Impact of long-term mining activity on groundwater dynamics in a mining district in Xinjiang coal Mine Base, Northwest China: insight from geochemical fingerprint and machine learning.

Long-term coal mining could lead to a serious of geo-environmental problems. However, less comprehensive identification of factors controlling the groundwater dynamics were involved in previous studies. This study focused on 68 groundwater samples collected before and after mining activities, Self-Organizing Maps (SOM) combining with Principal Component Analysis (PCA) derived that the groundwater samples were classified into five clusters. Clusters 1-5 (C1-C5) represented the groundwater quality affected by different hydrochemical processes, mainly including mineral (carbonate and evaporite) dissolution and cation exchange, which were controlled by the hydrochemical environment at different stages of mining activities. Combining with the time-series data, the Extreme Gradient Boosting Decision Trees (XGBoost) derived that the mine water inflow (feature relative importance of 40.0%) and unit goaf area (feature relative importance of 29.2%) were dominant factors affecting the confined groundwater level, but had less or lagged impact on phreatic groundwater level. This was closely related to the height of the water flow fractured zone and hydraulic connection between aquifers. The results of this study on the coupled evolution of groundwater dynamics could enhance our understanding of the effects of mining on aquifer systems and contribute to the prevention of water hazards in the coalfields.

Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity.

A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.

Accumulation of γδT cells in the decidua is promoted by RANKL which up-regulates ICAM-1 via NF-κB.

Decidual γδT (dγδT) cells help maintain maternal-fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL up-regulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs) and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the quantity of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL over-expression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 up-regulation. Taken together, our data show that DSC-derived RANKL up-regulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and in turn, RSA.

Doxorubicin-based ENO1 targeted drug delivery strategy enhances therapeutic efficacy against colorectal cancer.

Alpha-enolase (ENO1), a multifunctional protein with carcinogenic properties, has emerged as a promising cancer biomarker because of its differential expression in cancer and normal cells. On the basis of this characteristic, we designed a cell-targeting peptide that specifically targets ENO1 and connected it with the drug doxorubicin (DOX) by aldehyde-amine condensation. A surface plasmon resonance (SPR) assay showed that the affinity for ENO1 was stronger (KD = 2.5 µM) for the resulting cell-targeting drug, DOX-P, than for DOX. Moreover, DOX-P exhibited acid-responsive capabilities, enabling precise release at the tumor site under the guidance of the homing peptide and alleviating DOX-induced cardiotoxicity. An efficacy experiment confirmed that, the targeting ability of DOX-P toward ENO1 demonstrated superior antitumor activity against colorectal cancer than that of DOX, while reducing its toxicity to cardiomyocytes. Furthermore, in vivo metabolic distribution results indicated low accumulation of DOX-P in nontumor sites, further validating its targeting ability. These results showed that the ENO1-targeted DOX-P peptide has great potential for application in targeted drug-delivery systems for colorectal cancer therapy.

A New Strategy for Targeting UCP2 to Modulate Glycolytic Reprogramming as a Treatment for Sepsis A New Strategy for Targeting UCP2.

Sepsis is a severe and life-threatening disease caused by infection, characterized by a dysregulated immune response. Unfortunately, effective treatment strategies for sepsis are still lacking. The intricate interplay between metabolism and the immune system limits the treatment options for sepsis. During sepsis, there is a profound shift in cellular energy metabolism, which triggers a metabolic reprogramming of immune cells. This metabolic alteration impairs immune responses, giving rise to excessive inflammation and immune suppression. Recent research has demonstrated that UCP2 not only serves as a critical target in sepsis but also functions as a key metabolic switch involved in immune cell-mediated inflammatory responses. However, the regulatory mechanisms underlying this modulation are complex. This article focuses on UCP2 as a target and discusses metabolic reprogramming during sepsis and the complex regulatory mechanisms between different stages of inflammation. Our research indicates that overexpression of UCP2 reduces the Warburg effect, restores mitochondrial function, and improves the prognosis of sepsis. This discovery aims to provide a promising approach to address the significant challenges associated with metabolic dysfunction and immune paralysis.

Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies.

BACKGROUND: Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. METHODS: Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. RESULTS: Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn't reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. CONCLUSION: Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.

Hyaluronan degradation by HYAL2 is essential for odontoblastic differentiation and migration of mouse dental papilla cells.

