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The incidence of hepatocellular carcinoma (HCC) is extremely high, and China accounts for approximately 50% of global liver cancer cases. Previous studies reported that CDC20 is involved in the occurrence and progression of a variety of malignant tumors. So, whether CDC20 will affect the development of HCC, we have conducted in-depth research on this. We selected Hep3B and HepG2 for cell culture, and performed siRNA transfection, lentiviral infection, western blot, MTS determination, cell cycle determination, apoptosis test, immunodeficiency test, clone survival test and subcutaneous parthenogenesis in nude mice. Knockdown of CDC20 greatly enhanced the radiation efficacy on the growth retardation in HepG2, and protein level of CDC20 was decreased for the activation of P53 by radiation. Downregulation of CDC20 combined with radiation can inhibit proliferation, aggravate DNA damage, increase G2/M arrest, and promote apoptosis of HCC cells to a greater extent, and the relative survival fraction of HCC cells was gradually reduced with radiation dose increased in P53 mutated Hep3B cells. After knocking down CDC20 in HCC, Bcl-2 was down-regulated and Bax expression increased. Down-regulation of CDC20 can inhibit further invasion by promoting the radiosensitivity of HCC. In this study, we found that that CDC20 was highly expressed in HCC and participated in radio resistance of HCC cells with P53 mutation Bcl-2/Bax via signaling pathway. This study is the first to present evidence that CDC20 may play a role in improving the efficacy of radiotherapy in HCC.

Background The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid β-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. Methods Distribution of lipids in GBC was described by LC–MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5′ and 3′ rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. Results Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N 6 -methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. Conclusions LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.

Background Gemcitabine plus platinum as the first-line chemotherapy for cholangiocarcinoma (CCA) has limited efficacy. The aim of this study was to evaluate the effectiveness of modified FOLFIRINOX (mFOLFIRINOX) compared to that of gemcitabine plus oxaliplatin (Gemox) for patients with locally advanced or metastatic CCA. Methods From January 2016 to December 2019, consecutive patients who were diagnosed with locally advanced or metastatic CCA were treated with either mFOLFIRINOX or Gemox as a first-line chemotherapy. The main endpoint was Progression free survival (PFS). The second endpoints were Overall survival (OS), Disease control rate (DCR) and incidence of severe toxicity (grade 3–4). Tumors were evaluated at baseline and thence every 4–6 weeks. The study was designed and carried out in accordance with the principles of the declaration of Helsinki, approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-D-2020-154) and registered with ClinicalTrials.gov , number NCT04305288 (registration date: 12/03/2020). Results Of 49 patients in this study, 27 were in the FOLFIRINOX regimen group and 22 in the Gemox regimen group. There were no significant differences between groups in baseline characteristics. The DCR was 77.8% in the mFOLFIRINOX group and 63.5% in the Gemox group. The corresponding median PFS was 9.9 months (95% confidence interval [CI], 7.3–12.4) in the mFOLFIRINOX group versus 6.4 months (95% CI,3.6–9.2, p  = 0.040) in the Gemox group. The corresponding median OS was 15.7 months (95% CI, 12.5–19.0) versus 12.0 months (95% CI, 9.3–14.8, p  = 0.099). Significantly more grade 3–4 vomiting occurred in the mFOLFIRINOX than the Gemox groups (7 (25.9%) vs 1 (4.5%), p  = 0.044). Conclusions First-line mFOLFIRINOX offered more promising results in patients with advanced or metastatic CCA.

IntroductionGallbladder cancer (GBC) is an aggressive type of digestive system cancer with a dismal outcome. Given the lack of effective treatment options, the disease rapidly reoccurs and 5-year survival rate is <5%. Our team previously found that a significant percentage of GBC tissues harboured mutations of the ErbB-related pathway. Afatinib is a chemically synthesised drug specifically targeting the ErbB pathway mutations. However, its efficacy in the treatment of patients with GBC remains unknown. Circulating tumour DNA (ctDNA) refers to a proportion of cell-free DNA in the blood which is released by apoptotic and necrotic cells from tumours in situ, metastatic foci or circulating tumour cells. ctDNA-based liquid biopsy is a non-invasive pathological detection method that offers additional value to evaluate the therapeutic efficacy of antitumour drugs.Methods and analysisWe conduct a multicentre and randomised study on afatinib combined with gemcitabine and oxaliplatin (GEMOX) in patients with ErbB pathway mutated GBC. Clinical and biological evaluation involving ErbB pathway ctDNA detection will be made during the 3-year follow-up after participation. The primary objective of this clinical trial is to evaluate the clinical efficacy of afatinib. Disease-free survival is the primary end point and will be correlated with plasma ctDNA of patients in the treatment with afatinib. In addition, we will evaluate the sensitivity and specificity of plasma ctDNA for monitoring tumour recurrence and progression. Finally, we will assess the safety of afatinib by keeping an eye on the safety indicators.Ethics and disseminationThe study was approved by the medical-ethical review committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The clinical trials results, even inconclusive, will be published in peer-reviewed journals.Trial registration numberNCT04183712.

A system is said to be critically observable if the operator can always determine whether the current state belongs to a set of critical states. Due to the communication failures, systems may suffer from intermittent loss of observations, which makes the system not critically observable. In this sense, to characterize critical observability in a quantitative way, this paper extends the notion of critical observability to stochastic discrete event systems modeled as partially observable probabilistic finite automata. Two new notions, called step-based almost critical observability and almost critical observability are proposed, which describe a measure of critical observability for a given system against intermittent loss of observations. We introduce a new language operation to obtain a probabilistic finite automaton describing the behavior of the plant system under intermittent loss of observations. Based on this structure, we also present verification methodologies to check the aforementioned two notions and analyze the complexity. Finally, the results are applied to a raw coal processing system, which shows the effectiveness of the proposed methods.

