Hypoxia differently regulates the proportion of ALDHhi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/ß-catenin pathway.

BACKGROUND: Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self-renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non-small cell lung cancer (NSCLC) remains unclear. METHODS: The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit ß-catenin while pcDNA3-ß-catenin (S33Y) plasmid enhanced the expression of ß-catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real-time PCR. RESULTS: We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, ß-catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by ß-catenin inhibitor or siRNA knockdown, whereas increased after ß-catenin overexpression. Furthermore, hypoxia treatment suppressed E-cadherin expression in H520 cells and enhanced N-cadherin and ß-catenin expression, while this effect was completely opposite in A549 cells. CONCLUSION: The hypoxia-EMT-ß-catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

Schaumann bodies deposited along myenteric plexus of the muscularis propria is a unique histopathological feature of Crohn's disease.

AIMS: Schaumann bodies were first identified in sarcoidosis by Dr Schaumann in 1941. They were also detected in 10% of Crohn's disease (CD) cases in a study involving patients with surgically resected CD. However, the characteristics and significance of Schaumann bodies in CD have yet to be fully elucidated. This study aimed to determine the pathological features and diagnostic significance of Schaumann bodies in various bowel diseases. METHODS: Overall, 278 bowel specimens were collected from patients with CD, intestinal tuberculosis, ulcerative colitis, intestinal schistosomiasis, diverticulosis and idiopathic mesenteric vasculopathy. The frequency, pathology and clinical features of patients with Schaumann bodies were studied. RESULTS: Schaumann bodies were present exclusively in CD (27.0%, 38 of 141) and were not detected in other intestinal diseases within the series. In CD, Schaumann bodies were deposited along the myenteric plexus of the muscularis propria (84.2%, 32 of 38). These bodies were small (diameter: 60.3±32.7 µm) and exhibited a low density in the intestinal wall (1.1±0.4 per low-power field). The majority were located within the cytoplasm of multinucleated giant cells (84.2%, 32 of 38) and were not found within or adjacent to granulomas. Notably, the number of female patients with CD and Schaumann bodies was higher than that of males. CONCLUSION: Schaumann bodies are common in resected CD specimens, and their characteristic deposition pattern may serve as a diagnostic indication for CD.

Efficacy of immune checkpoint inhibitors in non-small cell lung cancer with NTRK family mutations.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients harboring neurotrophin receptor kinase (NTRK) family mutations remains obscure. METHODS: The Zehir cohort from cBioPortal was used to analyze the mutations (MT) frequency of NTRK family in patients with NSCLC, and their correlation with clinical characteristics and patient survival. The influence of NTRK MT on ICIs efficacy was evaluated in ICIs-treated patients from Samstein cohort and further validated by use of data from OAK/POPLAR cohort. RESULTS: In the Zehir cohort, a significant difference was observed in median overall survival (mOS) between patients with NTRK MT and wild-type (WT) (mOS: 18.97 vs. 21.27 months, HR = 1.34, 95%CI 1.00-1.78; log-rank P = 0.047). In Samstein cohort, the mOS of NTRK mutant patients receiving ICIs has improved compared to WT patients (mOS: 21.00 vs. 11.00 months, log-rank P = 0.103). Notably, in subgroup analysis, ICIs significantly prolonged mOS in patients with NTRK3 MT than in WT patients (mOS: not available vs. 11.00 months, HR = 0.36, 95%CI 0.16-0.81; log-rank P = 0.009). Identical mOS between NTRK MT and WT patients receiving ICIs treatment (mOS: 13.24 vs. 13.50 months, log-rank P = 0.775) was observed in OAK/POPLAR cohort. Moreover, a similar programmed death ligand 1 (PD-L1) expression, but higher tumor mutational burden (TMB), blood TMB (bTMB) and enriched anti-tumor immunity were observed in NTRK MT compared to WT (P < 0.05). CONCLUSION: Taking high TMB or bTMB into consideration, patients with NTRK mutant NSCLC could benefit from ICIs treatment.

Changes in brain structure and related functional connectivity during menstruation in women with primary dysmenorrhea.

