Exosomes from TNF-α preconditioned human umbilical cord mesenchymal stromal cells inhibit the autophagy of acinar cells of severe acute pancreatitis via shuttling bioactive metabolites.

Severe acute pancreatitis (SAP) is a common critical disease of the digestive system, with high mortality and a lack of effective prevention and treatment measures. Despite mesenchymal stromal cell transplantation having the potential to treat SAP, its clinical application prospect is limited, and the mechanism is unclear. Here, we reveal the therapeutic role of exosomes from TNF-α-preconditioned human umbilical cord mesenchymal stromal cells (HUCMSCs) in attenuating SAP and show that it is partly dependent on exosomal metabolites. Bioactive metabolomics analysis showed that 48 metabolites be significantly differentially expressed between the two groups (Exo-Ctrl group versus Exo-TNF-α group). Then, the further functional experiments indicated that 3,4-dihydroxyphenylglycol could be a key molecule mediating the therapeutic effect of TNF-α-preconditioned HUCMSCs. The animal experiments showed that 3,4-dihydroxyphenylglycol reduced inflammation and oxidative stress in the pancreatic tissue and inhibited acinar cell autophagy in a rat model of SAP. Mechanistically, we revealed that 3,4-dihydroxyphenylglycol activated the mTOR pathway to inhibit acinar cell autophagy and alleviate SAP. In summary, our study demonstrated that exosomes from TNF-α-preconditioned HUMSCs inhibit the autophagy of acinar cells of SAP by shuttling 3,4-dihydroxyphenylglycol and inhibiting the mTOR pathway. This study revealed the vital role and therapeutic potential of metabolite-derived exosomes in SAP, providing a new promising method to prevent and therapy SAP.

The efficacy and safety of laparoscopic common bile duct exploration and cholecystectomy for the treatment of difficult common bile duct stones combined with gallstones: a multicenter retrospective study.

PURPOSE: To analyze the benefits of laparoscopic common bile duct exploration and laparoscopic cholecystectomy (LCBDE + LC) versus endoscopic retrograde cholangiopancreatography and/or endoscopic sphincterotomy following laparoscopic cholecystectomy (ERCP/EST + LC) for difficult common bile duct stones combined with gallstones. METHODS: A retrospective analysis of consecutive patients with difficult common bile duct stones combined with gallstones in three hospitals from January 2016 to January 2021 was performed. RESULTS: ERCP/EST + LC contributed to reducing postoperative drainage time. However, LCBDE + LC showed a higher rate of complete clearance, along with lower postoperative hospital stays, expenses and incidence of postoperative hyperamylasemia, pancreatitis, re-operation and recurrence. In addition, LCBDE + LC showed safe and feasible performance in the elderly and patients with previous upper abdominal surgery. CONCLUSION: It is an effective and safe method for LCBDE + LC for difficult common bile duct stones combined with gallstones.

Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges.

Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.

Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue.

Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency. Here, we report that mouse organic cation transporter 3 (Oct3; Slc22a3) is highly expressed in WAT and displays the greatest uptake rate of NE as a selective non-neural route of NE clearance in white adipocytes, which differs from other known routes such as adjacent neurons or macrophages. We further show that adipocytes express high levels of NE degradation enzymes Maoa, Maob, and Comt, providing the molecular basis on NE clearance by adipocytes together with its reuptake transporter Oct3. Under NE administration, ablation of Oct3 induces higher body temperature, thermogenesis, and lipolysis compared with littermate controls. After prolonged cold challenge, inguinal WAT (ingWAT) in adipose-specific Oct3-deficient mice shows much stronger browning characteristics and significantly elevated expression of thermogenic and mitochondrial biogenesis genes than in littermate controls, and this response involves enhanced ß-adrenergic receptor (ß-AR)/protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (Creb) pathway activation. Glycolytic genes are reprogrammed to significantly higher levels to compensate for the loss of ATP production in adipose-specific Oct3 knockout (KO) mice, indicating the fundamental role of glucose metabolism during beiging. Inhibition of ß-AR largely abolishes the higher lipolytic and thermogenic activities in Oct3-deficient ingWAT, indicating the NE overload in the vicinity of adipocytes in Oct3 KO adipocytes. Of note, reduced functional alleles in human OCT3 are also identified to be associated with increased basal metabolic rate (BMR). Collectively, our results demonstrate that Oct3 governs ß-AR activity as a NE recycling transporter in white adipocytes, offering potential therapeutic applications for metabolic disorders.

Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting oxidative stress in rats.

To investigate whether bone marrow mesenchymal stem cells (BMSCs) attenuate pancreatic injury via mediating oxidative stress in severe acute pancreatitis (SAP). The SAP model was established in rats. Phosphate buffered saline (PBS) or BMSCs were injected into the rats by tail veins. ML385 was used to down-regulate Nrf2 expression in rats. Pancreatic pathological score was used to evaluated pancreatic injury. Inflammatory-associated cytokines, serum lipase and amylase, levels of myeloperoxidase, malondialdehyde, reactive oxygen species and superoxide dismutase, as well as catalase activity were measured for injury severity evaluation. ML385 aggravates oxidative stress in SAP + ML385 group, compared with SAP + PBS group. BMSCs transplantation alleviated pancreatic injury and enhance antioxidant tolerance in SAP + BMSCs group, while ML385 administration weakened this efficacy in SAP + BMSCs + ML385 group. In addition, BMSCs promoted Nrf2 nuclear translocation via PI3K/AKT signaling pathway. Besides, BMSCs reduced inflammatory response by inhibiting NF-κB signaling pathway in SAP. BMSCs can inhibit oxidative stress and reduce pancreatic injury via inducing Nrf2 nuclear translocation in SAP.

Safety and efficacy of laparoscopic common bile duct exploration for the patients with difficult biliary stones: 8 years of experiences at a single institution and literature review.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) has gained wide popularity for the treatment of choledocholithiasis. However, it remains unclear whether LCBDE is a better alternative option for the patients with difficult biliary stones. Thus, the aim of the present study was to explore the safety and efficacy of LCBDE for these patients by retrospectively analyzing our data and combing with literature review. METHODS: Between September 2011 and February 2019, 1064 consecutive patients who underwent LCBDE at Shanghai Tenth People's Hospital were reviewed. The clinical data of patients with difficult biliary stones were selected and retrospectively analyzed. RESULTS: Of these patients, 334 cases were confirmed with difficult biliary stones, and the overall complete stone clearance rate was 98.8% (330/334). 34 cases (10.2%) were performed with laser lithotripsy. A total of 296 patients (88.6%) underwent primary closure of common bile duct, and T-tube drainage was indwelled in 38 patients (11.4%). No bile duct injury, bleeding, perforation and surgery-related deaths were observed. The overall morbidity rate was 6.6%. 16 cases (4.8%) occurred in bile leakage with primary closure procedure, and all of them were managed successfully with conservative therapy. The median follow-up period was 9 months with stone recurrence occurring in 9 patients (2.7%). There was no evidence of bile duct stricture in all cases. CONCLUSIONS: The current study suggests that LCBED is a considerable safe and effective option for the patients with difficult biliary stones. A randomized clinical trial is needed to further evaluate the benefit of LCBDE in this subgroup.

Management and long-term outcomes of acute right colonic diverticulitis and risk factors of recurrence.

BACKGROUND: Acute right-sided colonic diverticulitis (RCD) is a common disease in Asian populations for which the optimal treatment remains controversial. The aim of this study was to investigate management and evaluate long-term outcomes of treatment in patients with acute RCD. METHODS: We retrospectively collected and analyzed clinical data for patients with acute RCD admitted to the Tongren Hospital, Shanghai Jiao Tong University School of Medicine from December 2015 to December 2020. The patients were divided into two groups, according to primary treatment strategy, which was either conservative treatment or surgical treatment. RESULTS: A total of 162 consecutive patients with acute RCD were enrolled in the study. There was no significant difference in age, sex, history of abdominal surgery, medical co-morbidities, fever, previous history of RCD, treatment success rate and incidence of complications between the conservative and surgery groups. However, the recurrence rate in conservative groups was significantly higher than in surgery groups (16.53% vs 2.44%, P = 0.020). And more frequent bowel movements and previous history of RCD increased the risk of recurrence of acute RCD. Moreover, there was no significant difference in either treatment success rate or the overall recurrence rate between the patients with uncomplicated diverticulitis and patients with complicated diverticulitis. CONCLUSIONS: Surgical treatment is also safe and effective for acute RCD. Surgical treatment should mainly be considered for patients with acute RCD with recurrence risk factors (more frequent bowel movements and previous history of RCD) or with complicated acute RCD.