Objective Hyperreflective foci (HRF) are small, punctate lesions ranging from 20 to 50 μ m and exhibiting high reflective intensity in optical coherence tomography (OCT) images of patients with diabetic retinopathy (DR). The purpose of the model proposed in this paper is to precisely identify and segment the HRF in OCT images of patients with DR. This method is essential for assisting ophthalmologists in the early diagnosis and assessing the effectiveness of treatment and prognosis. In this study, we introduce an HRF segmentation algorithm based on KiU-Net, the algorithm that comprises the Kite-Net branch using up-sampling coding to collect more detailed information and a three-layer U-Net branch to extract high-level semantic information. To enhance the capacity of a single-branch network, we also design a cross-attention block (CAB) which combines the information extracted from two branches. The experimental results demonstrate that the number of parameters of our model is significantly reduced, and the sensitivity (SE) and the dice similarity coefficient (DSC) are respectively improved to 72.90 % and 66.84 % . Considering the SE and precision(P) of the segmentation, as well as the recall ratio and recall P of HRF, we believe that this model outperforms most advanced medical image segmentation algorithms and significantly relieves the strain on ophthalmologists. Purpose Hyperreflective foci (HRF) are small, punctate lesions ranging from 20 to 50 μm with high reflective intensity in optical coherence tomography (OCT) images of patients with diabetic retinopathy (DR). This study aims to develop a model that precisely identifies and segments HRF in OCT images of DR patients. Accurate segmentation of HRF is essential for assisting ophthalmologists in early diagnosis and in assessing the effectiveness of treatment and prognosis. Methods We introduce an HRF segmentation algorithm based on the KiU-Net architecture. The model comprises two branches: a Kite-Net branch that uses up-sampling coding to capture detailed information, and a three-layer U-Net branch that extracts high-level semantic information. To enhance the capacity of the network, we designed a cross-attention block (CAB) that combines the information extracted from both branches, effectively integrating detail and semantic features. Results Experimental results demonstrate that our model significantly reduces the number of parameters while improving performance. The sensitivity (SE) and Dice Similarity Coefficient (DSC) of our model are improved to 72.90% and 66.84%, respectively. Considering the SE and precision (P) of the segmentation, as well as the recall ratio and precision of HRF detection, our model outperforms most advanced medical image segmentation algorithms Conclusion The proposed HRF segmentation algorithm effectively identifies and segments HRF in OCT images of DR patients, outperforming existing methods. This advancement can significantly alleviate the burden on ophthalmologists by aiding in early diagnosis and treatment evaluation, ultimately improving patient outcomes.

Proteotoxicity induced by misfolded or aggregated proteins causes progressive neuronal damage. The endoplasmic reticulum (ER) protein quality control (ERQC) pathways are responsible for mitigating the accumulation of these misfolded or aggregated proteins, thus reducing proteotoxicity. Enhancing ERQC pathways is a promising strategy for treating neurodegenerative diseases. However, the mechanisms governing the initiation and degradation of misfolded or aggregated proteins in neurons remain largely unknown in vivo. In studying the maturation of proAVP in mouse AVP neurons, this study discovers that autophagy and ER‐associated degradation (ERAD) ERQC pathways collaborate to maintain proAVP maturation and protect AVP neuron survival against proteotoxicity. Autophagy deficiency in mouse AVP neurons leads to the late‐onset of diabetes insipidus. Mechanistically, autophagy selectively degrades mutant proAVP aggregates and endogenous HRD1 of the SEL1L‐HRD1 ERAD complex through FAM134B mediated ER‐phagy. HRD1 induction is responsible for reducing proAVP aggregation and maintaining AVP neuron function and survival under autophagy deficiency. Thus, autophagy and ERAD form a dual‐protection system that orchestrates prohormone maturation and endocrine neuron survival, providing new insights in the complexity of neuroendocrinology and the intrinsic mechanism of neurodegenerative diseases, with therapeutic potential in protein folding diseases. By studying the maturation mechanisms of vasopressin (AVP), this manuscript identifies FAM134B‐mediated ER‐phagy as a critical pathway for degrading both aggregated proAVP and the key ERAD component, HRD1. HRD1 induction mitigates proAVP aggregation and support AVP neuron function in the absence of autophagy. The findings establish autophagy and ERAD as a dual‐protection system for neuroendocrine proteostasis.

Diabetes Insipidus In this dynamic cover illustration, a football match symbolizes the protein quality control system during prohormone maturation in the endoplasmic reticulum (ER). The offensive and defensive plays represent two possible fates of proAVP: scoring a goal signifies correct folding and secretion, ensuring neuronal function and survival, while conceding a goal symbolizes misfolding and aggregation, leading to neuronal damage or even loss. Two key defenders play a crucial role–Player 2 represents ERAD, which is a house‐keeping mechanism in clearing misfolded proteins in the ER, and Player 1 represents ER‐phagy, which is the last line of defense by removing proAVP aggregates that beyond the capacity of Player 1. This cover creatively visualizes the findings of Jun Cui, Ling Qi, Guojun Shi , and co‐workers described in article number 2411662, highlighting how autophagy and ERAD coordinate to prevent prohormone aggregation and maintain neuroendocrine function. The cover art was created by Coloring Guangzhou.