circEIF3I facilitates the recruitment of SMAD3 to early endosomes to promote TGF-ß signalling pathway-mediated activation of MMPs in pancreatic cancer.

BACKGROUND: Among digestive tract tumours, pancreatic ductal adenocarcinoma (PDAC) shows the highest mortality trend. Moreover, although PDAC metastasis remains a leading cause of cancer-related deaths, the biological mechanism is poorly understood. Recent evidence demonstrates that circular RNAs (circRNAs) play important roles in PDAC progression. METHODS: Differentially expressed circRNAs in normal and PDAC tissues were screened via bioinformatics analysis. Sanger sequencing, RNase R and actinomycin D assays were performed to confirm the loop structure of circEIF3I. In vitro and in vivo functional experiments were conducted to assess the role of circEIF3I in PDAC. MS2-tagged RNA affinity purification, mass spectrometry, RNA immunoprecipitation, RNA pull-down assay, fluorescence in situ hybridization, immunofluorescence and RNA-protein interaction simulation and analysis were performed to identify circEIF3I-interacting proteins. The effects of circEIF3I on the interactions of SMAD3 with TGFßRI or AP2A1 were measured through co-immunoprecipitation and western blotting. RESULTS: A microarray data analysis showed that circEIF3I was highly expressed in PDAC cells and correlated with TNM stage and poor prognosis. Functional experiments in vitro and in vivo revealed that circEIF3I accelerated PDAC cells migration, invasion and metastasis by increasing MMPs expression and activity. Mechanistic research indicated that circEIF3I binds to the MH2 domain of SMAD3 and increases SMAD3 phosphorylation by strengthening the interactions between SMAD3 and TGFßRI on early endosomes. Moreover, AP2A1 binds with circEIF3I directly and promotes circEIF3I-bound SMAD3 recruitment to TGFßRI on early endosomes. Finally, we found that circEif3i exerts biological functions in mice similar to those of circEIF3I in humans PDAC. CONCLUSIONS: Our study reveals that circEIF3I promotes pancreatic cancer progression. circEIF3I is a molecular scaffold that interacts with SMAD3 and AP2A1 to form a ternary complex, that facilitates the recruitment of SMAD3 to early endosomes and then activates the TGF-ß signalling pathway. Hence, circEIF3I is a potential prognostic biomarker and therapeutic target in PDAC.

Caprin-1 influences autophagy-induced tumor growth and immune modulation in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. METHODS: Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. RESULTS: Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. CONCLUSIONS: Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.

Gut microbiota affects pancreatic fibrotic progression through immune modulation in chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by chronic progressive pancreatic inflammation, which leads to the permanent damage of exocrine and endocrine cells. CP causes irreversible morphological and functional changes, and the clinical manifestations includes abdomen pain, steatorrhea and diabetes. CP induces changes in the composition of gut microbiota that could be used as potential biomarkers for pancreatic fibrosis evaluation. Gut microbiota has emerged as key regulator of immunomodulation and gut microbiota-induced immune activation has not been explored in CP. In current study, we profiled gut microbial signatures in mouse CP model, and found that higher proportion of Streptomyces, Turicibacter, Methylobacterium, Enterococcus and Candidatus_Paenicardiniummore were positively associated with the occurrence of pancreatic fibrosis. We then identified increased CD3+T cells and macrophage infiltration in mouse and human CP tissues by transcriptome sequencing data from GEO database. Subsequently, we demonstrated that fecal microbiota transplantation (FMT) from CP mouse (FMT-CP) exacerbated pancreatic fibrosis by increasing CD4+T cells and macrophage infiltration compared to fecal samples obtained from healthy mouse donor (FMT-HC). Our study describes the link between gut microbiota dysbiosis and immune activation in pancreatic fibrotic progression, and highlights the potential therapeutic roles of FMT and CP treatment.

Pore-Scale Study on Shale Oil-CO2-Water Miscibility, Competitive Adsorption, and Multiphase Flow Behaviors.

