[Recombinant Schistosoma japonicum cystatin alleviates acute liver injury in mice by inhibiting endoplasmic reticulum stress, inflammation and hepatocyte apoptosis].

OBJECTIVE: To investigate the protective effect of recombinant Schistosoma japonicum cystatin (rSj-Cys) against acute liver injury induced by lipopolysaccharide (LPS) and D-GalN in mice. METHODS: Adult male C57BL/6J mice with or without LPS/D-GaIN-induced acute liver injury were given intraperitoneal injections of rSj-Cys or PBS 30 min after modeling (n=18), and serum and liver tissues samples were collected from 8 mice in each group 6 h after modeling. The survival of the remaining 10 mice in each group within 24 h was observed. Serum levels of ALT, AST, TNF-α and IL-6 of the mice were measured, and liver pathologies was observed with HE staining. The hepatic expressions of macrophage marker CD68, Bax, Bcl-2 and endoplasmic reticulum stress (ERS)-related proteins were detected using immunohistochemistry or immunoblotting, and TUNEL staining was used to detect hepatocyte apoptosis. RESULTS: The survival rates of PBS- and rSj-Cys-treated mouse models of acute liver injury were 30% and 80% at 12 h and were 10% and 60% at 24 h after modeling, respectively; no death occurred in the two control groups within 24 h. The mouse models showed significantly increased serum levels of AST, ALT, IL-6 and TNF-α and serious liver pathologies with increased hepatic expressions of CD68 and Bax, lowered expression of Bcl-2, increased hepatocyte apoptosis, and up-regulated expressions of ERS-related signaling pathway proteins GRP78, CHOP and NF-κB p-p65. Treatment of the mouse models significantly lowered the levels of AST, ALT, IL-6 and TNF-α, alleviated liver pathologies, reduced hepatic expressions of CD68, Bax, GRP78, CHOP and NF-κB p-p65, and enhanced the expression of Bcl-2. In the normal control mice, rSj-Cys injection did not produce any significant changes in these parameters compared with PBS. CONCLUSION: rSj-Cys alleviates LPS/D-GalN-induced acute liver injury in mice by suppressing ERS, attenuating inflammation and inhibiting hepatocyte apoptosis.

Retraction Note: Correlation between GDF15, MMP7 and gastric cancer and its prognosis.

The article "Correlation between GDF15, MMP7 and gastric cancer and its prognosis", by L. Lu, G.-Q. Ma, X.-D. Liu, R.-R. Sun, Q. Wang, M. Liu, P.-Y. Zhang, published in Eur Rev Med Pharmacol Sci 2017; 21 (3): 535-541-PMID: 28239815 has been retracted by the Editor in Chief. Following some concerns raised on PubPeer (link: https://pubpeer.com/publications/C14F62B3ACFEA9BA5AFA33141DAFE0), the Editor in Chief has started an investigation to assess the validity of the results as well as possible figure manipulation. The authors have been informed about the journal's investigation but have remained unresponsive and have not provided the study's raw data. The journal investigation revealed a figure duplication between panels A and B of Figure 6. Consequently, the Editor in Chief mistrusts the results presented and has decided to retract the article. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/12162.

[Endoscopic ultrasound-guided liver biopsy: current status and prospects].

Liver biopsy is an important means of clinical diagnosis and treatment of liver diseases, but it is not easily accepted by patients because of its invasiveness. The most commonly employed liver biopsy approaches are percutaneous or transjugular. Endoscopic ultrasound-guided liver biopsy (EUS-LB), a newly emerging transjugular technique, has been widely studied and applied in recent years, but its application in China is less common. The EUS-LB has the advantages of high safety and comfort, simultaneous sampling of both liver lobes, and adequate sampling volume; however, it also has the disadvantages of high requirements for hardware, operators, and cost. This article reviews the clinical application of EUS-LB in accordance with pertinent research findings from recent years and discusses its advantages, disadvantages, and implementation feasibility.

[Analysis of the efficacy and safety of pulsed radiofrequency for the treatment of thoracic postherpetic neuralgia in elderly patients with different pain phenotypes].

