NEK2 contributes to radioresistance in esophageal squamous cell carcinoma by inducing protective autophagy via regulating TRIM21.

BACKGROUND: Radiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms. METHODS: Human esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM). RESULTS: In the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21. CONCLUSION: These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.

Microascones, Decahydrofluorene-Class Alkaloids from the Marine-Derived Fungus Microascus sp. SCSIO 41821.

Eight new decahydrofluorene-class alkaloids, microascones A and B (1 and 2), 2,3-epoxyphomapyrrolidone C (3), 14,16-epiascomylactam B (4), 24-hydroxyphomapyrrolidone A (5), and microascones C-E (6-8), along with five known analogs (9-13) were isolated from the marine-derived fungus Microascus sp. SCSIO 41821. Compounds 1 and 2 have an unprecedented complex macrocyclic alkaloid skeleton with a 6/5/6/5/6/5/13 polycyclic system. Their structures and absolute configurations were determined by spectroscopic analysis, quantum chemical calculations of ECD spectra, and 13C NMR chemical shifts. Compounds 10-13 showed selective enzyme inhibitory activity against PTPSig, PTP1B, and CDC25B, and 4, 9, and 10 exhibited strong antibacterial activity against seven tested pathogens. Their structure-bioactivity relationship was discussed, and a plausible biosynthetic pathway for 1-8 was also proposed.

Prediction of positive pulmonary nodules based on machine learning algorithm combined with central carbon metabolism data.

BACKGROUND: Lung cancer causes a huge disease burden, and early detection of positive pulmonary nodules (PPNs) as an early sign of lung cancer is extremely important for effective intervention. It is necessary to develop PPNs risk recognizer based on machine learning algorithm combined with central carbon metabolomics. METHODS: The study included 2248 participants at high risk for lung cancer from the Ma'anshan Community Lung Cancer Screening cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) was used to screen 18 central carbon-related metabolites in plasma, recursive feature elimination (RFE) was used to select all 42 features, followed by five machine learning algorithms for model development. The performance of the model was evaluated using area under the receiver operator characteristic curve (AUC), accuracy, precision, recall, and F1 scores. In addition, SHapley Additive exPlanations (SHAP) was performed to assess the interpretability of the final selected model and to gain insight into the impact of features on the predicted results. RESULTS: Finally, the two prediction models based on the random forest (RF) algorithm performed best, with AUC values of 0.87 and 0.83, respectively, better than other models. We found that homogentisic acid, fumaric acid, maleic acid, hippuric acid, gluconic acid, and succinic acid played a significant role in both PPNs prediction model and NPNs vs PPNs model, while 2-oxadipic acid only played a role in the former model and phosphopyruvate only played a role in the NPNs vs PPNs model. This model demonstrates the potential of central carbon metabolism for PPNs risk prediction and identification. CONCLUSION: We developed a series of predictive models for PPNs, which can help in the early detection of PPNs and thus reduce the risk of lung cancer.

Research on adults with subthreshold depression after aerobic exercise: a resting-state fMRI study based on regional homogeneity (ReHo).

Objective: Subthreshold depression (StD)/subsyndromal depression refers to a threatening precursor to depression. Aerobic exercise is a promising self-supportive adjunctive intervention and an effective measure for StD. Our study utilizes regional homogeneity (ReHo) to investigate the impact of aerobic exercise on resting-state brain function. Methods: A total of 78 subjects, aged between 18 and 48 years, (StD group, n = 44; healthy control (HC) group, n = 34) engaged in moderate-intensity aerobic exercise 3-4 times per week for 8 weeks. Resting-state brain function and structural images were acquired before and after the exercise intervention. The ReHo method was employed to analyze abnormal changes in regional brain function, and a correlation analysis was performed using the Patient Health Questionnaire-9 (PHQ-9) and Self-Rating Anxiety Scale (SAS) scores. Results: The principal observation reveals synchronous abnormalities in the right anterior cingulate gyrus of the brain in StD subjects compared to HCs at baseline, with these differences dissipating after the implementation of aerobic exercise. After completing the aerobic exercise program, the StD group exhibited a difference in the right middle cingulate gyrus, while the left supplementary motor area (SMA) was altered in the HC group. Conclusion: Disparities in neural synchronization are evident between HCs and StD subjects, and the implementation of aerobic exercise intervention can effectively mitigate these distinctions, leading to a significant reduction in depressive symptoms among StD subjects. The primary mechanism of StD symptoms may involve the inhibition of the anterior cingulate gyrus, while the effects of aerobic exercise may be related to the modulation of neural synchronization of emotional reflexes. The discovery of these fMRI evidence findings may offer novel strategies for early detection and intervention in cases of StD.