Due to the fracturing fluid imbibition and primary water, oil-water two-phase fluids generally exist in shale nanoporous media. The effects of water phase on shale oil recovery and geological carbon sequestration via CO2 huff-n-puff is non-negligible. Meanwhile, oil-CO2 miscibility after CO2 huff-n-puff also has an important effect on oil-water two-phase flow behaviors. In this work, by considering the oil-CO2 competitive adsorption behaviors and the effects of oil-CO2 miscibility on water wettability, an improved multicomponent and multiphase lattice Boltzmann method is proposed to study the effects of water phase on CO2 huff-n-puff. Additionally, the effects of oil-CO2 miscibility on oil-water flow behaviors and relative permeability are also discussed. The results show that due to Jamin's effect of water droplets in oil-wetting pores and the capillary resistance of bridge-like water phase in water-wetting pores, CO2 can hardly diffuse into the oil phase, causing a large amount of remaining oil. As water saturation increases, Jamin's effect and the capillary resistance become more pronounced, and the CO2 storage mass gradually decreases. Then, based on the results from molecular dynamics simulations, the influences of oil-CO2 miscibility on oil-water relative permeability in calcite nanoporous media are studied, and as the oil mass percentage in the oil-CO2 miscible system decreases, the oil/water relative permeability decreases/increases. The improved lattice Boltzmann model can be readily extended to quantitatively calculate geological CO2 storage mass considering water saturation and calculate the accurate oil-water relative permeability based on the real 3D digital core.

Fibrinogen-like Protein 1 as a Predictive Marker for the Incidence of Severe Acute Pancreatitis and Infectious Pancreatic Necrosis.

Background and Objectives: Acute pancreatitis (AP) is defined as an acute inflammatory disorder of the pancreas and is a common gastrointestinal disease. Since currently used indicators lack specifics and cannot accurately reflect the phase of disease, better diagnostic approaches need to be explored. Fibrinogen-like protein 1 (FGL-1) is a reactant in acute inflammatory diseases and is increased in the plasma of AP patients. In the current study, we aim to investigate the clinical benefits of FGL-1 in predicting the severity of AP and infected pancreatic necrosis (IPN), which can improve the diagnostic efficiency of AP. Materials and Methods: In this study, 63 patients diagnosed with AP from December 2018 to September 2019 were enrolled. Regarding the severity of AP, patients were separated into severe acute pancreatitis (SAP, n = 12) and No-SAP groups (n = 51). On the basis of infective conditions, patients were divided into IPN (n = 9) and No-IPN (n = 54) groups. The demographic data (sex and age) and blood parameters (WBC, HCT, glucose, calcium, FIB, APTT, PCT, CRP, and FGL-1) were retrospectively analyzed. Results: The plasma FGL-1 levels were increased in both SAP (p < 0.01) and IPN (p < 0.05) subgroups compared to the healthy control group. Multivariate analysis showed that elevated plasma FGL-1 (p < 0.01) and PCT levels (p < 0.05) within 72 h after the onset of AP were positively correlated with the severity of AP, while increased plasma FGL-1 (p < 0.01) and CRP (p < 0.05) levels were positively correlated with the occurrence of IPN. The combination of FGL-1 and PCT showed superiority to both individual markers in SAP prediction. However, the combination of FGL-1 and CRP showed no diagnostic advantage over CRP in IPN prediction. Conclusions: Plasma FGL-1 within 72 h after the onset could be used for the stratification of AP and its infectious complications. The combination of PCT and FGL-1 presents an enormous advantage for the early identification of SAP.

HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy.

The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.

Histologic characterization of the post-radiation urethral stenosis in men treated for prostate cancer.