Background: Neuroimaging studies have identified altered brain structures and functions in women with primary dysmenorrhea (PDM). However, previous studies focused on either structural or functional changes in specific brain regions rather than combining structural and functional analysis. Therefore, this prospective cross-sectional study aimed to investigate the changes in whole brain structure, and functional variation along with structural abnormalities in women with PDM during menstruation. Methods: In all, 31 patients with PDM (PTs) and 31 healthy controls (HCs) were recruited. Voxel-based morphometry (VBM) and surface-based morphometry (SBM) analyses were applied to investigate structural changes based on high-resolution T1-weighted magnetic resonance images. Functional connectivity (FC) analysis was performed to evaluate functional variations related to the brain regions that showed structural group differences. Pearson correlation analysis was performed to assess the relationship between neuroimaging changes and clinical measures. Results: Compared to HCs, PTs had reduced gray matter volume (GMV) in the right superior temporal gyrus (STG) and reduced thickness in the bilateral orbitofrontal cortex (OFC), left postcentral gyrus (PoCG), and left superior occipital gyrus (SOG). Among these areas, the STG and PoCG are responsible for altered resting-state FC patterns in PTs. Results showed decreased FC between the STG and the left cerebellar posterior lobe (poCb), the right dorsolateral prefrontal cortex (DLPFC), and the left precentral gyrus (PrCG). Results also showed decreased FC between the PoCG and the right precuneus and the right DLPFC. We also found greater FCs between the PoCG and the bilateral poCb, the left middle temporal gyrus (MTG), and the left angular gyrus. In addition, the FCs between the STG and poCb, and DLPFC in PTs were positively correlated with history and Cox menstrual symptom scale (CMSS) scores, respectively, while the FCs between STG and PrCG were negatively correlated with the onset age of PDM. Conclusions: Our research found structural abnormalities and related FC changes in several brain regions that were mainly involved in the emotional and sensory aspects of menstrual pain in PDM. These findings could help us understand the occurrence of PDM from a neuroimaging perspective.

The safety profile of EGFR/ALK-TKIs administered immediately before or after ICIs in advanced NSCLC.

BACKGROUND: As more therapeutic targets are being discovered in advanced non-small cell lung cancer (NSCLC), it is pivotal for clinicians to correctly sequence immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for delivery of safe and effective treatment. Our present study aimed to assess the safety profile of sequential treatment of TKIs and ICIs in advanced NSCLC. METHODS: We retrospectively analyzed the data of 64 patients who underwent sequential treatment of EGFR/ALK-TKIs and ICIs, including all the EGFR/ALK-TKIs and ICIs approved by National Medical Products Administration (NMPA) in China. RESULTS: The decrease in hemoglobin was the most common adverse event (54.5 % and 44.4 %) for all patients. For TKIs post-treatment with ICIs group, the incidence rate of decrease in white blood cells was 32.7 %. Liver toxicity was also common for this sequential therapy: treatment-related elevation in ALT (30.9 %) and AST (25.5 %). In addition, grade 3 or higher skin toxicity occurred in 2 patients, and grade 3 or higher neuritis was observed in 1 patient. Interstitial pneumonia was also observed in 1 patient. For patients within the group of TKIs pre-treatment with ICIs, the most common adverse event was hepatic toxicity, the elevation in ALT and AST was 33.3 % and 22.2 % respectively. It was worth noting that the incidence rate of grade 3 or higher elevation in ALT and AST was 22.2 %. Other adverse events such as blood toxicity, skin rash, and diarrhea were also observed in this sequential treatment, but most of which was slight. CONCLUSION: Although the adverse event did not significantly increase in the sequential treatment pattern of our study, careful consideration should be given to the possibility of an increased risk of some adverse event when TKIs were pre/post-treated with ICIs.

Advances in pharmacokinetics and pharmacodynamics of PD-1/PD-L1 inhibitors.

Immune checkpoint inhibitors (ICIs) are a group of drugs designed to improve the therapeutic effects on various types of malignant tumors. Irrespective of monotherapy or combinational therapies as first-line and later-line therapy, ICIs have achieved benefits for various tumors. Programmed cell death protein-1 (PD-1) / ligand 1 (PD-L1) is an immune checkpoint that suppresses antitumor immunity, especially in the tumor microenvironment (TME). PD-1/PD-L1 immune checkpoint inhibitors block tumor-related downregulation of the immune system, thereby enhancing antitumor immunity. In comparison with traditional small-molecule drugs, ICIs exhibit pharmacokinetic characteristics owing to their high molecular weight. Furthermore, different types of ICIs exhibit different pharmacodynamic characteristics. Hence, ICIs have been approved for different indications by the Food and Drug Administration (FDA) and National Medical Products Administration (NMPA). This review summarizes pharmacokinetic and pharmacodynamic studies of PD-1/ PD-L1 inhibitors to provide a reference for rational clinical application.