Mesenchymal stromal cell therapy for pancreatitis: Progress and challenges.

Pancreatitis is a common gastrointestinal disease with no effective therapeutic options, particularly for cases of severe acute and chronic pancreatitis (CP). Mesenchymal stromal cells (MSCs) are multipotent cells with diverse biological properties, including directional migration, paracrine, immunosuppressive, and antiinflammatory effects, which are considered an ideal candidate cell type for repairing tissue damage caused by various pathogenies. Several researchers have reported significant therapeutic efficacy of MSCs in animal models of acute and CP. However, the specific underlying mechanisms are yet to be clarified and clinical application of MSCs as pancreatitis therapy has rarely been reported. This review mainly focuses on the potential and challenges in clinical application of MSCs for treatment of acute and CP, along with discussion of the underlying molecular mechanisms.

Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans.

OBJECTIVE: Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DESIGN: We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. RESULTS: Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. CONCLUSION: Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

Bone marrow-derived mesenchymal stem cells alleviate severe acute pancreatitis-induced multiple-organ injury in rats via suppression of autophagy.

Patients with severe acute pancreatitis (SAP) represent a substantial challenge to medical practitioners due to the high associated rates of morbidity and mortality and a lack of satisfactory therapeutic outcomes. In a previous study, our group demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) can ameliorate SAP; however, the mechanisms of action remain to be fully understood. BMSCs were intravenously injected into SAP rats 12 h after experimental induction of SAP using sodium taurocholate (NaT). Histopathological changes and the levels of pro-inflammatory mediators were assessed by hematoxylin and eosin (H&E) staining and ELISA, respectively. Autophagy levels were assessed using qRT-PCR, western blotting, immunohistochemistry, immunofluorescence, and transmission electron microscopy. AR42J cells and human umbilical vein endothelial cells (HUVECs) were administered BMSC-conditioned media (BMSC-CM) after NaT treatment, and cell viability was measured using a Cell Counting Kit-8 (CCK-8) and flow cytometry. In vivo, BMSCs effectively reduced multiple systematic inflammatory responses, suppressed the activation of autophagy, and improved intestinal dysfunction. In vitro, BMSC-CM significantly improved the viability of injured cells, promoted angiogenesis, and decreased autophagy. We therefore propose that the administration of BMSCs alleviates SAP-induced multiple organ injury by inhibiting autophagy.

Bone marrow-derived mesenchymal stromal cells ameliorate severe acute pancreatitis in rats via hemeoxygenase-1-mediated anti-oxidant and anti-inflammatory effects.

BACKGROUND AND AIMS: It has been previously verified that mesenchymal stromal cells (MSCs) have a good therapeutic effect on severe acute pancreatitis (SAP) and the potential for regeneration of damaged pancreatic tissue, but the exact molecular mechanism remains unclear. In this study, we demonstrated the therapeutic effect of bone morrow MSCs (BMSCs) on SAP, probably by targeting heme oxygenase-1 (HO-1). METHODS: Six hours after SAP induction, either phosphate-buffered saline (PBS) or BMSCs were transfused into the caudal vein of rats, zinc protoporphyrin (ZnPP) was administered intraperitoneally. Pancreatic pathological scoring, serum levels of amylase and inflammatory factors, as well as levels of reactive oxygen species (ROS), malondialdehyde (MDA) and myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) activity in the pancreas were evaluated. RESULTS: Our data showed that BMSCs significantly reduce inflammation and oxidative stress, reduce apoptosis and promote angiogenesis of damaged pancreas. Moreover, BMSCs increased the level of HO-1 in the serum and pancreatic tissue in rats with SAP. In addition, the protective effect of BMSCs was partially neutralized by the HO-1 activity inhibitor ZnPP, suggesting a key role of HO-1 in the therapeutic effect of BMSCs on SAP. CONCLUSIONS: BMSCs ameliorated SAP, probably by inducing expression of HO-1, which can exert anti-inflammatory and anti-oxidant effects, reduce apoptosis and promote angiogenesis.

