Rat tight junction proteins are disrupted after subchronic exposure to okadaic acid.

Okadaic acid (OA), a lipophilic phycotoxin distributed worldwide, causes diarrheic shellfish poisoning and even leads to tumor formation. Currently, the consumption of contaminated seafood is the most likely cause of chronic OA exposure, but there is a serious lack of relevant data. Here, the Sprague-Dawley rats were exposure to OA by oral administration at 100 µg/kg body weight, and the tissues were collected and analyzed to assess the effect of subchronic OA exposure. The results showed that subchronic OA administration disturbed colonic mucosal integrity and induced colitis. The colonic tight junction proteins were disrupted and the cell cycle of colonic epithelial cells was accelerated. It is inferred that disruption of the colonic tight junction proteins might be related to the development of chronic diarrhea by affecting water and ion transport. Moreover, the accelerated proliferation of colonic epithelial cells indicated that subchronic OA exposure might promote the restitution process of gut barrier or induce tumor promoter activity in rat colon.

A Prospective Study Comparing Cancer Detection Rates of Transperineal Prostate Biopsies Performed by Junior Urologists versus a Senior Consultant in a Real-World Setting.

INTRODUCTION: Prostate biopsy (PB) is a typical daily practice method for the diagnosis of prostate cancer (PCa). This study aimed to compare the PCa detection rates and peri- and postoperative complications of PB among 3 residents and a consultant. PATIENTS AND METHODS: A total of 343 patients who underwent PB between August 2018 and July 2019 were involved in this study. Residents were systematically trained for 2 weeks by a consultant for performing systematic biopsy (SB) and targeted biopsy (TB). And then, 3 residents and the consultant performed PB independently every quarter due to routine rotation in daily practice. The peri- and postoperative data were collected from a prospectively maintained database (www.pc-follow.cn). The primary outcome and secondary outcome were to compare the PCa detection rates and complications between the residents and consultant, respectively. RESULTS: There was no significant difference between the residents and consultant in terms of overall PCa detection rates of SB and TB or further stratified by prostate-specific antigen value and prostate imaging reporting and data system (PI-RADS) scores. We found the consultant had more TB cores (175 cores vs. 86-114 cores, p = 0.043) and shorter procedural time (mean 16 min vs. 19.7-20.1 min, p < 0.001) versus the residents. The complication rate for the consultant was 6.7% and 5%-8.2% for the residents, respectively (p = 0.875). CONCLUSIONS: The residents could get similar PCa detection and complication rates compared with that of the consultant after a 2-week training. However, the residents still need more cases to shorten the time of the biopsy procedure.

Autophagy coupled to translation is required for long-term memory.

An increase in protein synthesis following learning is a fundamental and evolutionarily conserved mechanism of long-term memory. To maintain homeostasis, this protein synthesis must be counterbalanced by mechanisms such as protein degradation. Recent studies reported that macroautophagy/autophagy, a major protein degradation mechanism, is required for long-term memory formation. However, how learning regulates autophagy and recruits it into long-term memory formation remains to be established. Here, we show that inhibitory avoidance in rats significantly increases the levels of autophagy and lysosomal degradation proteins, including BECN1/beclin 1, LC3-II, SQSTM1/p62 and LAMP1, as well as autophagic flux in the hippocampus. Moreover, pharmacological inhibition or targeted molecular disruption of the learning-induced autophagy impairs long-term memory, leaving short-term memory intact. The increase in autophagy proteins results from active translation of their mRNA and not from changes in their total mRNA levels. Additionally, the induction of autophagy requires the immediate early gene Arc/Arg3.1. Finally, in contrast to classical regulation of autophagy in other systems, we found that the increase in autophagy upon learning is dispensable for the increase in protein synthesis. We conclude that coupling between learning-induced translation and autophagy, rather than translation per se, is an essential mechanism of long-term memory.Abbreviations: AAV: adeno-associated virus; ARC/ARG3.1: activity regulated cytoskeletal-associated protein; ATG: autophagy related; DG: dentate gyrus; GFP: green fluorescent protein; IA: inhibitory avoidance; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; ODN: oligodeoxynucleotide; qPCR: quantitative polymerase chain reaction; SBI: SBI0206965; SQSTM1/p62: sequestosome 1; SUnSET: surface sensing of translation; TRAP: translating ribosome affinity purification; ULK1: unc-51 like kinase 1.

Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis.

DT-13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT-13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis-related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non-muscle myosin IIA (NM IIA)-induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT-13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (-)002Dblebbistatin or MYH-9 shRNA, the synergistic inhibition effect of DT-13 and TPT on aerobic glycolysis was eliminated in BGC-823 cells. Immunohistochemical analysis revealed selective up-regulation of NM IIA while specific down-regulation of p-CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.

Prognostic role of the pre-treatment platelet-lymphocyte ratio in pancreatic cancer: a meta-analysis.

BACKGROUND AND AIMS: Recently, the pre-treatment platelet-lymphocyte ratio (PLR), which is based on blood parameters, was accepted as a prognostic factor for patients with various cancers. Numerous studies have investigated the prognostic role of the PLR in pancreatic cancer; however, it remains unclear. Therefore, we conducted this meta-analysis to evaluate the relationship between the pre-treatment PLR and overall survival (OS) in pancreatic cancer. MATERIALS AND METHODS: We performed a systematic literature search of the PubMed, Embase and Web of Science databases for relevant studies that explored the prognostic role of the pre-treatment PLR in pancreatic cancer. The hazard ratios (HRs) and 95% confidence intervals (CIs) related to OS were pooled using a random effects model. RESULTS: Fourteen retrospective cohort studies involving 2,260 patients were included in this meta-analysis. Compared with low PLR, high PLR was a predictor of shorter OS (HR = 1.24, 95% CI: 1.10-1.39, I2 = 74%). CONCLUSIONS: In this meta-analysis, high pre-treatment PLR was a bio-predictor of short OS in patients with pancreatic cancer, suggesting that PLR could be used to predict prognosis of patients with pancreatic cancer before treatment. However, additional well-designed and large-scale studies are necessary.

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo.

Combination therapy has a higher success rate for many cancers compared to mono-therapy. The treatment of Topotecan (TPT) on gastric cancer (GC) is limited by its toxicity and the potential drug resistance. We found that the combination of the saponin monomer 13 from the dwarf lilyturf tuber (DT-13), performing anti-metastasis and anti-angiogenesis effects, with TPT synergistically induced apoptotic cytotoxicity in GCs with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR. With TPT, DT-13 promoted EGFR ubiquitin--mediated degradation through myosin IIA-induced and Src/ caveolin-1 (Cav-1)-induced endocytosis of EGFR; inhibited EGFR downstream signalling and then increased the pro-apoptotic effects. Moreover, the synergistic pro-apoptotic efficacy of DT-13 and TPT in GCs with high EGFR expression was eliminated by both the NM II inhibitor (-)-blebbistatin and MYH-9 shRNA. The combination therapy of DT-13 with TPT showed stronger anti-tumour effects in vivo compared with their individual effects. Moreover, the results of combination therapy revealed selective upregulation of pro-apoptotic activity in TUNEL assays and cleaved caspase-3 and NM IIA in immunohischemical analysis; while specific downregulation of p-extracellular regulated kinase 1/2 (p-ERK1/2), EGFR and Cav-1 in immunohischemical analysis. Collectively, these findings have significant clinical implications for patients with tumours harbouring high EGFR expression due to the possible high sensitivity of this regimen.

Removal of numerous vesical magnetic beads with a self-made magnetic sheath.

