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.

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.

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.

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.

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.

Construction and validation of a prognostic model of pyroptosis related genes in hepatocellular carcinoma.

Pyroptosis plays an important role in the occurrence and development of cancer. We are interested in determining the prognostic value of pyroptosis-related genes in hepatocellular carcinoma (HCC). In this study, we searched the original transcriptome data of The Cancer Genome Atlas (TCGA) and identified the related expressed genes by co-expression analysis. Differentially expressed genes were identified by using univariate analysis, the least absolute shrinkage and selection operator (LASSO) and multivariate analysis to screen for genes related to prognosis of HCC. Ultimately, we established a prognostic model for five genes, namely GSDME, DHX9, TREM2, SQSTM1 and GLMN. Survival analysis showed that the overall survival rate of HCC patients with high risk score was significantly lower than that of HCC patients with low risk score, and this signal could be used as an independent prognostic indicator of HCC. Receiver operating characteristic curve analysis confirmed the accuracy of this prognostic signal, and was further verified in a Gene Expression Omnibus (GEO) dataset (GSE14520) and the International Cancer Genome Consortium (ICGC) databases. In addition, nomograms based on the five identified prognostic genes were established and verified internally in TCGA cohort. Additionally, we also analyzed the gene mutations of the model genes and the correlation between immune cells of the model genes. In summary, this study identified for the first time a 5-gene prognostic signature associated with pyroptosis, which can be used as a promising prognostic biomarker and provide some potentially useful therapeutic targets for HCC.

Evaluation of the Effect of Tobacco Use on Buccal Mucosa Graft Histology.

OBJECTIVE: To assess the effect of tobacco use on oral mucosal tissue harvested for urethroplasty. MATERIALS AND METHODS: Retrospective histologic and immunohistochemical (IHC) evaluation of available buccal mucosa tissue samples from patients that underwent buccal mucosa graft urethroplasty from 2018 to 2020. Patients were asked about tobacco use during pre-operative workup. Patients were counseled on and provided resources to aid in cessation of tobacco use, but surgical cases were not canceled or delayed if patients are unable cease all tobacco use. Patients that ceased use 3 months prior to surgery were considered former users. A single pathologist blinded to the smoking status evaluated the buccal mucosa specimens for histologic changes. Quantitative IHC for p75 and Sox2 were obtained. These investigative markers were selected due to their clear and direct involvement in oral mucosa's regenerative mechanism. Current tobacco users, former users and control patients were compared using ANOVA and Chi-square analyses. RESULTS: Study cohort was 16 current users, 16 former users, 32 controls. Demographics did not differ across the groups. Blinded histologic analysis between all groups found no differences. Pair-wise statistical analysis found greater collagen density in the control group compared to current users (P = .01). No differences were found between former and current users or former users and controls. IHC analysis did not demonstrate any difference in the amount or localization of epithelial stem cell markers. CONCLUSION: Our study of buccal mucosa did not find clear or clinically significant histologic or IHC differences between patients with or without a history of tobacco use.

Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA) high interleukin-6 (IL-6) low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMA low IL-6 high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.

Histological Evaluation of Vaginal Cavity Remnants Excised During Neourethral Stricture Repair in Transgender Men.

OBJECTIVE: To determine the prevalence of patients who require vaginal cavity remnant excision and obliteration during neourethral stricture repair and to characterize the histological composition of the excised tissue. METHODS: A retrospective review was performed of all transgender men who underwent neourethral stricture repair. Preoperative imaging and operative reports were reviewed to determine the presence of a vaginal cavity remnant that was excised and obliterated during neourethral reconstruction. Pathology slides were reviewed by 2 pathologists to determine if there was presence of stratified squamous epithelium consistent with vaginal tissue within the vaginal cavity remnant. RESULTS: A total of 47 consecutive transgender men underwent neourethral stricture repair between January 2014 and December 2020. Of these, 18 patients (38%) with a mean age of 37 years (23-59) underwent excision and obliteration of a vaginal cavity remnant. Seventy eight percent (14/18) had a prior phalloplasty and 22% (4/18) had a prior metoidioplasty. Primary vaginectomy type was not associated with whether or not a patient had a vaginal cavity remnant (P = .12). Histological evaluation demonstrated the presence of vaginal epithelium in all vaginal cavity remnant specimens. CONCLUSION: A high percentage of transgender men with neourethral strictures present with vaginal cavity remnants despite prior vaginectomy. Pathological evaluation confirms that all vaginal cavity remnant specimens contain vaginal epithelium that was either incompletely excised or regenerated. While the implications of this residual vaginal epithelium require further investigation, total removal of vaginal tissue primarily or during reconstruction is important given the risk of associated symptoms.