The coordination between odontoblastic differentiation and directed cell migration of mesenchymal progenitors is necessary for regular dentin formation. The synthesis and degradation of hyaluronan (HA) in the extracellular matrix create a permissive niche that directly regulates cell behaviors. However, the role and mechanisms of HA degradation in dentin formation remain unknown. In this work, we present that HA digestion promotes odontoblastic differentiation and cell migration of mouse dental papilla cells (mDPCs). Hyaluronidase 2 (HYAL2) is responsible for promoting odontoblastic differentiation through degrading HA, while hyaluronidase 1 (HYAL1) exhibits negligible effect. Silencing Hyal2 generates an extracellular environment rich in HA, which attenuates F-actin and filopodium formation and in turn inhibits cell migration of mDPCs. In addition, activating PI3K/Akt signaling significantly rescues the effects of HA accumulation on cytodifferentiation. Taken together, the results confirm the contribution of HYAL2 to HA degradation in dentinogenesis and uncover the mechanism of the HYAL2-mediated HA degradation in regulating the odontoblastic differentiation and migration of mDPCs.

ABA functions in low phosphate-induced anthocyanin accumulation through the transcription factor ABI5 in Arabidopsis.

KEY MESSAGE: ABI5 functions in ABA-mediated anthocyanin accumulation in plant response to low phosphate. Low phosphate (LP)-induced anthocyanin biosynthesis and accumulation play an important role in plant adaptive response to phosphate starvation conditions. However, whether and how the stress phytohormone abscisic acid (ABA) participates in LP-induced anthocyanin accumulation remain elusive. Here, we report that ABA is required for LP-induced anthocyanin accumulation in Arabidopsis thaliana. Disrupting ABA DEFICIENT2 (ABA2), a key ABA-biosynthetic gene, or BETA-GLUCOSIDASE1 (BG1), a major gene implicated in converting conjugated ABA to active ABA, significantly impairs LP-induced anthocyanin accumulation, as LP-induced expression of the anthocyanin-biosynthetic genes Chalcone Synthase (CHS) is dampened in the aba2 and bg1 mutant. In addition, LP-induced anthocyanin accumulation is defective in the mutants of ABA signaling pathway, including ABA receptors, ABA Insensitive2, and the transcription factors ABA Insensitive5 (ABI5), suggesting a role of ABI5 in ABA-mediated upregulation of anthocyanin-biosynthetic genes in plant response to LP. Indeed, LP-induced expression of CHS is repressed in the abi5-7 mutant but further promoted in the ABI5-overexpressing plants compared to the wild-type. Moreover, ABI5 can bind to and transcriptionally activate CHS, and the defectiveness of LP-induced anthocyanin accumulation in abi5-7 can be restored by overexpressing CHS. Collectively, our findings illustrates that ABI5 functions in ABA-mediated LP-induced anthocyanin accumulation in Arabidopsis.

RBP-J regulates homeostasis and function of circulating Ly6Clo monocytes.

Notch-RBP-J signaling plays an essential role in the maintenance of myeloid homeostasis. However, its role in monocyte cell fate decisions is not fully understood. Here, we showed that conditional deletion of transcription factor RBP-J in myeloid cells resulted in marked accumulation of blood Ly6Clo monocytes that highly expressed chemokine receptor CCR2. Bone marrow transplantation and parabiosis experiments revealed a cell-intrinsic requirement of RBP-J for controlling blood Ly6CloCCR2hi monocytes. RBP-J-deficient Ly6Clo monocytes exhibited enhanced capacity competing with wildtype counterparts in blood circulation. In accordance with alterations of circulating monocytes, RBP-J deficiency led to markedly increased population of lung tissues with Ly6Clo monocytes and CD16.2+ interstitial macrophages. Furthermore, RBP-J deficiency-associated phenotypes could be genetically corrected by further deleting Ccr2 in myeloid cells. These results demonstrate that RBP-J functions as a crucial regulator of blood Ly6Clo monocytes and thus derived lung-resident myeloid populations, at least in part through regulation of CCR2.

Polycationic Open-Shell Cyclophanes: Synthesis of Electron-Rich Chiral Macrocycles, and Redox-Dependent Electronic States.

