FOXD1 promotes chemotherapy resistance by enhancing cell stemness in colorectal cancer through ß­catenin nuclear localization.

Forkhead box D1 (FOXD1) serves a critical role in colorectal cancer (CRC). FOXD1 expression is an independent prognostic factor in patients with CRC; however, the molecular mechanism and signaling pathway of FOXD1 that regulates cell stemness and chemoresistance has not been fully characterized. The aim of the present study was to further validate the effect of FOXD1 on the proliferation and migration of CRC cells, and to delve into the possible potential of FOXD1 in the clinical treatment of CRC. The effect of FOXD1 on cell proliferation was assessed using Cell Counting Kit 8 (CCK­8) and colony formation assays. The effect of FOXD1 on cell migration was assessed by wound­healing and Transwell assays. The effect of FOXD1 on cell stemness was assessed by spheroid formation in vitro and limiting dilution assays in vivo. The expression of stemness associated proteins, leucine rich repeat containing G protein­coupled receptor 5 (LGR5), OCT4, Sox2 and Nanog, and epithelial­mesenchymal transition associated proteins, E­cadherin, N­cadherin and vimentin, were detected by western blotting. Proteins interrelationships were assessed by a co­immunoprecipitation assay. Oxaliplatin resistance was assessed using CCK­8 and apoptosis assays in vitro, and using a tumor xenograft model in vivo. By constructing FOXD1 overexpression and knockdown stably transfected strains of colon cancer cells, it was revealed that the overexpression of FOXD1 increased CRC cell stemness and chemoresistance. By contrast, knockdown of FOXD1 produced the opposite effects. These phenomena were caused by the direct interaction between FOXD1 and ß­catenin, thus promoting its nuclear translocation and the activation of downstream target genes, such as LGR5 and Sox2. Notably, inhibition of this pathway with a specific ß­catenin inhibitor (XAV­939) could impair the effects induced by the overexpression of FOXD1. In summary, these results indicated that FOXD1 may promote cell stemness and the chemoresistance of CRC by binding directly to ß­catenin and enhancing ß­catenin nuclear localization; therefore, it may be considered a potential clinical target.

IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration.

BACKGROUND: Interleukin-17A (IL-17A), a proinflammatory cytokine primarily secreted by Th17 cells, γδT cells and natural killer T (NKT) cells, performs essential roles in the microenvironment of certain inflammation-related tumours by regulating cancer growth and tumour elimination proved in previous literature. In this study, the mechanism of IL-17A that induces mitochondrial dysfunction promoted pyroptosis has been explored in colorectal cancer cells. METHOD: The records of 78 patients diagnosed with CRC were reviewed via the public database to evaluate clinicopathological parameters and prognosis associations of IL-17A expression. The colorectal cancer cells were treated with IL-17A, and the morphological characteristics of those cells were indicated by scanning electron microscope and transmission electron microscope. After IL-17A treatment, mitochondrial dysfunction was tested by mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). The expression of pyroptosis associated proteins including cleaved caspase-4, cleaved gasdermin-D (GSDMD), IL-1ß, receptor activator of nuclear NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein containing a card (ASC), and factor-kappa B was measured through western blotting. RESULTS: Positive IL-17A protein expression was observed in CRC compared to the non-tumour tissue. IL-17A expression indicates a better differentiation, earlier stage, and better overall survival in CRC. IL-17A treatment could induce mitochondrial dysfunction and stimulate intracellular reactive oxygen species (ROS) production. Furthermore, IL-17A could promote pyroptosis of colorectal cancer cells and significantly increase the secretion of inflammatory factors. Nevertheless, the pyroptosis induced by IL-17A could be inhibited through the pre-treatment with Mito-TEMPO (a mitochondria-targeted superoxide dismutase mimetic with superoxide and alkyl radical scavenging properties) or Z-LEVD-FMK (caspase-4 inhibitor, fluoromethylketone). Additionally, after being treated with IL-17A, an increasing number of CD8 + T cells showed in mouse-derived allograft colon cancer models. CONCLUSION: IL-17A, as a cytokine mainly secreted by γδT cells in the colorectal tumour immune microenvironment, can regulate the tumour microenvironment in multiple ways. IL-17A could induce mitochondrial dysfunction and pyroptosis through the ROS/NLRP3/caspase-4/GSDMD pathway, and promote intracellular ROS accumulation. In addition, IL-17A can promote the secretion of inflammatory factors such as IL-1ß、IL-18 and immune antigens, and recruit CD8 + T cells to infiltrate tumours.