Modulatory effects of aerobic training on the degree centrality of brain functional activity in subthreshold depression.

BACKGROUND: Aerobic training has been shown to effectively prevent the progression of depressive symptoms from subthreshold depression (StD) to major depressive disorder (MDD), and understanding how aerobic training promotes changes in neuroplasticity is essential to comprehending its antidepressant effects. Few studies, however, have quantified the alterations in spontaneous brain activity before and after aerobic training for StD. METHODS: Participants included 44 individuals with StD and 34 healthy controls (HCs). Both groups underwent moderate aerobic training for eight weeks, and resting state functional magnetic resonance imaging (rs-fMRI) data were collected before and after training. The degree centrality (DC) changes between the two groups and the DC changes in each group before and after training were quantified. RESULTS: The rs-fMRI results showed that compared with the HCs, the DC values of the StD group in the orbital region of the left inferior frontal gyrus significantly depreciated at baseline. After aerobic training, the results of the follow-up examination revealed no significant difference in the DC values between the two groups. In addition, compared with baseline, the StD group exhibited an significant decrease in the DC values of the left dorsolateral superior frontal gyrus; while the HCs group exhibited an significant decrease in the DC values of the left thalamus. No statistically significant connection was seen between changes in DC values and psychological scale scores in the StD group. CONCLUSIONS: Our findings suggest that regular aerobic training can enhance brain plasticity in StD. In addition, we demonstrated that DC is a relevant and accessible method for evaluating the functional plasticity of the brain induced by aerobic training in StD.

Prenylated indole diketopiperazine alkaloids as phosphatase inhibitors from the marine-derived fungus Talaromyces purpureogenus.

Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data including NMR, HR-ESI-MS, and electronic circular dichroism calculations, together with chemical analysis of hydrolysates. Compounds 1-5 represent the first example of spirocyclic indole diketopiperazines biosynthesized from the condensation of L-tryptophan and L-alanine. Compounds 2 and 4-5 showed selective inhibitory activities against phosphatases TCPTP and MEG2 with IC50 value of 17.9-29.7 µM, respectively. Compounds 4-5 exhibited mild cytotoxic activities against two human cancer cell lines H1975 and HepG-2.

Effects of Tibetan medicine Longdan zhike tablet on chronic obstructive pulmonary disease through MAPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Longdan zhike tablet (LDZK) is a Tibetan medicine formula commonly used in the highland region of Tibet, China, to ameliorate respiratory diseases, such as acute bronchitis and asthma. In Chinese traditional medicine, some herbal formulas with anti-inflammatory properties targeting the respiratory system are clinically adopted as supplementary therapies for chronic obstructive pulmonary disease (COPD). However, the specific anti-COPD effects of LDZK remain to be evaluated. AIM OF THE STUDY: The aim of this study is to identify the principal bioactive compounds in LDZK, and elucidate the effects and mechanisms of the LDZK on COPD. METHODS: High-resolution mass spectrometry was utilized for a comprehensive characterization of the chemical composition of LDZK. The therapeutic effects of LDZK were assessed on the LPS-papain-induced COPD mouse model, and LPS-induced activation model of A549 cells. The safety of LDZK was evaluated by orally administering a single dose of 30 g/kg to rats and monitoring physiological and biochemical indicators after a 14-day period. Network pharmacology and Western blot analysis were employed for mechanism prediction of LDZK. RESULTS: A comprehensive analysis identified a total of 45 compounds as the major constituents of LDZK. Oral administration of LDZK resulted in notable ameliorative effects in respiratory function, accompanied by reduced inflammatory cell counts and cytokine levels in the lungs of COPD mice. Acute toxicity tests demonstrated a favorable safety profile at a dose equivalent to 292 times the clinically prescribed dose. In vitro studies revealed that LDZK exhibited protective effects on A549 cells by mitigating LPS-induced cellular damage, reducing the release of NO, and downregulating the expression of iNOS, COX2, IL-1ß, IL-6, and TNF-α. Network pharmacology and Western blot analysis indicated that LDZK primarily modulated the MAPK signaling pathway and inhibited the phosphorylation of p38/ERK/JNK. CONCLUSIONS: LDZK exerts significant therapeutic effects on COPD through the regulation of the MAPK pathway, suggesting its potential as a promising adjunctive therapy for the treatment of chronic inflammation in COPD.