Objective: To analyze the efficacy and safety of pulsed radiofrequency (PRF) for the treatment of thoracic postherpetic neuralgia (PHN) in elderly patients with different pain phenotypes. Methods: A total of 201 elderly thoracic PHN patients, including 110 males and 91 females aged (72.2±6.9) years who received high-voltage, long-duration PRF at the dorsal root ganglion at Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine from January 2020 to December 2022, were retrospectively included. The neuropathic pain symptom inventory (NPSI) was used to evaluate the five different pain phenotypes, which included superficial spontaneous pain, deep spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia, and to analyze the distribution of the five pain phenotypes. The numerical rating scale (NRS) and NPSI scores of all patients were compared before treatment and three months after treatment to evaluate the efficacy and safety of PRF for different pain phenotypes and pain phenotype combinations. Results: All patients had two or more pain phenotypes, and 50.2% (101/201) of the patients had five pain phenotypes at the same time. Compared with those before treatment, three months after treatment, the NPSI scores for superficial spontaneous pain, deep spontaneous pain, paroxysmal pain, evoked pain and paresthesia/dysesthesia decreased (all P<0.05), and the scores decreased byï¼»M（Q1，Q3）］3.0 (2.0, 4.0), 1.5 (0.5, 2.5), 3.0 (2.5, 4.0), 2.3 (1.0, 4.0), and 1.0 (0.5, 2.0) points, respectively, the differences were statistically significant (P<0.001). The decrease in the NPSI score in patients with paroxysmal pain was greater than that in patients with the other 4 pain phenotypes (all P<0.05). After treatment, the NRS score decreased by 4.0 (3.0, 5.0), 4.0 (3.0, 5.0), 4.0 (3.0, 5.0) and 5.0 (4.0, 6.0) points in patients with 2, 3, 4 and 5 pain phenotypes, respectively, and the difference was statistically significant (P<0.001). The decrease in the NRS score was greater in patients with a combination of 5 pain phenotypes than that in patients with a combination of 3 and 4 pain phenotypes (all P<0.05). No complications, such as pneumothorax, haematoma or infection, occurred in any of the patients during treatment. Conclusion: PRF has different therapeutic effects on PHN patients with different pain phenotypes, it has the best effect on paroxysmal pain, and the treatment is safe.

A novel strategy for predicting the efficacy of temozolomide treatment for metastatic pheochromocytomas/paragangliomas.

BACKGROUND: There are few studies on the efficacy of temozolomide (TMZ) in the treatment of Metastatic pheochromocytoma / paraganglioma (MPP) patients. And it remains unclear which MPP patients may benefit from TMZ treatment. METHODS: This was a prospective study. MPP patients were enrolled. Patients were treated with TMZ until disease progression or intolerable toxicities. The primary endpoints were disease control rate (DCR) and objective response rate (ORR). Secondary endpoints included biochemical response rate progression-free survival (PFS) and safety. We compared the difference between effective and ineffective groups, to explore which patients are more suitable for TMZ treatment. RESULTS: 62 patients with MPP were enrolled and tumor response were evaluated in 54 patients. The DCR was 83% (35/42), and the ORR was 24% (10/41) among the progressive patients. PFS was 25.2 ± 3.1 months. The most common adverse event was nausea (41/55). We found that 92.9% (13/14) of patients with MGMT methylation greater than 7% respond to treatment. For the patients with MGMT methylation less than 7%, Ki-67 index could be used to guide the use of TMZ in these patients. Among the patients with Ki-67 index less than 5%, 66% (8/12) patients showed respond to treatment, and only 33% (4/12) patients with Ki-67 index more than 5% showed respond to TMZ. CONCLUSIONS: This study indicated that TMZ is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. We recommended to MGMT methylation analysis test and Ki-67 index to guide TMZ application.

[Clinical status and challenges of new drugs for metabolic dysfunction-associated fatty liver disease].

Metabolic dysfunction-associated fatty liver disease (MASLD) is a major public health problem that seriously affects human health. At present, some good progress has been made in the research and development of new drugs for MASLD, but there is still great space for exploration. This paper summarizes and analyzes the reasons in the current clinical status and challenges for the research and development of new drugs for MASLD.