Exosome-mediated inhibition of microRNA-449a promotes the amplification of mouse retinal progenitor cells and enhances their transplantation in retinal degeneration mouse models.

Inherited and age-related retinal degenerations are the commonest causes of blindness without effective treatments. Retinal progenitor cells (RPCs), which have the multipotency to differentiate into various retinal cell types, are regarded as a promising source of cell transplantation therapy for retinal degenerative diseases. However, the self-limited expansion of RPCs causes difficulty in cell source supply and restrict its clinical treatment. In this work, we found that inhibition of microRNA-449a (miR-449a) in RPCs can promote proliferation and inhibit apoptosis of RPCs, partially through upregulating Notch signaling. Further optimization of transduction miR-449a inhibitor into RPCs by endothelial cell-derived exosomes can promote the survival of RPCs transplanted in vivo and reduce cell apoptosis in retinal degeneration mouse models. In summary, these studies have shown that exosome-miR-449a inhibitor can effectively promote the expansion of RPCs in vitro and enhance transplanted RPCs survival in vivo, which might provide a novel intervention strategy for retinal degenerations in the future.

MicroRNA-582-5p Contributes to the Maintenance of Neural Stem Cells Through Inhibiting Secretory Protein FAM19A1.

Epigenetic regulations on the maintenance of neural stem cells (NSCs) are complicated and far from been fully understood. Our previous findings have shown that after blocking Notch signaling in NSCs in vivo, the stemness of NSCs decreases, accompanied by the downregulated expression of miR-582-5p. In the current study, we further investigated the function and mechanism of miR-582-5p in the maintenance of NSCs in vitro and in vivo. After transfecting a mimic of miR-582-5p, the formation of neurospheres and proliferation of NSCs and intermediate progenitor cells (NS/PCs) were enhanced, and the expression of stemness markers such as Sox2, Nestin, and Pax6 also increased. The results were reversed after transfection of an inhibitor of miR-582-5p. We further generated miR-582 knock-out (KO) mice to investigate its function in vivo, and we found that the number of NSCs in the subventricular zone (SVZ) region decreased and the number of neuroblasts increased in miR-582 deficient mice, indicating reduced stemness and enhanced neurogenesis of NSCs. Moreover, RNA-sequencing and molecular biological analysis revealed that miR-582-5p regulates the stemness and proliferation of NSCs by inhibiting secretory protein FAM19A1. In summary, our research uncovered a new epigenetic mechanism that regulates the maintenance of NSCs, therefore providing novel targets to amplify NSCs in vitro and to promote neurogenesis in vivo during brain pathology and aging.

γ-secretase inhibitor disturbs the morphological development of differentiating neurons through affecting Notch/miR-342-5p.