π-Conjugated chiral nanorings with intriguing electronic structures and chiroptical properties have attracted considerable interests in synthetic chemistry and materials science. We present the design principles to access new chiral macrocycles (1 and 2) that are essentially built on the key components of main-group electron-donating carbazolyl moieties or the π-expanded aza[7]helicenes. Both macrocycles show the unique molecular conformations with a (quasi) figure-of-eight topology as a result of the conjugation patterns of 2,2',7,7'-spirobifluorenyl in 1 and triarylamine-coupled aza[7]helicene-based building blocks in 2. This electronic nature of redox-active, carbazole-rich backbones enabled these macrocycles to be readily oxidized chemically and electrochemically, leading to the sequential production of a series of positively charged polycationic open-shell cyclophanes. Their redox-dependent electronic states of the resulting multispin polyradicals have been characterized by VT-ESR, UV-vis-NIR absorption and spectroelectrochemical measurements. The singlet (ΔES-T = -1.29 kcal mol-1) and a nearly degenerate singlet-triplet ground state (ΔES-T(calcd) = -0.15 kcal mol-1 and ΔES-T(exp) = 0.01 kcal mol-1) were proved for diradical dications 12+2• and 22+2•, respectively. Our work provides an experimental proof for the construction of electron-donating new chiral nanorings, and more importantly for highly charged polyradicals with potential applications in chirospintronics and organic conductors.

PARP inhibitor plus radiotherapy reshape the immune suppressive microenvironment and potentiate the efficacy of immune checkpoint inhibitors in tumors with IDH1 mutation.

Isocitrate dehydrogenase 1 mutant (IDH1mut) tumors respond poorly to immunotherapy, but are more sensitive to chemoradiotherapy and poly (ADP-ribose) polymerase inhibition (PARPi). Accordingly, some efforts have aimed to capitalize on the IDH1 mutation rather than reverse it. Moreover, radiotherapy (RT) and PARPi can stimulate antitumor immunity, raising the possibility of reversing the immunosuppression caused by IDH1 mutation while killing the tumor. To assess this possibility, we treated IDH1mut tumors and cells with RT + PARPi. RT + PARPi showed enhanced efficacy over either modality alone both in vitro and in vivo. RT + PARPi induced more DNA damage and activated the cGAS-STING pathway more. IFNß, CXCL10, and CCL5 were also more highly expressed at both the mRNA and protein levels. In two different tumor models, RT + PARPi increased infiltration and cytolytic function of CD8+ T cells, with one model also showing increased CD8+T cell proliferation. RT+PARPi also increased PD-L1 expression and enhanced checkpoint inhibition. Knocking out cGAS reversed the increased CD8+ T cell infiltration and the antitumor effect of RT+PARPi. We conclude that RT + PARPi reshapes the IDH1mut tumor immunosuppressive microenvironment, thereby augmenting checkpoint inhibition.

The rumen microbiota contributed to the development of mastitis induced by subclinical ketosis.

BACKGROUND: Mastitis is a serious disease which affects animal husbandry, particularly in cow breeding. The etiology of mastitis is complex and its pathological mechanism is not yet fully understood. Our previous research in clinical investigation has revealed that subclinical ketosis can increase the number of somatic cell counts (SCC) in milk, although the underlying mechanism remains unclear. Recent studies have further confirmed the significant role of mastitis. RESULTS: In this study, we aimed to examine the SCC, rumen microbiota, and metabolites in the milkmen of cows with subclinical ketosis. Additionally, we conducted a rumen microbiota transplant into mice to investigate the potential association between rumen microbiota disturbance and mastitis induced by subclinical ketosis in dairy cows. The study has found that cows with subclinical ketosis have a higher SCC in their milk compared to healthy cows. Additionally, there were significant differences in the rumen microbiota and the level of volatile fatty acid (VFA) between cows with subclinical ketosis and healthy cows. Moreover, transplanting the rumen microbiota from subclinical ketosis and mastitis cows into mice can induce mammary inflammation and liver function damage than transplanting the rumen flora from healthy dairy cows. CONCLUSIONS: In addition to the infection of mammary gland by pathogenic microorganisms, there is also an endogenous therapeutic pathway mediated by rumen microbiota. Targeted rumen microbiota modulation may be an effective way to prevent and control mastitis in dairy cows.

Lactobacillus reuteri inhibits Staphylococcus aureus-induced mastitis by regulating oxytocin releasing and gut microbiota in mice.