N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is a high mortality disease, for which there is a lack of effective therapies. Previous research has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs), which have immunomodulatory and antioxidant properties, have potential for the treatment of SAP. It remains unclear, however, whether the free radical scavenger N-acetylcysteine (NAC) can enhance the therapeutic efficacy of BMSC transplantation in SAP. In this study, we investigated the effect of combining treatment with NAC and BMSCs in a rat model of SAP. METHODS: SAP was induced by injection of sodium taurocholate into the pancreatic duct and, after successful induction of SAP, the rats were treated with BMSCs and NAC, either singly or in combination. RESULTS: After 3 days, serum levels of amylase, proinflammatory factors, malondialdehyde, and reactive oxygen species were significantly decreased in animals treated with BMSCs or NAC, compared with vehicle-treated animals. In contrast, total glutathione, superoxide dismutase and catalase were markedly increased after treatment with BMSCs or NAC. However, oxidative stress markers and inflammatory factors were significantly improved in the SAP + BMSCs + NAC group compared with those in the SAP + NAC group and the SAP + BMSCs group. CONCLUSIONS: Combined NAC and BMSC therapy was found to alleviate oxidative stress damage to the pancreas and to inhibit the inflammatory response to a significantly greater extent than single therapy with either BMSCs or NAC. Because NAC enhances the therapeutic efficacy of BMSC transplantation in a rat model of SAP, combined therapy may provide a promising new approach for the treatment of SAP.

Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting necroptosis in rats.

The treatment and prognosis for severe acute pancreatitis (SAP) is currently unsatisfactory showing a high incidence of morbidity and mortality. Here, we investigated the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on SAP in rats and explored the possible mechanisms. The common bile duct of each model rat was occluded at the liver hilum, and the induction of SAP was achieved by retrograde perfusion of 3% sodium taurocholate (NaT). Prepared BMSCs were intravenously injected via the tail vein. Pancreatic acinar cells (PACs) were isolated from rat pancreas, and induced by TNF-α. In the present study, we found that necroptosis was activated in NaT-induced acute-necrotized pancreatitis, and transplanted BMSCs could inhibit necroptosis, repair pancreatic injury, and reduce systemic inflammatory response. In addition, necrostatin-1 (Nec-1), as the inhibitor of receptor-interacting protein kinase 1 (RIPK1), could also reduce SAP to some extent. Besides, we detected that BMSCs could also promote regeneration of damaged pancreatic tissues. Furthermore, in vitro, we also investigated that BMSCs could suppress TNF-α-induced necroptosis and improve the viability of PACs. In addition, Nec-1 and knockdown of receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain-like protein (MLKL) could also inhibit necrosis of PACs induced by TNF-α. BMSCs ameliorated SAP and reduced injury of PACs by suppressing the activation of the necroptosis signaling pathway.

Anticoagulants is a risk factor for spontaneous rupture and hemorrhage of gallbladder: a case report and literature review.

BACKGROUND: The spontaneous rupture of the gallbladder is extremely rare, majority of ruptures occur secondary to traumatic injuries. Here, we report a case of spontaneous rupture of the gallbladder with probably cause of oral anticoagulants. CASE PRESENTATION: A 51-year-old woman presented to the emergency room with sudden-onset severe abdominal pain, as well as hypotension and low level of hemoglobin. Abdominal computed tomography (CT) scan showed a 2.5 cm filling defect and discontinuity in the wall of the gallbladder body, and a massive hematocele in the abdominal cavity. Past medical history was significant for hypertension and had been taking daily aspirin for the past three years because of interventional surgery for cerebral aneurysms, but no history of recent abdominal trauma or past episodes of biliary colic. The patient underwent an urgent laparoscopic abdominal exploration and the gallbladder was removed. The pathology just showed chronic cholecystitis and the patient recovered well. CONCLUSION: Long-term use of anticoagulants may increase the risk of gallbladder rupture and hemorrhage, which is a lethal condition. Rapid diagnosis and timely surgical intervention are the most important measures to treat the patient.

