Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma.

AIMS: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC). METHODS: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4. RESULTS: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC. CONCLUSIONS: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.

Clinicopathological and immune characterization of mismatch repair deficient endocervical adenocarcinoma.

Endocervical adenocarcinoma (ECA) is reported increasingly often in young women, and this aggressive disease lacks effective methods of targeted therapy. Since mismatch repair deficiency (dMMR) is an important biomarker for predicting response to immune checkpoint inhibitors, it is important to investigate the clinicopathological features and immune microenvironment of dMMR ECAs. We assessed 617 ECAs from representative tissue microarray sections, gathered clinicopathologic information, reviewed histological characteristics, and performed immunohistochemical staining for MMR, programmed cell death 1 (PD-L1), and other immune markers. Of 617 ECA samples, 20 (3.2%) cases had dMMR. Among them, loss of MMR-related proteins expression was observed in 17/562 (3.0%) human papilloma virus-associated (HPVA) adenocarcinoma and 3/55 (5.5%) non-HPV-associated (NHPVA) adenocarcinoma. In NHPVA cohort, dMMR status was observed in 3 (3/14, 15.0%) patients with clear cells. dMMR ECAs had a higher tendency to have a family history of cancer, larger tumor size, p16 negative, HPV E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) negative, and lower ki-67 index. Among the morphological variables evaluated, poor differentiation, necrosis, stromal tumor-infiltrating lymphocytes, peritumoral lymphocytes, and lymphoid follicles were easily recognized in the dMMR ECAs. In addition, dMMR ECAs had higher CD3+, CD8+, CD38+, CD68+ and PD-1+ immune cells. A relatively high prevalence of PD-L1 expression was observed in dMMR ECAs. dMMR ECAs were significantly more likely to present with a tumor-infiltrating lymphocytes -high/PD-L1-positive status. In conclusion, dMMR ECAs have some specific morphological features and a critical impact on the immune microenvironment, which may provide insights into improving responses to immunotherapy-included comprehensive treatment for ECAs in the future.

Mining the interpretable prognostic features from pathological image of intrahepatic cholangiocarcinoma using multi-modal deep learning.

BACKGROUND: The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application. METHODS: We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations. RESULTS: The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration. CONCLUSIONS: We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.

Directed Electron Delivery from a Pb-Free Halide Perovskite to a Co(II) Molecular Catalyst Boosts CO2 Photoreduction Coupled with Water Oxidation.

The development of high-performance photocatalytic systems for CO2 reduction is appealing to address energy and environmental issues, while it is challenging to avoid using toxic metals and organic sacrificial reagents. We here immobilize a family of cobalt phthalocyanine catalysts on Pb-free halide perovskite Cs2AgBiBr6 nanosheets with delicate control on the anchors of the cobalt catalysts. Among them, the molecular hybrid photocatalyst assembled by carboxyl anchors achieves the optimal performance with an electron consumption rate of 300±13 µmol g-1 h-1 for visible-light-driven CO2-to-CO conversion coupled with water oxidation to O2, over 8 times of the unmodified Cs2AgBiBr6 (36±8 µmol g-1 h-1), also far surpassing the documented systems (<150 µmol g-1 h-1). Besides the improved intrinsic activity, electrochemical, computational, ex-/in situ X-ray photoelectron and X-ray absorption spectroscopic results indicate that the electrons photogenerated at the Bi atoms of Cs2AgBiBr6 can be directionally transferred to the cobalt catalyst via the carboxyl anchors which strongly bind to the Bi atoms, substantially facilitating the interfacial electron transfer kinetics and thereby the photocatalysis.

Selective his bundle pacing eliminates crochetage sign: A case report.

BACKGROUND: Crochetage sign is a specific electrocardiographic manifestation of ostium secundum atrial septal defects (ASDs), which is associated with the severity of the left-to-right shunt. Herein, we reported a case of selective his bundle pacing (S-HBP) that eliminated crochetage sign in a patient with ostium secundum ASD. CASE SUMMARY: A 77-year-old man was admitted with a 2-year history of chest tightness and shortness of breath. Transthoracic echocardiography revealed an ostium secundum ASD. Twelve-lead electrocardiogram revealed atrial fibrillation with a prolonged relative risk interval, incomplete right bundle branch block, and crochetage sign. The patient was diagnosed with an ostium secundum ASD, atrial fibrillation with a second-degree atrioventricular block, and heart failure. The patient was treated with selective his bundle pacemaker implantation. After the procedure, crochetage sign disappeared during his bundle pacing on the electrocardiogram. CONCLUSION: S-HBP eliminated crochetage sign on electrocardiogram. Crochetage sign may be a manifestation of a conduction system disorder.