A study on expression of GRP78 and CHOP in neutrophil endoplasmic reticulum and their relationship with neutrophil apoptosis in the development of sepsis.

We investigated the relationship between neutrophil apoptosis and endoplasmic reticulum stress (ERS) in sepsis and its mechanism. A prospective cohort study was conducted by recruiting a total of 58 patients with sepsis. Peripheral blood samples were collected on 1, 3, 5 and 7 days after admission to the ICU. The expressions of endoplasmic reticulum specific glucose regulatory protein 78 (GRP78), C/EBP homologous protein (CHOP), apoptosis signal-regulating kinase 1 (ASK1), Bcl-2-like 11 (BIM), death receptor 5 (DR5), c-Jun N-terminal kinases (JNK) and p38 were detected by Western blot and PCR. The subcellular location of CHOP and GRP78 was observed by immunofluorescence analysis. Spearman correlation was used to analyze the correlation between the expression of chop protein and the apoptosis rate of peripheral blood neutrophils. Healthy volunteers in the same period were selected as the healthy control group. The expression of GRP78 protein was significantly elevated on the first day of ICU admission and showed a decreasing trend on the third, fifth and seventh day, but was significantly higher than the corresponding healthy control group. The expression of CHOP protein reached the highest level on the third day. The expression of chop protein in each group was significantly higher than that in the corresponding healthy control group. Immunofluorescence staining clearly showed that the CHOP protein accumulated in the nucleus, with an elevation in the intensity of GRP78. The neutrophil apoptosis rate of sepsis patients on the 1st, 3rd, 5th and 7th day of ICU stay was significantly higher than that of the healthy control group, with the highest apoptosis rate on the 3rd day, and then decreased gradually. CHOP protein expression level was significantly positively correlated with neutrophil apoptosis rate in sepsis patients. Endoplasmic reticulum stress occurs in neutrophils during the development of sepsis. GRP78 protein and CHOP protein may be involved in the pathological process of neutrophil apoptosis in sepsis.

[Current status and challenges of clinical research and development of new drugs for liver diseases].

Liver disease is a serious public health problem worldwide, affecting human health. However, there are still many unmet needs for the treatment of liver disease, especially with new therapeutic drugs. At present, there is no treatment method to eradicate the hepatitis B virus, nor are there therapeutic drugs for liver fibrosis, liver failure, and others. Chemotherapy and targeted immunotherapy are still unsatisfactory for liver cancer. This article provides an overview of the current status and challenges that arise in new drug research and development for liver diseases.

[Challenges and optimization strategies for clinical research and the development of new drugs for liver fibrosis].

Liver fibrosis is a key step in the developmental process of various chronic liver diseases, including cirrhosis. Therefore, the focus and difficulty of liver disease research have always been on how to reverse liver fibrosis. However, due to complex mechanisms, difficulties in endpoint evaluation, a lack of non-invasive diagnostic methods, and other factors, the research and development of new drugs are hindered and lengthy. Currently, some new drugs are being researched and developed, which signifies the prospect is optimistic.

Multi-center Dose Prediction Using Attention-aware Deep learning Algorithm Based on Transformers for Cervical Cancer Radiotherapy.

AIMS: Accurate dose delivery is crucial for cervical cancer volumetric modulated arc therapy (VMAT). We aimed to develop a robust deep-learning (DL) algorithm for fast and accurate dose prediction of cervical cancer VMAT in multicenter datasets and then explore the feasibility of the DL algorithm to endometrial cancer VMAT with different prescriptions. MATERIALS AND METHODS: We proposed the AtTranNet algorithm for three-dimensional dose prediction. A total of 367 cervical patients were enrolled in this study. Three hundred twenty-two cervical patients from 3 centers were randomly divided into 70%, 10%, and 20% as training, validation, and testing sets, respectively. Forty-five cervical patients from another center were selected for external testing. Moreover, 70 patients of endometrial cancer with different prescriptions were further selected to test the model. Prediction precision was evaluated by dosimetric difference, dose map, and dose-volume histogram metrics. RESULTS: The prediction results were all clinically acceptable. The mean absolute error within the body in internal testing was 0.66 ± 0.63%. The maximum |δD| for planning target volume was observed in D98, which is 1.24 ± 2.73 Gy. The maximum |δD| for organs at risk was observed in Dmean of bladder, which is 4.79 ± 3.14 Gy. The maximum |δV| were observed in V40 of pelvic bones, which is 4.77 ± 4.48%. CONCLUSION: AtTranNet showed the feasibility and reasonable accuracy in the dose prediction for cervical cancer in multiple centers. The model can also be generalized for endometrial cancer with different prescriptions without any transfer learning.