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer.

Nearly one third of men will incur biochemical recurrence after treatment for localized prostate cancer. Androgen deprivation therapy (ADT) is the therapeutic mainstay; however, some patients will transition to a castrate resistant state (castrate resistant prostate cancer, CRPC). Subjects with CRPC may develop symptomatic metastatic disease (mCRPC) and incur mortality several years later. Prior to metastatic disease, however, men acquire non-metastatic CRPC (nmCRPC) which lends the unique opportunity for intervention to delay disease progression and symptoms. This review addresses current therapies for nmCRPC, as well as novel therapeutics and pathway strategies targeting men with nmCRPC.

Beneficial Diets and Pancreatic Cancer: Molecular Mechanisms and Clinical Practice.

Pancreatic cancer (PC) is a malignant tumor with high invasiveness, easy metastatic ability, and chemoresistance. Patients with PC have an extremely low survival rate due to the difficulty in early diagnosis. It is estimated that nearly 90% of PC cases are caused by environmental risk factors. Approximately 50% of PC cases are induced by an unhealthy diet, which can be avoided. Given this large attribution to diet, numerous studies have assessed the relationship between various dietary factors and PC. This article reviews three beneficial diets: a ketogenic diet (KD), a Mediterranean diet (MD), and a low-sugar diet. Their composition and impact mechanism are summarized and discussed. The associations between these three diets and PC were analyzed, and we aimed to provide more help and new insights for the prevention and treatment of PC.

Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib.

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.

Anatomic versus non-anatomic resection for hepatocellular carcinoma, do we have an answer? A meta-analysis.

BACKGROUND: Anatomic resection (AR) is widely performed for hepatocellular carcinoma (HCC), but it is generally not considered superior to non-anatomic resection (NAR) in terms of prognosis. So we compared the prognosis of AR with that of NAR for HCC. METHODS: We searched for articles about AR versus NAR for HCC published between January 1998 and December 2018 in PubMed, Cochrane Library, EMBASE and Wanfang database. Meta-analysis was performed on patient characteristics, tumor characteristics, operative characteristics, perioperative outcomes and long-term outcomes. RESULTS: A total of 38 studies involving 9122 patients were included: 5062 were in the AR group and 4060 in the NAR group. Only one study included in our meta-analysis was randomized controlled trial, and others were comparative cohort studies. The AR group had an advantage over NAR group in the aspect of age, liver cirrhosis level and liver reserve function; but had a disadvantage in the aspect of tumor size, AFP level, operation time, blood loss, microvascular invasion, pathological differentiation and postoperative complication. The AR group gained 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS) benefits versus NAR group, but there was significant heterogeneity between groups in terms of patient and tumor characteristics. CONCLUSION: AR is superior to NAR regarding the long-term outcomes considering the relatively acceptable heterogeneity. More prospective randomized controlled trials are required to further confirm the actual effect of AR or NAR on survival for HCC with less heterogeneity.

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.

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.

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.

HMGB1 represses the anti-cancer activity of sunitinib by governing TP53 autophagic degradation via its nucleus-to-cytoplasm transport.

Sunitinib, a multikinase inhibitor approved for a number of cancer indications has a low response rate. Identifying mechanisms of resistance could lead to rational combination regimens that could improve clinical outcomes. Here we report that resistance to sunitinib therapy was driven by autophagic degradation of TP53/p53. Deletion of ATG7 or ATG5 suppressed TP53 degradation, as did knockdown of SQSTM1/p62. Mechanistically, the transport of TP53 from the nucleus to the cytoplasm was essential for the sunitinib-induced autophagic degradation of TP53 and did not require TP53 nuclear export signals (NESs). Moreover, TP53 degradation was achieved by the transport of its nuclear binding target, HMGB1, which shifted TP53 from the nucleus to the cytoplasm. The inhibition of HMGB1 sensitized cancer cells to sunitinib. Importantly, sunitinib induced the degradation of all TP53 proteins, except for TP53 proteins with mutations in the interaction domain of TP53 with HMGB1 (amino acids 313 to 352). In conclusion, our data identify an alternative HMGB1-mediated TP53 protein turnover mechanism that participates in the resistance of sunitinib and suggest HMGB1 as a potential therapeutic target for improving clinical outcomes of sunitinib.