Correction: Identification of serum prognostic marker miRNAs and construction of microRNA-mRNA networks of esophageal cancer.

[This corrects the article DOI: 10.1371/journal.pone.0255479.].

Grey matter structural alterations in anxiety disorders: a voxel-based meta-analysis.

Anxiety disorders (ADs) are a group of prevalent and destructive mental illnesses, but the current understanding of their underlying neuropathology is still unclear. Employing voxel-based morphometry (VBM), previous studies have demonstrated several common brain regions showing grey matter volume (GMV) abnormalities. However, contradictory results have been reported among these studies. Considering that different subtypes of ADs exhibit common core symptoms despite different diagnostic criteria, and previous meta-analyses have found common core GMV-altered brain regions in ADs, the present research aimed to combine the results of individual studies to identify common GMV abnormalities in ADs. Therefore, we first performed a systematic search in PubMed, Embase, and Web of Science on studies investigating GMV differences between patients with ADs and healthy controls (HCs). Then, the anisotropic effect-size signed differential mapping (AES-SDM) was applied in this meta-analysis. A total of 24 studies (including 25 data sets) were included in the current study, and 906 patients with ADs and 1003 HCs were included. Compared with the HCs, the patients with ADs showed increased GMV in the left superior parietal gyrus, right angular gyrus, left precentral gyrus, and right lingual gyrus, and decreased GMV in the bilateral insula, bilateral thalamus, left caudate, and right putamen. In conclusion, the current study has identified some abnormal GMV brain regions that are related to the pathological mechanisms of anxiety disorders. These findings could contribute to a better understanding of the underlying neuropathology of ADs.

Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial.

Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control. Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046). Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3-35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%-90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT. Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment. Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program.

Systemic therapy with or without local intervention for oligometastatic oesophageal squamous cell carcinoma (ESO-Shanghai 13): an open-label, randomised, phase 2 trial.

BACKGROUND: The efficacy of local therapy for patients with oligometastatic oesophageal squamous cell carcinoma is unclear. We aimed to assess the efficacy of local plus systemic therapy compared with systemic therapy alone in patients with oligometastatic oesophageal squamous cell carcinoma. METHODS: The ESO-Shanghai 13 trial was a randomised, open-label, multicentre, phase 2 trial. Patients (aged ≥18 years) were recruited from six hospitals in China with histological confirmation of oligometastatic oesophageal squamous cell carcinoma with a controlled primary tumour and one to four metastatic lesions. Eligible patients were randomly assigned via a computer-generated schedule in a 1:1 ratio to receive either systemic therapy alone (ie, systemic therapy only group) or combined systemic and local therapy (ie, systemic and local therapy group). The systemic therapy regimens in both groups were at the discretion of the investigator and included chemotherapy alone, anti-PD-1 antibodies alone, or chemotherapy plus anti-PD-1 antibodies. Local therapy-radiotherapy, surgery, or thermal ablation-was delivered to all metastatic lesions for patients in the systemic and local therapy group. Randomisation was balanced dynamically on three factors: the number of disease sites, the lines of systemic therapy, and the location of the metastases. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, defined as the time from randomisation to progression or death from any cause in the intention-to-treat population. The safety population included all patients who had undergone random assignment and at least one of the intended therapies. This trial is registered with ClinicalTrials.gov, NCT03904927. The trial is ongoing but closed to new participants. FINDINGS: 116 patients were screened for enrolment between March 5, 2019, and Sept 16, 2021, and 104 patients who met the eligibility criteria were randomly assigned to the systemic and local therapy group (n=53) or the systemic therapy only group (n=51). 20 (38%) patients in the systemic plus local therapy group and 23 (45%) patients in the systemic therapy only group received anti-PD-1 antibody-based systemic therapy; three patients in the systemic and local therapy group did not receive systemic therapy. At a median follow-up of 30·5 months (IQR 24·7-37·8), median progression-free survival was 15·3 months (95% CI 10·1-20·5) in the systemic and local therapy group versus 6·4 months (5·2-7·6) in the systemic therapy only group (stratified hazard ratio 0·26 [95% CI 0·16-0·42]; stratified log rank p<0·0001). Grade 1-2 acute oesophagitis was more common in the systemic and local therapy group than in the systemic therapy only group (10 [19%] vs one [2%] patients; p=0·036). The number of patients who had grade 3 or worse treatment-related adverse events was similar between groups (25 [47%] vs 21 [41%]; p=0·538), with the most common adverse events being leukocytopenia (17 [32%] vs 18 [35%]) and neutropenia (19 [36%] vs 20 [39%]). Treatment-related deaths occurred in two patients in the systemic and local therapy group and one patient in the systemic therapy only group. INTERPRETATION: The addition of local treatment for metastases could significantly improve progression-free survival among patients with oligometastatic oesophageal squamous cell carcinoma being treated with systemic therapy. Our findings suggest that combining local and systemic therapy could be a treatment option for patients with oligometastatic oesophageal squamous cell carcinoma, but further support from phase 3 trials is required. FUNDING: Science and Technology Commission of Shanghai Municipality, National Nature Science Foundation of China, and Shanghai Municipal Health Commission. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Minimal residual disease guided radical chemoradiotherapy combined with immunotherapy after neoadjuvant immunochemotherapy followed by adjuvant immunotherapy for esophageal squamous cell cancer (ECMRD-001): a study protocol for a prospective cohort study.