PURPOSE: To evaluate histological changes in stenotic urethral tissue post-radiation therapy. Treatment of prostate cancer by radiation therapy carries a risk of off-target injury to the membranous urethra causing urethral stenosis. Limited characterization of post-radiation urethral stenosis exists in the literature. We hypothesize that specific histopathologic parameters distinguish this stricture etiology. METHODS: Eighty-two consecutive patients with membranous urethral stenosis underwent urethroplasty between 2013 and 2018. Seventy specimens (86.4%) were available for evaluation: 51 from patients without radiation exposure and 19 from patients with history of radiation therapy for prostate cancer. All specimens were reviewed by a pathologist blinded to patient/stricture information. Histological scoring system was used for the quantification of collagen density, collagen organization, hyalinized fibrosis, vascular density, spindle-cell change, necrosis, hemorrhage, fat entrapment, vacuolation, acute and chronic inflammation, and foreign-body giant cells. Differences in histologic outcomes between groups were statistically analyzed. RESULTS: Post-radiation specimens had a higher collagen density (p = 0.01), higher collagen organization (p = 0.001), increased hyalinized fibrosis (p = 0.03), fat entrapment (p = 0.005) and spindle cell change (p = 0.005) when compared to membranous specimens without prior exposure to radiation. Post-radiation specimens also had a significantly decreased vascularity compared to specimens of non-radiated etiology (p = 0.0005). Fibrous connective tissue degenerative change with vacuolation was pronounced in post-radiation specimens and seldom seen in those without radiation (p = 0.0001). CONCLUSIONS: Membranous urethral stenosis following radiation demonstrates specific histologic characteristics including vascular loss and increased scarring (collagen density, organization). This histologic grading system may be used in grading severity of radiation damage, and conceivably adopted for correlation with clinical outcomes.

Liquid buccal mucosa graft endoscopic urethroplasty: a validation animal study.

PURPOSE: To validate a novel method of urethral stricture treatment using liquid buccal mucosal grafts (LBMG) to augment direct vision internal urethrotomy (DVIU) in an animal model. MATERIALS AND METHODS: A rabbit stricture model was used to test this method. Strictures were induced in 26 rabbits using electroresection of urethral epithelium. The animals were randomized into two groups: Group-1, treated with DVIU and LBMG in fibrin glue, and Group-2, DVIU with fibrin glue only. LBMG was prepared by suspension of mechanically minced buccal mucosa micrografts in fibrin glue. This LBMG-fibrin glue mixture was later injected into the urethrotomies of Group-1 animals. All animals were killed at 24 weeks after repeat retrograde urethrogram (RUG) and urethroscopy by surgeon blinded to the treatment arm. Radiographic images and histological specimens were reviewed by a radiologist and a pathologist, respectively, blinded to the treatment arm. Stricture treatment was considered a success if a diameter measured on RUG increased by ≥ 50% compared to pre-treatment RUG diameter. Histological specimens were assessed for the presence of BMG engraftment. RESULTS: In Group-1, 8/12(67%) animals demonstrated engraftment of LBMG, compared to none in Group-2 (p = 0.0005). 7/12(58%) in Group-1 showed radiographic resolution/improvement of strictures compared to 5/13 Group-2 rabbits (38%, p = 0.145). The median percent change for the Group-1 was 59%, compared to 41.6% for Group-2 (p = 0.29). CONCLUSION: This proof-of-concept study demonstrates feasibility of LBMG for endoscopic urethral stricture repairs. Further studies are needed to establish the role of this novel concept in treatment of urethral strictures.

Macrophage-secreted TSLP and MMP9 promote bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis.

Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients. METHODS: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation. RESULTS: We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents. CONCLUSIONS: Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy.

All-trans retinoic acid synergizes with topotecan to suppress AML cells via promoting RARα-mediated DNA damage.

BACKGROUND: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic. METHODS: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis. RESULTS: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model. CONCLUSIONS: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies.

[The clinical characteristics of twenty-five cases of acute HIV-1 infection in China].