During neurodevelopment, differentiation of neural stem/progenitor cells (NSPCs) into neurons are regulated by many factors including Notch signaling pathway. Herein, we report the effect of a Notch signaling blocker, i.e. γ -secretase inhibitor (GSI), on this differentiating process, especially on the morphological development. NSPCs were cultured and induced to differentiate with or without GSI. The neurite outgrowth was impeded by GSI application and the expression of a Notch signaling downstream effector miR-342-5p increased with the downregulated expression of Notch effectors Hes1 and Hes5. Upregulated expression of miR-342-5p in differentiating NSPCs could shorten the neurite length of progeny neurons, which was similar to the effect of GSI. To avoid the possible influence from astrocytes into neurons, we directly applied cultured neurons, on which GSI could shorten the processes and RBP-J knockdown could also reduce the neurite length. Similarly, transfection of miR-342-5p mimics or inhibitors into PC12 cells led to shorter or longer processes of cells compared with control ones. Furthermore, in differentiating NSPCs, GSI-induced shorter neurites could be partially rescued by miR-342-5p inhibitors, and STAT3 was one of the possible targets of miR-342-5p during this differentiating process as indicated by results of Western Blot test, luciferase reporter assay and GFP reporter assay. To further demonstrate the role of STAT3, it was introduced into GSI-treated neurons and the GSI-affected neurites could also be partially rescued. In conclusion, GSI could influence the morphological development of neurons and the possible mechanism involved Notch/miR-342-5p and STAT3. These results would be informative for future therapeutic research.

Efficacy of neoadjuvant CapeOX/mFOLFOX6 without radiation for patients with baseline resectable mid-low locally advanced rectal cancer.

OBJECTIVES: Chemotherapy without radiation therapy for locally advanced rectal cancer (LARC) has attracted increasing attention, but the optimal schema remains controversial. In this study, we aimed to assess the efficacy and toxicity of neoadjuvant chemotherapy (nCT) of two regimens for patients with mid-low baseline resectable LARC. METHODS: A retrospective study was performed in 131 patients with baseline resectable LARC in a single center between April 2016 and August 2020. All patients received four cycles of neoadjuvant CapeOX or mFOLFOX6 before surgery. Clinical characteristics, pathological response, and survival status were then assessed. RESULTS: After a 1:1 propensity score matching, 96 patients were enrolled, including 48 receiving CapeOX and 48 receiving mFOLFOX6. The objective regression rates were 50.00% and 58.33%, and the pathological complete response rates were 6.25% and 8.33%, respectively, in the CapeOX and mFOLFOX6 groups. Patients who received mFOLFOX6 had a better tumor regression grade (TRG) than those who received CapeOX (P = 0.005). Patients in both groups had similar survival outcomes. CONCLUSIONS: The nCT has shown promising tumor response and survival outcomes, which can be a treatment option for baseline resectable LARC. For the two regimens, mFOLFOX6 provided better TRG than CapeOX, although no differences were observed in disease-free survival and OS.

Transmembrane Protein Ttyh1 Maintains the Quiescence of Neural Stem Cells Through Ca2+/NFATc3 Signaling.

The quiescence, activation, and subsequent neurogenesis of neural stem cells (NSCs) play essential roles in the physiological homeostasis and pathological repair of the central nervous system. Previous studies indicate that transmembrane protein Ttyh1 is required for the stemness of NSCs, whereas the exact functions in vivo and precise mechanisms are still waiting to be elucidated. By constructing Ttyh1-promoter driven reporter mice, we determined the specific expression of Ttyh1 in quiescent NSCs and niche astrocytes. Further evaluations on Ttyh1 knockout mice revealed that Ttyh1 ablation leads to activated neurogenesis and enhanced spatial learning and memory in adult mice (6-8 weeks). Correspondingly, Ttyh1 deficiency results in accelerated exhaustion of NSC pool and impaired neurogenesis in aged mice (12 months). By RNA-sequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1. Our research uncovered new endogenous mechanisms that regulate quiescence versus activation of NSCs, therefore provide novel targets for the intervention to activate quiescent NSCs to participate in injury repair during pathology and aging.

Detection and Clinical Value of Circulating Tumor Cells as an Assisted Prognostic Marker in Colorectal Cancer Patients.