Mastitis is the most frequent disease of cows and has well-recognized detrimental effects on animal wellbeing and dairy farm profitability. With the advent of the postantibiotic era, alternative antibiotic agents, especially probiotics, have received increasing attention in the treatment of mastitis. Based on research showing that Lactobacillus reuteri (L. reuteri) has anti-inflammatory effects, this study explored the protective effects and mechanisms of L. reuteri against mastitis induced by Staphylococcus aureus (S. aureus) in mice. First, mice with S. aureus-induced mastitis were orally administered L. reuteri, and the inflammatory response in the mammary gland was observed. The results showed that L. reuteri significantly inhibited S. aureus-induced mastitis. Moreover, the concentration of oxytocin (OT) and protein expression of oxytocin receptor (OTR) were measured, and inhibition of OTR or vagotomy reversed the protective effect of L. reuteri or its culture supernatant (LCS) on S. aureus-induced mastitis. In addition, in mouse mammary epithelial cells (MMECs), OT inhibited the inflammation induced by S. aureus by inhibiting the protein expression of OTR. It was suggested that L. reuteri protected against S. aureus-induced mastitis by releasing OT. Furthermore, microbiological analysis showed that the composition of the microbiota was altered, and the relative abundance of Lactobacillus was significantly increased in gut and mammary gland after treatment with L. reuteri or LCS. In conclusion, our study found the L. reuteri inhibited the mastitis-induced by S. aureus via promoting the release of OT, and treatment with L. reuteri increased the abundance of Lactobacillus in both gut and mammary gland.

Lineage regulators TFAP2C and NR5A2 function as bipotency activators in totipotent embryos.

During the first lineage segregation, a mammalian totipotent embryo differentiates into the inner cell mass (ICM) and trophectoderm (TE). However, how transcription factors (TFs) regulate this earliest cell-fate decision in vivo remains elusive, with their regulomes primarily inferred from cultured cells. Here, we investigated the TF regulomes during the first lineage specification in early mouse embryos, spanning the pre-initiation, initiation, commitment, and maintenance phases. Unexpectedly, we found that TFAP2C, a trophoblast regulator, bound and activated both early TE and inner cell mass (ICM) genes at the totipotent (two- to eight-cell) stages ('bipotency activation'). Tfap2c deficiency caused downregulation of early ICM genes, including Nanog, Nr5a2, and Tdgf1, and early TE genes, including Tfeb and Itgb5, in eight-cell embryos. Transcription defects in both ICM and TE lineages were also found in blastocysts, accompanied by increased apoptosis and reduced cell numbers in ICMs. Upon trophoblast commitment, TFAP2C left early ICM genes but acquired binding to late TE genes in blastocysts, where it co-bound with CDX2, and later to extra-embryonic ectoderm (ExE) genes, where it cooperatively co-occupied with the former ICM regulator SOX2. Finally, 'bipotency activation' in totipotent embryos also applied to a pluripotency regulator NR5A2, which similarly bound and activated both ICM and TE lineage genes at the eight-cell stage. These data reveal a unique transcription circuity of totipotency underpinned by highly adaptable lineage regulators.

Health insurance as a moderator in the relationship between financial toxicity and medical cost-coping behaviors: Evidence from patients with lung cancer in China.

OBJECTIVE: This study investigates the relationship between financial toxicity and medical cost-coping behaviors (MCCB) in Chinese patients with lung cancer, with a particular focus on the moderating role of health insurance. METHODS: We surveyed 218 patients with lung cancer and assessed their Comprehensive Score for Financial Toxicity (COST) and self-reported MCCB. Patients were categorized into Urban Employee's Basic Medical Insurance (UEBMI) group and Urban-Rural Resident Basic Medical Insurance Scheme (URRBMI) groups by their medical insurance, and matched for socioeconomic, demographic, and disease characteristics via propensity score. RESULTS: Significant different characteristics were noted between UEBMI patients and URRBMI patients. Patients with UEBMI had higher COST scores but lower levels of MCCB compared to URRBMI patients in the original dataset. After data matching, multivariate logit regression analysis showed that better financial toxicity was associated with lower levels of MCCB (OR = 0.95, 95% CI: 0.92-0.99). Health insurance type did not have a direct association with cost-coping behaviors, but an interaction was observed between health insurance type and financial toxicity. Among patients with URRBMI, better financial toxicity was associated with lower levels of cost-coping behaviors (OR = 0.89, 95% CI: 0.83-0.95). Patients with UEBMI had a lower probability of engaging in any cost-coping behaviors in situations of worse financial toxicity compared to patients with URRBMI. CONCLUSION: The findings suggest that financial toxicity is correlated with MCCB in Chinese patients with lung cancer. The type of health insurance, specifically UEBMI and URRBMI, plays a moderating role in this relationship. Understanding these dynamics is essential for developing targeted interventions and policies to mitigate financial toxicity and improve patients' management of medical costs.