OBJECTIVE: To summarize the clinical features, immunological and virological characteristics of HIV-1 infected patients in the acute phase for the sake of improving the understanding of acute HIV-1 infection and early diagnosis. METHODS: To retrospectively analyze the clinical manifestation and laboratory data of 25 patients with acute HIV infection, who were admitted to the Department of Infectious Diseases, Peking Union Medical College Hospital from 2006 to 2013. RESULTS: Among the total 25 patients, 19 (76%) patients were sexually transmitted, including 17 (68%) of whom were homosexual. Twenty two (88%) patients presented significant symptoms. Common symptoms consisted of fever (15 patients, 60%), cervical lymphoadenopathy (8 patients, 32%), skin rashes (6 patients, 24%), diarrhea (5 patients, 20%), shortness of breath (3 patients, 12%), sore throat (3 patients, 12%), and cough (3 patients, 12%), while only one case represented as Guillain-Barr syndrome, upper arm cellulitis, headache and vomiting, and perianal abscess. Laboratory examination indicated elevated peripheral lymphocytes (13 patients, 52%), abnormal liver function (11 patients, 44%), thrombocytopenia (1 patients, 4%). Notably, 2 patients (8%) revealed negative results of HIV antibody, who were diagnosed with positive plasma viral load. The average viral load was (4.68 ± 0.83) lg copies/ml. CD(+)(4) T cell count was 473 (343,621) cells/µl. CD(+)(8) T cell count was 1 296 (997, 2 177) cells/µl with maximal value of 7 984 cells/µl. The CD4/CD8 ratio was 0.33 (0.22, 0.53) including 24 (96%) patients with obvious inverted ratio. The positive rates of immune activation markers HLA-DR and CD38 on the surface of CD(+)(8) T cells were (74.9 ± 16.1) % and (84.9 ± 12.5) % respectively. The viral load had a significant positive correlation with the expression of HLA-DR and CD38. CONCLUSIONS: The most common symptoms of acute HIV-1 infection are fever, cervical lymphadenopathy, skin rashes and diarrhea. Significantly elevated CD(+)(8) T cell count, inverted CD4/CD8 ratio and abnormal immune activation markers contribute to the early diagnosis of acute HIV infection.

Preparation of dibenzo[e,g]isoindol-1-ones via Scholl-type oxidative cyclization reactions.

A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki-Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.

m-Aminophenylacetylene induces maternal care in a predatory spider.

Maternal care is critically important for the survival of offspring in various animals. Spiders in the family Lycosidae are known for their hunting ability and maternal care behaviors. Predation on newly hatched spiderlings (pulli) by mother spiders decreases when they come into contact, and they carry the pulli on their dorsal surface. However, the factors inducing maternal care in lycosid spiders have not been elucidated. In this study, we investigated maternal care in Pardosa pseudoannulata (Araneae, Lycosidae) females. We proposed that the physical interaction between pulli and mother spiders induces maternal care via m-aminophenylacetylene (m-A), a novel regulator of maternal care. The presence of pulli on the dorsal abdomen of non-mother spiders suppressed pulli predation and increased the pulli-carrying rate, and the absence of pulli on the mother spiders increased pulli predation and decreased the pulli-carrying rate. The compound m-A was abundant in mother spiders, and it could be induced in non-mother spiders when they carried pulli. The topical application of m-A to non-mother spiders and m-A injection decreased pulli predation and increased the pulli-carrying rate, respectively; these findings indicate that m-A in both internal tissues and the integument is required for the induction of maternal care behavior, and the interaction between pulli and females induces the production of m-A. In-depth study of the regulatory mechanism of maternal care will enhance our understanding of spider biology and behavior.

Declined Live Birth Rate from in vitro Fertilization Fresh Cycles Performed During Chinese New Year Holiday Season.

Purpose: This study aims to investigate the impact of the Chinese New Year (CNY) holiday season on the outcomes of In Vitro Fertilization (IVF) fresh embryo transfer cycles. Participants and Methods: This retrospective study analyzed 4688 patients who received their first IVF fresh cycle attempt between January 2017 and October 2021. Of these, 4449 women underwent IVF during non-holiday seasons, while 239 women were treated during the CNY holiday season. The study included women who underwent IVF treatment during the specified time frame. The primary outcome was the live birth rate (LBR). Results: The study found that the LBR of IVF performed during the CNY holiday season was 32.22%, which is significantly lower than that of the non-holiday season (43.38%, p<0.001). Multivariate logistic regression analysis showed that the CNY holiday season (OR=0.62, 95% CI 0.47-0.82, p=0.001) was an independent factor associated with the live birth rate. Propensity score matching (PSM) data analysis showed that the LBR in the CNY holiday season group was 31.78% compared to 42.64% in the non-holiday season group (p=0.005). Inverse probability of treatment weighting (IPTW) data also indicated that the CNY holiday season had a lower LBR than the non-holiday season (OR=0.64, 95% CI 0.47-0.87, p=0.005). Conclusion: IVF performed during the CNY holiday season results in a lower live birth rate, potentially indicating that certain lifestyle adjustments during this period, such as unhealthy dietary, tobacco and alcohol usage, sleep disruption, and emotional stress experienced could have some influence on the outcomes.