[High expression of UBE2S promotes progression of hepatocellular carcinoma by increasing cancer cell stemness].

OBJECTIVE: To investigate the expression of the ubiquitination enzyme UBE2S in different cell types in hepatocellular carcinoma (HCC) microenvironment and its impact on proliferation and stemness of HCC cells. METHODS: TCGA and CPTAC database were used to analyze the transcriptional and promoter methylation levels and protein expressions of UBE2S in HCC. Specific expression patterns of UBE2S, intercellular communication and key transcription factors in different cell types were analyzed based on single-cell sequencing data from TISCH website. We further examined UBE2S expressions in clinical samples of HCC tissues, HCC cells and T cells using immunohistochemistry and immunofluorescence staining. We also tested the effects of UBE2S knockdown on stemness of HCC-LM3 and HepG2 cells using clone formation experiments and sphere formation assay. RESULTS: Analysis based on TCGA database suggested significant overexpression of UBE2S in both paired and non-paired tumor tissues (P < 0.001), and its transcriptional level increased with tumor grades. The methylation level of UBE2S promoter was significantly decreased in HCC (P < 0.001), and its transcription level increased obviously in HCC with TP53 mutation (P < 0.001). Analysis of CPTAC database also demonstrated overexpression of UBE2S protein in HCC tissues (P < 0.001). Three prognostic models suggested that HCC patients with high UBE2S expression had poorer prognosis (P < 0.001). Single-cell sequencing data analysis revealed high expressions of UBE2S in T cells and high intensities of interaction between endothelial cells, epithelial cells and fibroblasts in HCC microenvironment. Immunohistochemistry and immunofluorescence staining demonstrated high UBE2S expressions in clinical samples of HCC tissues, HCC cells and T cells. In HCC-LM3 and HepG2 cells, UBE2S knockdown significantly inhibited cell clone formation and tumor sphere formation (P < 0.05). CONCLUSION: UBE2S is highly expressed in T cells in HCC microenvironment in close correlation with a poor prognosis. High UBE2S expression promotes the stemness of HCC cells.

[Clinicopathological and molecular characteristics of esophageal carcinoma with ductal differentiation: analysis of 17 cases].

Objective: To investigate the clinicopathological features and molecular genetic characteristics of esophageal carcinoma with ductal differentiation, and to summarize the experiences in its diagnosis and treatment. Methods: A total of 17 cases of esophageal carcinoma with ductal differentiation diagnosed in Ningbo Clinical Pathological Diagnosis Center, Ningbo, China from June 2011 to December 2022 were collected. The clinical information and pathological diagnosis was reviewed. The tumor histological features and immunohistochemical results were analyzed. The next-generation sequencing was performed to detect and analyze the gene mutations in tumor samples. Results: The 17 patients included in this study were 54-77 years old, with a median age of 66 years. There were 16 males and 1 female. Among them, 9 cases were mainly carcinoma with ductal differentiation. The squamous epithelium on the tumor's surface was accompanied by high-grade intraepithelial neoplasia. The tumor and atypical squamous epithelium were transitional, and the focus was accompanied by various proportions of squamous cell carcinoma component (less than 10%). The other 8 cases were mostly squamous cell carcinoma, basaloid squamous cell carcinoma or sarcomatoid carcinoma with various degrees of tumor specific differentiation and focal area of carcinoma with ductal differentiation (less than 10%). The tumor cells in the area with ductal differentiation were mainly arranged in small tubes, while the tubes showed a double-layer structure, including the inner cells and outer cells of the lumen. Immunohistochemical results showed that the outer cells of the tumorous tubules expressed p63, p40, CK5/6 and CK34ßE12, while the inner cells expressed CK7. Compared with esophageal squamous cell carcinoma reported in the literature, the frequency of gene mutations such as MYC (P=0.002), TP63 (P=0.002), CDKN1C (P=0.002) and NFE2L2 (P=0.045) was significantly lower in this group of cases. At the signaling pathway level, the mutation frequency of NOTCH signaling pathway (P=0.041) was significantly higher, while the mutation frequencies of NRF2 pathway (P=0.013) and PI3K pathway (P=0.009) were significantly lower than that of esophageal squamous cell carcinoma. Conclusion: Esophageal carcinoma with ductal differentiation is a type of esophageal carcinoma with unique morphology, and its molecular changes are also significantly different from those of conventional esophageal squamous cell carcinoma.