Influence of perceived social support on detection of social norm violation: evidence from N1 and N400.

Introduction: The perceived social support individuals receive from their others plays a crucial role in shaping conformity with social norms. However, the specific mechanism underlying perceived social support and the detection of social norms remains unclear. Methods: In this study, college students with high and low levels of perceived social support were asked to judge the appropriateness of stranger's behaviors (e.g., singing) in different situations (e.g., library). The participants' electroencephalography activities were analyzed aiming to uncover the neural mechanism underlying how perceived social support influences the detection of others' normative behavior. Results: The ERP results indicate that, for individuals with a lower level of perceived social support, larger amplitudes of the N1 component (related to primary processing) and the N400 component (related to cognitive conflict) were observed when detecting others' social norm violation compared to the conformity condition. However, for individuals with a higher level of perceived social support, no significant differences were found in detecting others' conformity or violation of social norms. Discussion: The results indicate that, when the perceived social support level of the individual is low, detecting others' social norm violation elicits deeper primary processing and stronger cognitive conflict compared to conformity condition.

The dual facilitatory and inhibitory effects of social pain on physical pain perception.

Pain is a multi-dimensional phenomenon that encompasses both physical pain experienced physiologically and social pain experienced emotionally. The interactions between them are thought to lead to increased pain load. However, the effect of social pain on physical pain perception during interactions remains unclear. Four experiments were conducted merging physical and social pains to examine the behavioral pattern and neural mechanism of the effect of social pain on physical pain perception. Seemingly paradoxical effects of social pain were observed, which both facilitated and inhibited physical pain perception under different attention orientations. Brain imaging revealed that the posterior insula encoded the facilitatory effect, whereas the frontal pole engaged in the inhibitory effect. At a higher level, the thalamus further modulated both processes, playing a switch-like role under different concern statuses of social pain. These results provide direct evidence for the dual-pathway mechanism of the effect of social pain on physical pain.

Construction of a BiVO4/VS-MoS2 S-scheme heterojunction for efficient photocatalytic nitrogen fixation.

Photocatalytic nitrogen (N2) reduction to ammonia (NH3), adopting H2O as the electron source, suffers from low efficiency owing to the sluggish kinetics of N2 reduction and the requirement of a substantial thermodynamic driving force. Herein, we present a straightforward approach for the construction of an S-scheme heterojunction of BiVO4/VS-MoS2 to successfully achieve photocatalytic N2 fixation, which is manufactured by coupling an N2-activation component (VS-MoS2 nanosheet) and water-oxidation module (BiVO4 nanocrystal) through electrostatic self-assembly. The VS-MoS2 nanosheet, enriched with sulfur vacancies, plays a pivotal role in facilitating N2 adsorption and activation. Additionally, the construction of the S-scheme heterojunction enhances the driving force for water oxidation and improves charge separation. Under simulated sunlight irradiation (100 mW cm-2), BiVO4/VS-MoS2 exhibits efficient photocatalytic N2 reduction activity with H2O as the proton source, yielding NH3 at a rate of 132.8 µmol g-1 h-1, nearly 7 times higher than that of pure VS-MoS2. This study serves as a noteworthy example of efficient N2 reduction to NH3 under mild conditions.

First record of the spider family Trechaleidae Simon, 1890 (Araneae) from China.

The family Trechaleidae Simon, 1890 is reported for the first time from China, including one new species: Shinobiuscona sp. nov. (♂♀). Morphological descriptions, photos and illustrations of the new species are provided. Taxonomic features of species belonging to the genus are briefly discussed. Photos of the female of Shinobiusorientalis (Yaginuma, 1967) are also presented to compare it with the new species.

Diagnosis of Alzheimer's disease: Towards accuracy and accessibility.