Live Birth Outcomes for PCOS Patients Under the Follicular-Phase Long-Acting GnRH Agonist Protocol or Antagonist Protocol - A Retrospective Chinese Cohort.

Objective: For patients with polycystic ovary syndrome (PCOS) to undergo in vitro fertilization (IVF) and embryo transfer (ET), there has been no consensus regarding which protocol is the most optimal for live birth rate in fresh cycles. We sought to evaluate depot gonadotropin-releasing hormone (GnRH) agonist protocol versus GnRH antagonist protocol in IVF outcomes for PCOS patients in a single fertility center. Methods: In this retrospective cohort, PCOS patients who visited the Second Hospital of Hebei Medical University reproductive center between February 2012 and December 2019 were screened, and 533 PCOS infertility patients were included undergoing their first IVF cycle, with 470 in the depot GnRH agonist group and 63 in the GnRH antagonist group. The primary of this study outcome was the fresh live birth rate (LBR). Results: PCOS women in the depot GnRH agonist group had a higher LBR (49.79%) than those in the GnRH antagonist group (34.92%, p = 0.027). The multivariable logistic regression also confirmed that women in the depot GnRH agonist group had a higher LBR than those in the GnRH antagonist group (OR = 1.83, 95% CI 1.05~3.18, p = 0.032). After propensity score matching (PSM), the LBR in the depot GnRH agonist group was higher (50.32%) than that of the GnRH antagonist group (35.48%), p = 0.033. The ovarian hyperstimulation syndrome (OHSS) rates were similar between the two groups, with 35 in the depot GnRH group and 6 in the GnRH antagonist group (p = 0.561). Conclusions: For PCOS patients in fresh embryo transfer cycles, the depot GnRH agonist protocol may lead to a higher LBR than the antagonist protocol with satisfied lower OHSS rates.

The Interaction of Microbiome and Pancreas in Acute Pancreatitis.

Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar cells. Secondary infection and sepsis are independent prognosticators for AP progression and increased mortality. Accumulating anatomical and epidemiological evidence suggests that the dysbiosis of gut microbiota affects the etiology and severity of AP through intestinal barrier disruption, local or systemic inflammatory response, bacterial translocation, and the regulatory role of microbial metabolites in AP patients and animal models. Recent studies discussing the interactions between gut microbiota and the pancreas have opened new scopes for AP, and new therapeutic interventions that target the bacteria community have received substantial attention. This review concentrates on the alterations of gut microbiota and its roles in modulating gut-pancreas axis in AP. The potential therapies of targeting microbes as well as the major challenges of applying those interventions are explored. We expect to understand the roles of microbes in AP diagnosis and treatment.

IGF2BP1-mediated N6-methyladenosine modification promotes intrahepatic cholangiocarcinoma progression.

N6-methyladenosine (m6A) RNA methylation and its associated RNA-binding protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) are involved in tumor initiation and progression. Here, we explored the biological function and clinical significance of IGF2BP1 in intrahepatic cholangiocarcinoma (iCCA). We found that IGF2BP1 expression was upregulated by H3K27 acetylation enrichment of its promoter, which positively correlated with poor clinicopathological characteristics and survival. Gain- and loss-of-function experiments showed that IGF2BP1 overexpression (knockdown) enhanced (attenuated) iCCA growth and metastasis in vitro and in vivo. Mechanistically, IGF2BP1 not only regulated the c-Myc/p16 axis to promote iCCA growth and inhibit senescence, but also activated the ZIC2/PAK4/AKT/MMP2 axis to induce tumor metastasis. More importantly, BTYNB, a recently identified IGF2BP1 inhibitor, exerted promising anti-tumor efficacy in a patient-derived xenograft (PDX) model, and IGF2BP1 conditional knockout (cKO) reduced the tumor burden. These results demonstrate the crucial role of IGF2BP1 in iCCA progression via m6A-dependent modification, highlighting IGF2BP1 as a potential therapeutic target in iCCA.