Novel alternative tools for metastatic pheochromocytomas/paragangliomas prediction.

OBJECTIVE: The existing prediction models for metastasis in pheochromocytomas/paragangliomas (PPGLs) showed high heterogeneity in different centers. Therefore, this study aimed to establish new prediction models integrating multiple variables based on different algorithms. DESIGN AND METHODS: Data of patients with PPGLs undergoing surgical resection at the Peking Union Medical College Hospital from 2007 to 2022 were collected retrospectively. Patients were randomly divided into the training and testing sets in a ratio of 7:3. Subsequently, decision trees, random forest, and logistic models were constructed for metastasis prediction with the training set and Cox models for metastasis-free survival (MFS) prediction with the total population. Additionally, Ki-67 index and tumor size were transformed into categorical variables for adjusting models. The testing set was used to assess the discrimination and calibration of models and the optimal models were visualized as nomograms. Clinical characteristics and MFS were compared between patients with and without risk factors. RESULTS: A total of 198 patients with 59 cases of metastasis were included and classified into the training set (n = 138) and testing set (n = 60). Among all models, the logistic regression model showed the best discrimination for metastasis prediction with an AUC of 0.891 (95% CI, 0.793-0.990), integrating SDHB germline mutations [OR: 96.72 (95% CI, 16.61-940.79)], S-100 (-) [OR: 11.22 (95% CI, 3.04-58.51)], ATRX (-) [OR: 8.42 (95% CI, 2.73-29.24)] and Ki-67 ≥ 3% [OR: 7.98 (95% CI, 2.27-32.24)] evaluated through immunohistochemistry (IHC), and tumor size ≥ 5 cm [OR: 4.59 (95% CI, 1.34-19.13)]. The multivariate Cox model including the above risk factors also showed a high C-index of 0.860 (95% CI, 0.810-0.911) in predicting MFS after surgery. Furthermore, patients with the above risk factors showed a significantly poorer MFS (P ≤ 0.001). CONCLUSIONS: Models established in this study provided alternative and reliable tools for clinicians to predict PPGLs patients' metastasis and MFS. More importantly, this study revealed for the first time that IHC of ATRX could act as an independent predictor of metastasis in PPGLs.

Activating two-dimensional semiconductors for photocatalysis: a cross-dimensional strategy.

The emerging two-dimensional (2D) semiconductors substantially extend materials bases for versatile applications such as semiconductor photocatalysis demanding semiconductive matrices and large surface areas. The dimensionality, while endowing 2D semiconductors the unique properties to host photocatalytic functionality of pollutant removal and hydrogen evolution, hurdles the activation paths to form heterogenous photocatalysts where the photochemical processes are normally superior over these on the mono-compositional counterparts. In this perspective, we present a cross-dimensional strategy to employ thenD (n= 0-2) clusters or nanomaterials as activation partners to boost the photocatalytic activities of the 2D semiconductors. The formation principles of heterogenous photocatalysts are illustrated specifically for the 2D matrices, followed by selection criteria of them among the vast 2D database. The computer investigations are illustrated in the density functional theory route and machine learning benefitted from the vast samples in the 2D library. Synthetic realizations and characterizations of the 2D heterogenous systems are introduced with an emphasis on chemical methods and advanced techniques to understand materials and mechanistic studies. The perspective outlooks cross-dimensional activation strategies of the 2D materials for other applications such as CO2removal, and materials matrices in other dimensions which may inspire incoming research within these fields.