BACKGROUND: Circulating tumor cells (CTCs) are cells that have been shed into the vasculature from a primary tumor and circulate in the bloodstream. It has been suggested that detecting CTCs could help the clinician to detect early metastasis or recurrence more effectively. This trial sets out to assess the detection and clinical value of CTCs as an assisted prognostic marker in patients with colon cancer and rectal cancer. METHODS: A prospective cohort of patients with colorectal cancer (CRC) was enrolled from July 2015 to February 2018 in Shanghai Minimally Invasive Surgery Center, Shanghai, China. In this study, 149 patients with CRC were enrolled and underwent surgical treatment. There were 79 cases of colon cancer and 70 cases of rectal cancer, including 93 males and 56 females. To investigate the correlativity and clinical value of CTCs, the patients were statistically analyzed in different subgroups: colon cancer group vs rectal cancer group, and left hemicolon cancer group vs right hemicolon cancer group. RESULTS: The results of analysis comparing CTC counts and clinical pathological features in colon and rectal cancer indicated that with increased tumor stage, the number of CTCs also increased, with significant statistical differences. CTC counts in patients with colon and rectal cancer showed positive correlations with TNM staging (P=0.001, 0.013, respectively), T staging (P=0.021, 0.001), N staging (P=0.014, 0.035) and M staging (P=0.018, 0.203). Detection of serum biomarkers in CTC-positive and CTC-negative groups indicated a significantly increasing expression in the CTC-positive group. To confirm the correlations between CTCs and histoembryological differences, analysis was conducted with the patients in two subgroups: left hemicolon cancer group and right hemicolon cancer group. The results showed that the positive rate of CTCs increased in both groups with the increase in tumor stage. The survival analysis indicated that there was a steep gradient in survival in the follow-up period, particularly in the CTC-positive group (P=0.000). Risk assessment curves showed that the change escalated more rapidly in the CTC-positive group. Furthermore, with the increase in T stage, changes in the survival curve and risk curve escalated more rapidly in the CTC-positive group. CONCLUSION: It was confirmed that in the left hemicolon cancer group, a much higher coincidence rate could be found on CTC-positive rate and clinicopathological features, than in the right hemicolon cancer group. The sensitivity of CTCs may be related to the histoembryological location of the tumor, lymphatic metastasis and the depth of infiltration. Monitoring CTCs may have value in evaluating clinical staging and estimating clinical prognosis.

Retrospective research of neoadjuvant therapy on tumor-downstaging, post-operative complications, and prognosis in locally advanced rectal cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is becoming increasingly important in locally advanced rectal cancer. Hence, such research has become a problem. AIM: To evaluate the downstaging effect of NAT, its impact on postoperative complications and its prognosis with different medical regimens. METHODS: Seventy-seven cases from Shanghai Ruijin Hospital affiliated with Shanghai Jiaotong University School of Medicine were retrospectively collected and divided into the neoadjuvant radiochemotherapy (NRCT) group and the neoadjuvant chemotherapy (NCT) group. The differences between the two groups in tumor regression, postoperative complications, rectal function, disease-free survival, and overall survival were compared using the χ 2 test and Kaplan-Meier analysis. RESULTS: Baseline data showed no statistical differences between the two groups, whereas the NRCT group had a higher rate of T4 (30/55 vs 5/22, P < 0.05) than the NCT groups. Twelve cases were evaluated as complete responders, and 15 cases were evaluated as tumor regression grade 0. Except for the reduction rate of T stage (NRCT 37/55 vs NCT 9/22, P < 0.05), there was no difference in effectiveness between the two groups. Preoperative radiation was not a risk factor for poor reaction or anastomotic leakage. No significant difference in postoperative complications and disease-free survival between the two groups was observed, although the NRCT group might have better long-term overall survival. CONCLUSION: NAT can cause tumor downstaging preoperatively or even complete remission of the primary tumor. Radiochemotherapy could lead to better T downstaging and promising overall survival without more complications.

Staged laparoscopic management of locally advanced gastric cancer with outlet obstruction.