Alzheimer's disease (AD) is a serious dementia afflicting aging population and is characterized by cognitive decline, amyloid-ß plaques, and neurofibrillary tangles. AD substantially impairs the life quality of the victims and poses a heavy burden on the society at large. The number of people with dementia due to AD, prodromal AD, and preclinical AD is estimated to stand at roughly 3.2, 69, and 315 million worldwide, respectively. Current clinical diagnosis is based on clinical symptoms, and clinical research demonstrated that positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers had excellent diagnostic performance. However, the application of CSF biomarker tests and PET are restricted by the invasiveness and high cost. The presence of clinical symptoms means that AD pathology has been progressing for many years, and only a few drugs have been approved for the traetemnt of AD. Therefore, early diagnosis is extremely important for controlling the outcomes caused by AD. In this review, we provided an overview of developing clinical diagnostic criteria, diagnostic strategies under clinical research, developing blood based-biomarker assays, and promising nanotechnologically-based assays.

Ant-eating spiders from Xizang, China (Araneae, Zodariidae).

Six species of the ant-eating spider of the family Zodariidae are described from Xizang, China, including five new species: Asceuachayusp. nov. (♀), A.dawaisp. nov. (♂♀), Mallinellamigusp. nov. (♂), M.mеdogsp. nov. (♂♀), and M.yadongsp. nov. (♂♀). The female of Cydrelalinzhiensis (Hu, 2001) is described here for the first time. Descriptions and photographs of all the species are provided.

Matrix-assisted laser desorption ionization mass spectrometry imaging reveals the spatial distribution of compounds that may exacerbate inflammation in garden ginseng and ginseng under forest.

Ginseng, a highly esteemed herbal medicine, has been utilized over 5000 years, predominantly in Far Eastern countries. Ginseng is categorized into garden ginseng (GG) and ginseng under forest (FG). However, in contrast to FG, excessive intake of GG may lead to potential adverse effects due to disruption of epithelial cell integrity, and the specific population groups that may be at higher risk. In this work, untargeted metabolomics were used to determine the heterogeneity between GG and FG, the data indicates that the content of Ethyl caffeate, Homoorientin, Citric acid and Quinic acid in GG were higher than in FG. Mass spectrometry imaging showed that ethyl caffeate and Homoorientin were concentrated on the brownish yellow exocarp of the primary root. Our experiments demonstrated that excessive exposure to ethyl caffeate and Homoorientin exacerbated the inflammatory response of HUVECs and reduced the expression of cell junctions. This suggest that the compounds causing adverse effects from excessive intake of GG are mainly concentrated in the yellow exocarp of the primary root of GG. These results suggest that untargeted metabolomics coupled with MALDI-MSI can visualize the spatial distribution of endogenous differential molecules of the same herb in different growth environments or developmental stages.

Efficacy and safety of non-cross-linked hyaluronic acid compound in the treatment of keratosis pilaris: A split-body randomized clinical trial.

BACKGROUND: Keratosis pilaris (KP) is a prevalent benign dermatological condition characterized by small bumps at the hair follicles alongside surrounding redness, significantly impacting both aesthetics and mental well-being. OBJECTIVE: This study investigated the potential benefits of a non-cross-linked hyaluronic acid (HA) compound for treating KP. METHODS: A split-body, investigator-blinded, randomized, intraindividual comparative clinical trial was conducted. The non-cross-linked HA compound was injected into KP-affected regions on both upper arms. The treatment was delivered across four sessions scheduled at 4-week intervals. Blinded physicians and patients assessed differences in erythema, skin roughness, and overall scores between treated and control areas at the final follow-up visit. At the 12th and 24th weeks post-treatment, a four-point scale was utilized to assess subjects' perceived treatment efficacy. Additionally, dermoscopic images, histological alterations, and adverse events were monitored. RESULTS: Physician assessments revealed a significant reduction in roughness and overall scores for treated areas compared to controls. Patient self-assessments also reflected improvements in roughness, redness, and overall scores for treated sides at the final visit, with 35.71% of patients demonstrating sustained improvement in redness and 71.43% reporting persistent improvements in roughness at 24th weeks post-treatment. The dermatoscopic examinations revealed a notable enhancement in both the quantity of follicular plugs and the extent of erythema among the subjects in the treatment group. Histopathological outcomes also demonstrated improvement. CONCLUSION: This study suggests that the non-cross-linked HA compound effectively improves skin roughness and promotes hair shaft growth in KP treatment, demonstrating a favorable safety profile. These findings position it as a potentially viable alternative therapy in clinical practice.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

A multi-classifier system integrated by clinico-histology-genomic analysis for predicting recurrence of papillary renal cell carcinoma.

Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.

Two cardenolide glycosides from the seed fairs of Asclepias curassavica and their cytotoxic activities / 中国天然药物

Two cardenolide glycosides, corotoxigenin 3-O-[β-D-glucopyranosyl-(1→4)-6-deoxy-β-D-glucopyranoside] (1) and coroglaucigenin 3-O-[β-D-glucopyranosyl-(1→4)-6-deoxy-β-D-glucopyranoside] (2), were isolated from the seed fairs of Asclepias curassavica. The structures of 1-2 were determined based on the combination of the analysis of their MS, NMR spectroscopic data and acid hydrolysis. The inhibitory effects of compounds 1 and 2 on human colorectal carcinoma cells (HCT116), non-small cell lung carcinoma cells (A549) and hepatic cancer cells (SMMC-7721) were evaluated. The results showed that both compounds 1 and 2 significantly inhibited the viability, proliferation, and migration of A549, HCT116 and SMMC-7721 cells, suggesting that compounds 1 and 2 can be applied in the treatment of lung, colon and liver cancers in clinical practice. This study may not only provide a scientific basis for clarifying the active ingredients in A. curassavica, but also help to understand its antitumor activity, which can promote the application of A. curassavica in clinical treatment of various cancers.

Chinese herbal medicines for prevention and treatment of colorectal cancer: From molecular mechanisms to potential clinical applications / 中西医结合学报

Worldwide, colorectal cancer (CRC) is one of the most common malignant tumors, leading to immense social and economic burdens. Currently, the main treatments for CRC include surgery, chemotherapy, radiotherapy and immunotherapy. Despite advances in the diagnosis and treatment of CRC, the prognosis for CRC patients remains poor. Furthermore, the occurrence of side effects and toxicities severely limits the clinical use of these therapies. Therefore, alternative medications with high efficacy but few side effects are needed. An increasing number of modern pharmacological studies and clinical trials have supported the effectiveness of Chinese herbal medicines (CHMs) for the prevention and treatment of CRC. CHMs may be able to effectively reduce the risk of CRC, alleviate the adverse reactions caused by chemotherapy, and prolong the survival time of patients with advanced CRC. Studies of molecular mechanisms have provided deeper insight into the roles of molecules from CHMs in treating CRC. This paper summarizes the current understanding of the use of CHMs for the prevention and treatment of CRC, the main molecular mechanisms involved in these processes, the role of CHMs in modulating chemotherapy-induced adverse reactions, and CHM's potential role in epigenetic regulation of CRC. The current study provides beneficial information on the use of CHMs for the prevention and treatment of CRC in the clinic, and suggests novel directions for new drug discovery against CRC.

Chinese herbal medicines for prevention and treatment of colorectal cancer: From molecular mechanisms to potential clinical applications / 中西医结合学报

Worldwide, colorectal cancer (CRC) is one of the most common malignant tumors, leading to immense social and economic burdens. Currently, the main treatments for CRC include surgery, chemotherapy, radiotherapy and immunotherapy. Despite advances in the diagnosis and treatment of CRC, the prognosis for CRC patients remains poor. Furthermore, the occurrence of side effects and toxicities severely limits the clinical use of these therapies. Therefore, alternative medications with high efficacy but few side effects are needed. An increasing number of modern pharmacological studies and clinical trials have supported the effectiveness of Chinese herbal medicines (CHMs) for the prevention and treatment of CRC. CHMs may be able to effectively reduce the risk of CRC, alleviate the adverse reactions caused by chemotherapy, and prolong the survival time of patients with advanced CRC. Studies of molecular mechanisms have provided deeper insight into the roles of molecules from CHMs in treating CRC. This paper summarizes the current understanding of the use of CHMs for the prevention and treatment of CRC, the main molecular mechanisms involved in these processes, the role of CHMs in modulating chemotherapy-induced adverse reactions, and CHM's potential role in epigenetic regulation of CRC. The current study provides beneficial information on the use of CHMs for the prevention and treatment of CRC in the clinic, and suggests novel directions for new drug discovery against CRC.