptosis, and increased Fkbp51 expression in melanocytes, consistent with histological observations in vivo. The oxidative stress-mediated mechanism underlying the induction of anti-apoptotic effects was verified using the reactive oxygen species scavenger N-acetylcysteine. CONCLUSIONS: The entry of ZnO NPs into the stratum basale of skin with epidermal barrier dysfunction resulted in melanoma-like skin lesions and an anti-apoptotic effect induced by oxidative stress, activating the NF-κB pathway in melanocytes.

TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31-/- mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

A Peptide Derived from IKK-Interacting Protein Attenuates NF-κB Activation and Inflammation.

The IκB kinase (IKK) complex plays a vital role in regulating the NF-κB activation. Aberrant NF-κB activation is involved in various inflammatory diseases. Thus, targeting IKK activation is an ideal therapeutic strategy to cure and prevent inflammatory diseases related to NF-κB activation. In a previous study, we demonstrated that IKK-interacting protein (IKIP) inhibits the phosphorylation of IKKα/ß and the activation of NF-κB through disruption of the formation of IKK complex. In this study, we identified a 15-aa peptide derived from mouse IKIP (46-60 aa of IKIP), which specifically suppressed IKK activation and NF-κB targeted gene expression via disrupting the association of IKKß and NEMO. Importantly, administration of the peptide reduced LPS-induced acute inflammation and attenuated Zymosan-induced acute arthritis in mice. These findings suggest that this IKIP peptide may be a promising therapeutic reagent in the prevention and treatment of inflammatory diseases.

Screening of the HBx transactivation domain interacting proteins and the function of interactor Pin1 in HBV replication.

Hepatitis B virus (HBV) X protein (HBx) has been determined to play a crucial role in the replication and transcription of HBV, and its biological functions mainly depend on the interaction with other host proteins. This study aims at screening the proteins that bind to the key functional domain of HBx by integrated proteomics. Proteins that specifically bind to the transactivation domain of HBx were selected by comparing interactors of full-length HBx and HBx-D5 truncation determined by glutathione-S-transferase (GST) pull-down assay combined with mass spectrometry (MS). The function of HBx interactor Pin1 in HBV replication was further investigated by in vitro experiments. In this study, a total of 189 proteins were identified from HepG2 cells that specifically bind to the transactivation domain of HBx by GST pull-down and subsequent MS. After gene ontology (GO) analysis, Pin1 was selected as the protein with the highest score in the largest cluster functioning in protein binding, and also classified into the cluster of proteins with the function of structural molecule activity, which is of great potential to be involved in HBV life cycle. The interaction between Pin1 and HBx has been further confirmed by Ni2+-NTA pulldown assay, co-immunoprecipitation, and immunofluorescence microscopy. HBsAg and HBeAg levels significantly decreased in Pin1 expression inhibited HepG2.2.15 cells. Besides, the inhibition of Pin1 expression in HepG2 cells impeded the restored replication of HBx-deficient HBV repaired by ectopic HBx expression. In conclusion, our study identified Pin1 as an interactor binds to the transactivation domain of HBx, and suggested the potential association between Pin1 and the function of HBx in HBV replication.

OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9.

CARD9 is an essential adaptor protein in antifungal innate immunity mediated by C-type lectin receptors. The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. OTUD1 directly interacted with CARD9 and cleaved polyubiquitin chains from CARD9, leading to the activation of the canonical NF-κB and MAPK pathway. OTUD1 deficiency impaired CARD9-mediated signaling and inhibited the proinflammatory cytokine production following fungal stimulation. Importantly, Otud1 -/- mice were more susceptible to fungal infection than wild-type mice in vivo. Collectively, our results identify OTUD1 as an essential regulatory component for the CARD9 signaling pathway and antifungal innate immunity through deubiquitinating CARD9.

Predictive factors of pathologically node-negative disease for HER2 positive and triple-negative breast cancer after neoadjuvant therapy.

BACKGROUND: With the improvement of the efficacy of neoadjuvant therapy (NAT) that is guided by molecular subtypes, the rate of pathologically node-negative disease after NAT (ypN0) is increasing for HER2 positive (HER2+) and triple-negative (TN) breast cancer patients. The necessity of axillary surgery for patients with high ypN0 has been questioned. This study aimed to identify patients among HER2+ and TN breast cancer with low risk for axillary metastases after NAT, and, perhaps, they are suitable for selective elimination of axillary surgery staging. METHODS: From January 2010 to August 2018, 865 breast cancer patients who underwent NAT were included in this retrospective clinical study, and 184 patients (21.3%,184/865) suffered from TN and HER2+ breast cancer and received full-course NAT. The correlation among clinicopathological characteristics of HER2+ and TN breast cancer and ypN0 were analyzed. RESULTS: Among the 184 HER2+ and TN breast cancer patients, tumor staging, lymph node staging and Ki-67 before NAT, clinically node-negative disease after NAT (ycN0), and breast radiologic and pathologic complete response (bpCR) were correlated with ypN0 (P<0.05). Lymph node staging before NAT (OR =0.363, P<0.001), ycN0 (OR =4.995, P<0.001) and bpCR (OR =11.285, P<0.001) were the independent effects of ypN0. The ypN0 rate after NAT in cN0/1 patients with bpCR and ycN0 (97.6%, 40/41) was significantly higher than that in cN2/3 patients (62.5%, 10/16) (P<0.001). Among the 37 patients with initial nodal ultrasonography showing cN0 disease, 17 of 17 (100.0%) with and 18 of 20 (90.0%) without bpCR had no evidence of residual nodal disease (P=0.178). Among the 42 patients with cN1 to ycN0, 23 of 24 (95.8%) with and 10 of 18 (55.6%) without bpCR had no evidence of residual nodal disease (P<0.001). Patients without bpCR had a relative risk for nodal residual metastases of 10.560 (95% CI: 2.720-41.003; P<0.001) compared with those with bpCR in cN1 group. CONCLUSIONS: In terms of HER2+ and TN breast cancer patients, clinical lymph node staging before NAT, ycN0 and bpCR were the independent predictors of ypN0. bpCR was highly correlated with nodal status after NAT. The risk of axillary lymph nodes residual metastases after NAT in the patients of bpCR with cN0 and cN1 to ycN0 was less than 5%, thus making it possible to selectively avoid axillary surgery.