Tumor Cell Derived Lnc-FSD2-31:1 Contributes to Cancer-Associated Fibroblasts Activation in Pancreatic Ductal Adenocarcinoma Progression through Extracellular Vesicles Cargo MiR-4736.

Pancreatic ductal adenocarcinoma (PDAC) presents with high mortality and short overall survival. Cancer-associated fibroblasts (CAFs) act as refuge for cancer cells in PDAC. Mechanisms of intracelluar communication between CAFs and cancer cells need to be explored. Long noncoding RNAs (lncRNAs) are involved in the modulation of oncogenesis and tumor progression of PDAC; however, specific lncRNAs and their mechanism of action have not been clarified clearly in tumoral microenvironment. This work aims to identify novel lncRNAs involved in cellular interaction between cancer cells and CAFs in PDAC. To this end, differentially expressed lncRNAs between long-term and short-term survival PDAC patients are screened. Lnc-FSD2-31:1 is found to be significantly increased in long-term survival patients. This work then discovers that tumor-derived lnc-FSD2-31:1 restrains CAFs activation via miR-4736 transported by extracellular vesicles (EVs) in vitro and in vivo. Mechanistically, EVs-derived miR-4736 suppresses autophagy and contributes to CAFs activation by targeting ATG7. Furthermore, blocking miR-4736 suppresses tumor growth in genetically engineered KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+, and Pdx-1-Cre) mouse model of PDAC. This study demonstrates that intratumoral lnc-FSD2-31:1 modulates autophagy in CAFs resulting in their activation through EVs-derived miR-4736. Targeting miR-4736 may be a potential biomarker and therapeutic target for PDAC.

Gut microbiota-derived nicotinamide mononucleotide alleviates acute pancreatitis by activating pancreatic SIRT3 signalling.

BACKGROUND AND PURPOSE: Gut microbiota dysbiosis induced by acute pancreatitis (AP) exacerbates pancreatic injury and systemic inflammatory responses. The alleviation of gut microbiota dysbiosis through faecal microbiota transplantation (FMT) is considered a potential strategy to reduce tissue damage and inflammation in many clinical disorders. Here, we aim to investigate the effect of gut microbiota and microbiota-derived metabolites on AP and further clarify the mechanisms associated with pancreatic damage and inflammation. EXPERIMENTAL APPROACH: AP rat and mouse models were established by administration of caerulein or sodium taurocholate in vivo. Pancreatic acinar cells were exposed to caerulein and lipopolysaccharide in vitro to simulate AP. KEY RESULTS: Normobiotic FMT alleviated AP-induced gut microbiota dysbiosis and ameliorated the severity of AP, including mitochondrial dysfunction, oxidative damage and inflammation. Normobiotic FMT induced higher levels of NAD+ (nicotinamide adenine dinucleotide)-associated metabolites, particularly nicotinamide mononucleotide (NMN). NMN administration mitigated AP-mediated mitochondrial dysfunction, oxidative damage and inflammation by increasing pancreatic NAD+ levels. Similarly, overexpression of the NAD+ -dependent mitochondrial deacetylase sirtuin 3 (SIRT3) alleviated the severity of AP. Furthermore, SIRT3 deacetylated peroxiredoxin 5 (PRDX5) and enhanced PRDX5 protein expression, thereby promoting its antioxidant and anti-inflammatory activities in AP. Importantly, normobiotic FMT-mediated NMN metabolism induced SIRT3-PRDX5 pathway activation during AP. CONCLUSION AND IMPLICATIONS: Gut microbiota-derived NMN alleviates the severity of AP by activating the SIRT3-PRDX5 pathway. Normobiotic FMT could be served as a potential strategy for AP treatment.