BACKGROUND: The prognosis of patients with locally advanced gastric cancer with outlet obstruction is poor. Gastrectomy with curative intent is often initially impossible or difficult. OBJECTIVE: We report our experience of curative distal gastrectomy after laparoscopic gastrojejunostomy and fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy to examine the feasibility and safety of this modified strategy for locally advanced gastric cancer with outlet obstruction, initially deemed unresectable. METHODS: Between October 2017 and June 2019, 15 patients diagnosed with locally advanced gastric cancer with outlet obstruction sequentially underwent gastrojejunostomy, received four cycles of FLOT chemotherapy, and underwent laparoscopic distal gastrectomy with curative intent (R0 resection + D2 lymphadenectomy). Clinical data were retrospectively collected and analyzed. RESULTS: R0 resection was possible in 12/15 patients, laparoscopically in 11, and one conversion to laparotomy was necessary. There was no perioperative mortality in the 12 patients. Pathologic evaluation of the resected specimens revealed that complete tumor grade regression 1a (TRG1a), TRG1b, TRG2, and TRG3 occurred in 3, 2, 4, and 3 patients, respectively. CONCLUSION: This case series showed that curative surgical resection was feasible as a staged approach for patients with locally advanced gastric cancer with outlet obstruction, after initial staged gastrojejunostomy and chemotherapy.

Controversies and consensus in transanal total mesorectal excision (taTME): Is it a valid choice for rectal cancer?

Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer. taTME is associated with the benefits of a higher rate of free distal resection margins (DRM) under direct visualization, better visualization of the mesorectal plane, and the feasibility of overcoming the restriction of the distal pelvis. Thus, it is increasingly used globally. In this review, we investigated whether taTME yields better short- and long-term outcomes than laparoscopic TME.

Comparative study of oncologic efficacy of cephalomedial to lateral dissection versus medial to lateral dissection in laparoscopic total mesorectal excision for rectal cancer: An RCT study.

BACKGROUND AND OBJECTIVES: We compared the 3-year overall survival between cephalomedial-to-lateral approach proctectomy (CEMP) and medial-to-lateral approach proctectomy (MAP) in patients undergoing laparoscopic total mesorectal excision for rectal cancer. The advantages of CEMP and the clinical value of No. 253 lymph nodes resection have not been objectively analyzed in literature. METHODS: This was a prospective, two-arm, multicenter, single-blinded, randomized trial. The primary endpoint was 3-year overall survival, and secondary endpoints included safety, feasibility, oncological radicality (including number of No. 253 lymph nodes harvested), short-term outcome, 3-year disease-free survival, rate of postoperative complications, mortality, and rate of recurrence. RESULTS: From May 2016 to July 2020, 506 patients were enrolled-256 in the CEMP group and 250 in the MAP group. Comparison of overall survival and disease-free survival showed that there was treatment benefit in the CEMP group (28.22 ± 12.12 vs. 27.44 ± 13.06, p = 0.485; 27.24 ± 12.01 vs. 26.42 ± 12.81; p = 0.457). More No. 253 lymph nodes were harvested in the CEMP group, and cases with positive No. 253 lymph nodes had worse prognosis in stage III. Surgical safety was equal for both approaches. CONCLUSIONS: Dissection of No. 253 lymph nodes may be important to improve clinical prognosis, but further studies with larger samples are needed to confirm this finding.

Effect of different reinforcement methods on anastomotic leakage prevention after laparoscopic double anastomosis.