One-Pot Synthesis of Indole-3-acetic Acid Derivatives through the Cascade Tsuji-Trost Reaction and Heck Coupling.

A practical palladium-mediated cascade Tsuji-Trost reaction/Heck coupling of N-Ts o-bromoanilines with 4-acetoxy-2-butenonic acid derivatives using a Pd(OAc)2/P( o-tol)3/DIPEA system is described for a straightforward synthesis of indole-3-acetic acid derivatives. This methodology was successfully applied to synthesize various substituted indole/azaindole-3-acetic acid derivatives and Almotriptan, which is a drug for the acute treatment of migraines. Moreover, a plausible cyclization mechanism has been proposed.

Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity.

Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFß pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 µM) as compared with those in controls. Zoledronate treatments in cells (50 µM) and mice (3 mg/kg) increased TGFß/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid ß-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.

Epidemiological and genetic analysis of hand-foot-mouth disease by enterovirus A71 in Taizhou, P. R. China, between 2010 and 2013.

Out of a population of 1,098 enteroviruses (EVs)-positive hand, foot, and mouth disease (HFMD) specimens, 352 were screened positive for EV-A71-accounting for 32.1% of all EV-positive specimens. This percentage denotes EV-A71 as the second major serotype of enteroviruse among HFMD suffers in Taizhou. An epidemic outbreak of EV-A71 among HFMD children was found in Taizhou in the second quarter of 2012. Phylogeny analysis based on the VP1 complete sequences leads us to find a sub-clade (designated TZ1-1) of EV-A71 circulating in Taizhou, whose emergence might be correlated with the epidemic outbreak. This correlation was further supported by the followed two analyses (namely skyline plot of population history and birth-death SIR simulation of epidemic history). And more importantly, at a positively selected site of VP1 caspid, a mutation of N31D was found to be a synapomorphy of TZ1-1 and its occurrence might be correlated with the epidemic outbreak. J. Med. Virol. 89:782-790, 2017. © 2016 Wiley Periodicals, Inc.

Characterization of VP1 gene of coxsackievirus A16 prevalent among hand foot mouth disease suffered children in Taizhou, P. R. China, between 2010 and 2013.

A total of 453 strains of Coxsackievirus A16 (CV-A16) were screened out of 1,509 hand-foot-mouth disease (HFMD) samples collected in Taizhou during the period from 2010 to 2013. And between first quarter of 2011 and first quarter of 2013, an outbreak of CV-A16 was found among the HFMD sufferers in Taizhou. Phylogenic analysis of VP1 sequences indicated a major CV-A16 sub-group in Taizhou, whose change pattern of effective population sizes was found to be similar to the pattern of the actual percentage changes of CV-A16 during the outbreak over the same period. More importantly, the sub-group all displayed a Leu (L) to Met (M) mutation at site-23 of capsid VP1 which might be correlated with the outbreak of CV-A16 in Taizhou.

Epidemiological and genetic analysis concerning the coxsackievirus A6 related endemic outbreak of hand-foot-mouth disease in Taizhou, China, during 2013.

A total of 1,098 strains of human enteroviruses (HEV), falling into 14 serotypes were detected upon analysis of 1,509 hand-foot-mouth disease (HFMD) samples collected in Taizhou during the period from July 2010 to December 2013. And a CV-A6 related HFMD outbreak was identified in Taizhou during 2013. Phylogenic analyses of complete VP1 sequences indicate that this outbreak of HFMD in Taizhou is closely related to the global outbreaks of CV-A6 related HFMD since 2008, but the analyses also indicate that the outbreak in Taizhou is rather an endemic outbreak in which a phylogenic sub-group of CV-A6 was identified whose members commonly acquired a mutation R→K at site 254 of VP1 protein. It is interesting that the emergence of the sub-group was inferred to contribute to the endemic outbreak in Taizhou in 2013.

A highly selective PI3Kδ inhibitor BGB-10188 shows superior preclinical anti-tumor activities and decreased on-target side effects on colon.

PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.