Targeted long-read sequencing for comprehensive detection of CYP21A2 mutations in patients with 21-hydroxylase deficiency.

BACKGROUND: 21-Hydroxylase deficiency (21-OHD) is caused by pathogenic CYP21A2 variations. CYP21A2 is arranged in tandem with its highly homologous pseudogene CYP21A1P; therefore, it is prone to mismatch and rearrangement, producing different types of complex variations. There were few reports on using only one method to detect different CYP21A2 variants simultaneously. AIMS: Targeted long-read sequencing method was used to detect all types of CYP21A2 variants in a series of patients with 21-OHD. METHODS: A total of 59 patients with 21-OHD were enrolled from Peking Union Medical College Hospital. Long-range locus-specific PCR and long-read sequencing (LRS) were performed to detect the pathogenic variants in CYP21A2. RESULTS: Copy-number variants of CYP21A2 were found in 25.4% of patients, including 5.1% with 3 copies of CYP21A2, 16.9% with 1 copy of CYP21A2, and 3.4% with 0 copy of CYP21A2. The remaining 74.6% of patients had 2 copies of CYP21A2. Pathogenic variants were identified in all 121 alleles of 59 patients. Specifically, single-nucleotide variants and small insertions/deletions (< 50 bp) were detected in 79 alleles, of which conversed from CYP21A1P were detected in 63 alleles, and rare variants were found in the other 16 alleles. Large gene conversions (> 50 bp) from pseudogene were detected in 10 alleles, and different chimeric genes (CYP21A1P/CYP21A2 or TNXA/TNXB) formed by large deletions were detected in 32 alleles. Of all variants, p.I173N was the most common variant (19.0%). CONCLUSIONS: Our study demonstrated that targeted long-read sequencing is a comprehensive method for detecting CYP21A2 variations, which is helpful for genetic diagnosis in 21-OHD patients.

Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1.

Aging can be associated with the accumulation of hypobranched glycogen molecules (polyglucosan bodies, PGBs), particularly in astrocytes of the hippocampus. While PGBs have a detrimental effect on cognition in diseases such as adult polyglucosan body disease and Lafora disease, the underlying mechanism and clinical relevance of age-related PGB accumulation remains unknown. Here, we have investigated the genetic basis and functional impact of age-related PGB accumulation in 32 fully sequenced BXD-type strains of mice which exhibit a 400-fold variation in PGB burden in 16-18 month old females. We mapped a major locus controlling PGB density in the hippocampus to chromosome 1 at 72-75 Mb (linkage of 4.9 -logP), which we defined as the Pgb1 locus. To identify potentially causal gene variants within Pgb1, we generated extensive hippocampal transcriptome datasets and identified two strong candidate genes for which mRNA correlates with PGB density-Smarcal1 and Usp37. In addition, both Smarcal1 and Usp37 contain non-synonymous allele variations likely to impact protein function. A phenome-wide association analysis highlighted a trans-regulatory effect of the Pgb1 locus on expression of Hp1bp3, a gene known to play a role in age-related changes in learning and memory. To investigate the potential impact of PGBs on cognition, we performed conditioned fear memory testing on strains displaying varying degrees of PGB burden, and a phenome-wide association scan of ~12,000 traits. Importantly, we did not find any evidence suggesting a negative impact of PGB burden on cognitive capacity. Taken together, we have identified a major modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype.

[Progress in pathophysiology research and update on diagnosis and treatment strategies for fecal incontinence].

The traditional barrier theory believes that fecal incontinence is related to an imbalance of the recto-anal barrier and the characteristics of stool. However, in clinical practice this theory proves unable to explain all types of fecal incontinence. In recent years, research on the mechanisms related to fecal incontinence has shifted to a new integrative concept with the rectum and anus as functional units, and the central-peripheral nervous system and internal and external anal sphincters as a control loop. The diagnosis and treatment strategy of fecal incontinence, which is replaced by sacral neuromodulation, is undergoing a quiet change. With the progressively aging population in China, the need to improve the diagnosis and treatment of fecal incontinence has become increasingly urgent. This article explores the trends in diagnosis and treatment and mechanism research from the perspective of recent advances in pathophysiological research and updated diagnosis and treatment methods for fecal incontinence.