Inhibitory effect of cadmium(II) ion on anodic electrochemically active biofilms performance in bioelectrochemical systems.

Cadmium(II) ion can affect the anode performance of bioelectrochemical systems (BES); however, how the presence of Cd2+ affect the extracellular electron transfer of anodic electrochemically active biofilms (EABs), the microbial viability and species composition of microorganism on the anode remain poorly understood. Here, we investigated the inhibitory effect of Cd2+ at different concentrations on the electrochemical performance and the biofilm community in mixed-culture enriched BES. The electrochemical performance of the BES was not inhibited at 2 mg L-1 Cd2+, while higher concentrations of 5-20 mg L-1 resulted in the decrease in the maximum power density, with 0.34 ±â€¯0.01 W m-2 at 5 mg L-1, 0.28 ±â€¯0.01 W m-2 at 10 mg L-1, and 0.17 ±â€¯0 W m-2 at 20 mg L-1, respectively. When adding 30 mg/L Cd2+, there was almost no power output. The decline of the power output was possibly ascribed to the suppressed viability and the change of species richness as evident from confocal laser scanning microscopy and microbial community analysis. Cyclic voltammogram and electrochemical impedance spectroscopy revealed that high concentration of Cd2+ exceeding 5 mg L-1 can inhibit the secretion of outer membrane cytochromes, thus reducing the electron transfer between the EABs and the anode surface. Analysis of bacterial structures showed a decrease in Geobacter accompanied by an increase in Stenotrophomonas and Azospira in response to Cd2+ at 10 and 20 mg L-1. This study added to the in-depth analysis of the inhibition of Cd2+ on EABs, and provided new insights into the removing Cd2+ and organics simultaneously in BES.

MiR-361-3p regulates ERK1/2-induced EMT via DUSP2 mRNA degradation in pancreatic ductal adenocarcinoma.

Metastasis remains one of the most intractable challenges in pancreatic ductal adenocarcinoma (PDAC) biology, and epithelial-to-mesenchymal transition (EMT) is essential to the epithelium-originated solid tumor metastasis cascade. Emerging evidence demonstrates that aberrant miRNA expression is involved in pancreatic cancer progression. We found that miR-361-3p was associated with an advanced stage of PDAC and poor prognosis. Hence, the effect of miR-361-3p on metastasis of PDAC cells was evaluated using Transwell assay and wound healing assay in vitro as well as orthotopic and liver metastasis pancreatic cancer models in vivo. Overexpression of miR-361-3p promoted pancreatic cancer cell migration and invasion in vitro, and miR-361-3p-elevated PDAC cells were prone to generating metastatic nodules in vivo. However, miR-361-3p showed no significant effect on the proliferation of PDAC cells in vivo or in vitro. Further study demonstrated that miR-361-3p could enhance EMT and ERK pathway activation, and ERK inhibitor could attenuate miR-361-3p-induced EMT. Luciferase assays, qPCR, and western blot and Ago2 co-immunoprecipitation were performed to identify the direct target of miR-361-3p. Mechanistic investigations identified DUSP2 as a direct target of miR-361-3p, and DUSP2 was revealed to be involved in miR-361-3p-induced EMT by directly leading to the inactivation of the ERK pathway. Moreover, we found that miR-361-3p-induced EMT was dependent on Ago2, the core component of RNA-induced silencing complex, while enforced expression of Ago2 enhanced the miR-361-3p-induced effect by promoting interference efficacy and specificity rather than regulating miR-361-3p stability and biogenesis. Thus, this study revealed that miR-361-3p functions as an oncomiR for promoting metastasis and identified the miR-361-3p/DUSP2/ERK axis as a novel EMT axis dependent on Ago2 in PDAC.