SARS-CoV-2 immunity in animal models.

The COVID-19 pandemic, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide health crisis due to its transmissibility. SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals. These complications encompass symptoms such as coughing, respiratory distress, fever, infectious shock, acute respiratory distress syndrome (ARDS), and even multiple-organ failure. Animal models serve as crucial tools for investigating pathogenic mechanisms, immune responses, immune escape mechanisms, antiviral drug development, and vaccines against SARS-CoV-2. Currently, various animal models for SARS-CoV-2 infection, such as nonhuman primates (NHPs), ferrets, hamsters, and many different mouse models, have been developed. Each model possesses distinctive features and applications. In this review, we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection, as well as the corresponding immune responses and applications of these models. A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients. Finally, we highlighted the current gaps in related research between animal model studies and clinical investigations, underscoring lingering scientific questions that demand further clarification.

Interferon therapy improves survival in patients with hepatitis B virus-related hepatocellular carcinoma after curative surgery: a meta-analysis.

BACKGROUND AND AIM: A novel study found interferon enhanced antitumor activity of anti-PD-1-based immunotherapy and played a crucial role in improving efficacy on HCC, but the opposite results about the efficacy of interferon on HBV-related HCC were obtained from previous clinical studies and meta-analyses. Thus, this meta-analysis aimed to re-evaluate whether interferon could improve survival and reduce recurrence of patients with HBV-related HCC after curative surgery. METHODS: MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to November 2022 and a meta-analysis was done. RESULTS: 10 trials with a total of 2062 subjects were screened. Interferon significantly improved 1-, 2-, 3- and 5-year OS and 1-, 2- and 3-year DFS, and reduced 2-, 3- and 5-year recurrence rates of patients with HBV-related HCC after curative surgery. However, interferon did not improve 8-year OS and 5-year DFS, did not reduce 1-year recurrence rate. CONCLUSIONS: Interferon may significantly reduce recurrence and improve DFS of patients with HBV-related HCC after curative surgery, and finally improve the OS. However, the efficacy advantage may gradually weaken as time goes on. The clinical application of interferon combined with NAs recommended in this meta-analysis is needed to be further studied.

Simultaneous production of high-frequency synthetic apomixis with high fertility and improved agronomic traits in hybrid rice.

The current apomixis system used in fixing heterozygosity suffers from the problems of low fertility and limited apomixis induction rate. This study implies that egg-cell-specific expression of dandelion's PAR combined with MiMe in hybrid rice can efficiently trigger highly fertile synthetic apomixis for effective clonal propagation of hybrids.

The utility of P-I-R classification in predicting the on-treatment histological and clinical outcomes of patients with hepatitis B and advanced liver fibrosis.

BACKGROUND AND AIMS: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. APPROACH AND RESULTS: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases ( p <0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55-56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). CONCLUSIONS: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.

Gut/rumen-mammary gland axis in mastitis: Gut/rumen microbiota-mediated "gastroenterogenic mastitis".

BACKGROUND: Mastitis is an inflammatory response in the mammary gland that results in huge economic losses in the breeding industry. The aetiology of mastitis is complex, and the pathogenesis has not been fully elucidated. It is commonly believed that mastitis is induced by pathogen infection of the mammary gland and induces a local inflammatory response. However, in the clinic, mastitis is often comorbid or secondary to gastric disease, and local control effects targeting the mammary gland are limited. In addition, recent studies have found that the gut/rumen microbiota contributes to the development of mastitis and proposed the gut/rumen-mammary gland axis. Combined with studies indicating that gut/rumen microbiota disturbance can damage the gut mucosa barrier, gut/rumen bacteria and their metabolites can migrate to distal extraintestinal organs. It is believed that the occurrence of mastitis is related not only to the infection of the mammary gland by external pathogenic microorganisms but also to a gastroenterogennic pathogenic pathway. AIM OF REVIEW: We propose the pathological concept of "gastroenterogennic mastitis" and believe that the gut/rumen-mammary gland axis-mediated pathway is the pathological mechanism of "gastroenterogennic mastitis". KEY SCIENTIFIC CONCEPTS OF REVIEW: To clarify the concept of "gastroenterogennic mastitis" by summarizing reports on the effect of the gut/rumen microbiota on mastitis and the gut/rumen-mammary gland axis-mediated pathway to provide a research basis and direction for further understanding and solving the pathogenesis and difficulties encountered in the prevention of mastitis.