Introduction: For locally advanced, inoperable esophageal cancer, concurrent chemoradiotherapy (CCRT) becomes the norm. Combining immunotherapy with radiotherapy has been shown to improve efficacy. Circulating tumor DNA (ctDNA) is a strong predictor of effectiveness and tumor recurrence and is indicative of minimal residual disease (MRD). Patients with inoperable stage II-III esophageal squamous cell carcinoma (ESCC) are enrolled in the ECMRD-001 trial to evaluate changes in MRD status before and after CCRT combined with immunotherapy and adjuvant immunotherapy following neoadjuvant immunochemotherapy. Methods and analysis: The ECMRD-001 trial is a prospective cohort study. Eligible patients will receive radical concurrent chemoradiotherapy combined with immunotherapy after neoadjuvant immunochemotherapy, followed by adjuvant immunotherapy for at least one year. Follow-up will be up to three years. MRD-related blood and tissue samples and T-cell immunohistobank related blood and tissue samples collected before, during and after treatment and follow-up will be grouped into sample collection time points. The relationship between MRD status at different time points and treatment efficacy is the primary outcome. Correlation between MRD status and immune microenvironment, radiotherapy dose, and tumor recurrence are the secondary outcomes. Examination of ctDNA mutations is the exploratory outcome. Discussion: ctDNA-based MRD may be a potential predictive marker for the efficacy and tumor recurrence of inoperable ESCC patients. Elevated ctDNA-MRD may predict tumor recurrence earlier than imaging. ctDNA-based MRD analysis and ctDNA-based MRD guided diagnosis and treatment should be implemented into clinical practice to improve efficacy and reduce tumor recurrence of inoperable stage II-III ESCC. Trial registration: The ECMRD-001 study has been registered at ClinicalTrials.gov as NCT05952661 (July 19, 2023), https://classic.clinicaltrials.gov/ct2/show/NCT05952661.

Corrigendum: The prognosis value of CONUT and SIS score for recurrent or metastatic esophageal squamous cell carcinoma patients treated with second-line immunotherapy.

[This corrects the article DOI: 10.3389/fonc.2023.1167625.].

A retrospective analysis of Stewart-Treves syndrome in the context of chronic lymphedema

Abstract Background stewart-treves syndrome (STS) is an angiosarcoma associated with chronic lymphedema. Objectives This article analyses the characteristics of twenty-two patients and proposes active intervention in lymphedema and the early diagnosis of STS. Methods Twenty-two patients with STS were diagnosed at the centre over an 11-year period. Clinical manifestations, a series of conventional analyses, and histopathology were used to study these cases retrospectively. Results The age range of 22 patients with STS was 15 to 78 years. The main clinical manifestations included multiple skin and subcutaneous nodules and scattered red or purplish-red rashes in the lymphoedematous limbs. These patients often showed clinical symptoms such as lymphedema, weakness, emaciation, pain, mass, lymphadenopathy and so on. The positive rates of ultrasonography, MRI and radionuclide imaging were 66.7% (6/9), 92.3% (12/13) and 18.2% (2/11), respectively. The main points regarding active intervention in lymphedema and early diagnosis of STS were summarized. Study limitations Since this was a retrospective study, the main points summarized by the author need to be further quantified in clinical work to guide the diagnosis of this kind of disease more conveniently. In addition, further clinical trials are needed to evaluate the role of lymphedema in the occurrence and development of malignant tumors. Conclusions STS can appear in lymphoedematous tissue many years after lymphedema onset. To avoid delays in the diagnosis and therapy of STS, physicians should actively look for signs or symptoms of malignant lymphedema during the follow-up period and promptly manage patients developing problems.