BACKGROUND AND OBJECTIVES: To investigate the effects of different suture reinforcement methods for anastomotic leakage and other postoperative complications after the use of a laparoscopic double stapling technique (DST). METHODS: We collected the data of 124 patients who underwent laparoscopic radical resection of colorectal cancer from July 2017 to September 2018 at our institution. Patients were divided into three groups according to the suture reinforcement methods: intermittent, continuous suture reinforcement, and non-reinforcement (n = 41, 41, and 42, respectively). One-way analysis of variance, χ2 , Fisher's exact, and nonparametric tests were used for statistical analysis. RESULTS: Among the 124 patients, there were no statistically significant differences in operation times, intraoperative blood loss, postoperative hospital stays and recovery of bowel movement. Nine patients were diagnosed with anastomotic leakage (AL). The incidences of serious AL in the intermittent and continuous suture reinforcement groups were lower than that in the control group, with lower reoperation rate, shorter average lengths of stay and lower treatment costs of two experimental groups. CONCLUSION: Intermittent and continuous sutures after laparoscopic DST is effective, safe, and feasible on anastomotic leakage prevention. These procedures could be popularized in rectal surgery on patients with high risk of AL.

Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma.

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/ß-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/ß-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.

Tweety-Homolog 1 Facilitates Pain via Enhancement of Nociceptor Excitability and Spinal Synaptic Transmission.

Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

Application of formative evaluation and teaching feedback in PBL teaching of Medical Genetics.

Medical Genetics is an important research content of basic medicine and closely related to clinical medicine. Medical Genetics can not only lay a solid theoretical foundation for understanding medical problems for medical students, but also provide them an indispensable technical means for clinical medical practice. In order to improve students' understanding and mastery of the core content of Medical Genetics and cultivate senior medical talents with innovative spirit and independent thinking abilities, the PBL (problem-based learning) teaching method was introduced in the teaching of medical genetics for students enrolled in the eight-year medical education program. By integrating formative evaluation and teaching feedback mechanism into PBL teaching, we have achieved good teaching effects. In this paper, we will discuss the importance and necessity of formative evaluation and teaching feedback in PBL teaching, introduce the PBL teaching plan, teaching process and teaching effect of Medical Genetics in our school, share our thoughts on PBL teaching mode, and provide new ideas for the teaching reform of Medical Genetics.

Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway.

BACKGROUND: Glioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells. However, identification of the signaling molecules and underlying mechanisms has not been completely elucidated. METHODS: Human samples and glioma cell lines were cultured in vitro to determine the effects of adenovirus (ADV) infection by sphere formation, RT-qPCR, western blotting, FACS and immunofluorescence. For in vivo analysis, mouse intracranial tumor model was applied. Bioinformatics analysis, gene knockdown by siRNA, RT-qPCR and western blotting were applied for further mechanistic studies. RESULTS: Infection of patient-derived glioma cells with ADV increases the formation of tumor spheres. ADV infection upregulated stem cell markers and in turn promoted the capacities of self-renewal and multi-lineage differentiation of the infected tumor spheres. These ADV infected tumor spheres had stronger potential to form xenograft tumors in immune-compromised mice. GSCs formation could be promoted by ADV infection via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1. Knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, HMGB1, a damage associated molecular pattern (DAMP) that triggers TLR signaling, also upregulated stemness markers in glioma cells. CONCLUSION: ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling. Video abstract.

Strategies and recommendations for the management of gastrointestinal surgery during the COVID-19 pandemic: experience shared by Chinese surgeons.

Novel coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing public-health pandemic worldwide. Although SARS-CoV-2 has been known to spread primarily through respiratory droplets, recent evidence also supports fecal/oral as an additional route of transmission, raising concerns over gastrointestinal (GI) transmission of the infection. Herein, we, as the front-line Chinese GI surgeons, would like to share our experience and lessons in the combat against COVID-19. It is essential to create science-based, rational, and practical strategies during the outbreak of COVID-19. Here, we provide multi-institutional consensus on minimizing disease transmission while continuing to provide care from all aspects for patients in GI surgery, including outpatient clinics, inpatient units, gastrointestinal endoscopy centers, and adjustments in perioperative care. Our experiences and recommendations are worth sharing and may help to establish specific infection-control and outcome measures.

FBXO22 degrades nuclear PTEN to promote tumorigenesis.

Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.