INTRODUCTION: Sexual curiosity and the quest for sexual excitement are the most frequent reasons for patients to introduce foreign bodies into the urethra or the bladder. Imagination and surgical skill are essential for urologists to retrieve such vesical foreign bodies. AIM: The aim of this study was to describe a novel method for retrieving vesical magnetic beads, which were inserted for autoeroticism by a male adolescent, with a self-made "magnetic sheath." METHODS: A 21-year-old young man inserted more than one hundred small magnetic beads into his urethra for sexual excitement, which lately caused symptoms of gross hematuria, frequent urination, and acute lower abdominal pain when walking or urinating. We invented a magnetic sheath by fixing a magnetic bead on the tip of an F9.5 ureteral access sheath to remove the foreign bodies in a minimally invasive way. MAIN OUTCOME MEASURE: The feasibility of using magnetic sheath to remove vesical foreign bodies; and operation duration. RESULTS: Under direct visualization of an F8/9.8 ureteroscope, the magnetic sheath could firmly attach to the magnetic bead inside the bladder and could easily pull out 5 to 15 beads each time. It took about 5 minutes to remove all of the 125 magnetic beads by utilizing our magnetic sheath. CONCLUSIONS: The self-made magnetic sheath can make the task of removal of magnetic foreign bodies easy to urologists, requiring less time and surgical skills. The new equipment provides a new method for urologists to deal with the challenging task of removing metal vesical foreign bodies which were self-inserted for masturbation.

Sphere formation reverses the metastatic and cancer stem cell phenotype of the murine mammary tumour 4T1, independently of the putative cancer stem cell marker Sca-1.

Breast cancer stem cells (BCSCs) initiate and sustain breast cancers, and several putative markers have been proposed to prospectively isolate BCSC from the non-cancer stem cell population. The candidate BCSC marker Sca-1 is a GPI-linked membrane protein expressed on activated lymphocytes, hematopoietic stem cells and mammary stem cells. Sca-1+ cells were purified from the murine mammary tumour cell line 4T1. However, this did not enrich for a stem-like, tumour initiating or metastatic cell population in vitro or in vivo. Sphere formation, which induced high levels of Sca-1, reduced BCSC gene expression with near complete loss of spontaneous metastasis from sphere-derived tumours. This was associated with decreased expression of TGFB2 and reduced activation of the TGFß signalling pathway in spheres. Both TGFB2 expression in vitro and spontaneous metastasis in vivo could be restored upon re-differentiation of sphere cells by exposure to serum, and this occurred with retention of the majority of Sca-1 expression. We conclude that while putative BCSC, including spheres, can have high Sca-1 expression, Sca-1 itself is not a marker of BCSC in established 4T1 tumours or the cell line.

[Comparison of long bone repair in tibia by vascularized fibular grafting of different sides].

OBJECTIVE: To evaluate the clinical effect of repair of massive bone defect in tibia by vascularized fibula grafting of either sides. METHODS: Twenty-four cases of massive bone defect in tibia, among which 14 case were repaired by vascularized fibula grafting of the other side and another 10 cases were repaired by those of the same side, from 1987 to 1997 were followed up for 3 to 13 years; the functions of the operated limbs were evaluated according to Enneking Score System, and the outcome of the fibula grafts were assessed by radiographic examination with reference to the standard established by International Symposium on Limb Salvage. RESULTS: The average recover rate of the operated limbs in those repaired by the other side grafting was 80.7%, and the average healing period of the fibula graft was 14 weeks with fracture of the graft in one case which made the operated lower limb shorten for about 2.5 cm; the fibula grafts were observed thickened in 43 weeks, on average, and the patients could walk independently without a crutch. While in those repaired by the same side grafting, the average recover rate of the operated limbs was 68.3%, the average healing period of the fibula graft was 17 weeks with fracture of the graft in 3 cases, in 2 of which the lower limbs were shortened for 2 cm and 4 cm respectively, and in the third one infection occurred and amputation was performed finally; the fibula grafts were observed thickened in 49 weeks, on average, which made it available for the patients to walk without a crutch. All of the data showed that there was a significant difference statistically between the differently treated cases. CONCLUSION: It's a good choice to repair massive bone defect in tibia by vascularized fibula grafting, and the vascularized fibula graft from the other side could promote the bone healing and accelerate the recover of the function of the operated lower limb.