Lower limb balance characteristics during tai chi chuan / Características de equilíbrio dos membros inferiores durante o tai chi chuan / Características del equilibrio de los miembros inferiores durante el tai chi chuan

ABSTRACT Introduction: Tai chi chuan training claims to not only promote the circulation of internal energy in the body to achieve a preventive and healing effect of diseases, but also to improve static and dynamic body balance. While the former claims are not validable, the question about the effectiveness of improving balance remains valid. Objective: Verify the characteristics of lower limb balance during tai chi chuan practice. Methods: Selected volunteers underwent a bioelectricity testing system via noninvasive surface electromyography to evaluate muscle activity during the exercises. The results were collected, cataloged and statistically work on corresponding graphs according to different content of literature research for objective analysis. Results: The variation of the displacement of the center of gravity was controlled within 0.1M, the most unstable time of the center of gravity was about 0.65s before the start of balance. In temporal terms, it is found that the order of discharge of each muscle tested in the vertical balance and unilateral support was as follows: the tibialis anterior muscle discharges first, the rectus femoris and biceps femoris second, finally gastrocnemius, gluteus medius and gluteus maximus joint discharge almost at the same time. Conclusion: Some benefit is perceived in the validity of improving lateral balance velocity, shortening the action completion time, and improving balance stability, improving the quality of action in practitioners of this exercise modality. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O treinamento do tai chi chuan alega não só promover a circulação de energia interna no corpo para alcançar um efeito preventivo e curador de doenças, mas também aprimorar o equilíbrio estático e dinâmico corporal. Enquanto as primeiras afirmações não são validáveis, o questionamento sobre a eficácia no aprimoramento do equilíbrio permanece válido. Objetivo: Verificar as características do equilíbrio nos membros inferiores durante a prática do tai chi chuan. Métodos: Voluntários selecionados passaram por um sistema de testes com bioeletricidade via eletromiografia superficial não invasiva para avaliar a atividade muscular durante os exercícios. Os resultados foram coletados, catalogados e estatisticamente trabalhos sobre gráficos correspondentes, de acordo com diferentes conteúdos de pesquisa literária, para análise objetiva. Resultados: A variação do deslocamento do centro gravitacional foi controlada dentro de 0,1M, o tempo mais instável do centro de gravidade foi cerca de 0,65s antes do início do equilíbrio. Em termos temporais, constata-se que a ordem de descarga de cada músculo testado no equilíbrio vertical e apoio unilateral foi a seguinte: o músculo tibial anterior descarrega primeiro, o reto femoral e bíceps femoral em segundo lugar, finalmente conjunto gastrocnêmico, glúteos médios e glúteo máximo descarregam quase ao mesmo tempo. Conclusão: Percebe-se algum benefício na validade de aprimorar a velocidade de balanço lateral, encurtar o tempo de conclusão da ação e melhorar a estabilidade do equilíbrio, melhorando a qualidade da ação em praticantes dessa modalidade de exercício. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El entrenamiento de Tai chi chuan pretende no sólo promover la circulación de la energía interna en el cuerpo para lograr un efecto preventivo y curativo contra las enfermedades, sino también mejorar el equilibrio corporal estático y dinámico. Mientras que las primeras afirmaciones no son válidas, la pregunta sobre la eficacia de la mejora del equilibrio sigue siendo válida. Objetivo: Verificar las características del equilibrio de los miembros inferiores durante la práctica del tai chi chuan. Métodos: Los voluntarios seleccionados se sometieron a un sistema de pruebas de bioelectricidad mediante electromiografía de superficie no invasiva para evaluar la actividad muscular durante los ejercicios. Los resultados fueron recogidos, catalogados y trabajados estadísticamente en los gráficos correspondientes según los diferentes contenidos de la investigación literaria para su análisis objetivo. Resultados: La variación del desplazamiento del centro de gravedad se controló dentro de 0,1M, el tiempo más inestable del centro de gravedad fue de unos 0,65s antes del inicio del equilibrio. En términos temporales, se encontró que el orden de descarga de cada músculo probado en el equilibrio vertical y el apoyo unilateral fue el siguiente: el músculo tibial anterior descarga primero, el recto femoral y el bíceps femoral segundo, finalmente el gastrocnemio, el glúteo medio y el glúteo mayor descargan casi al mismo tiempo. Conclusión: Se percibe algún beneficio en la validez de mejorar la velocidad de equilibrio lateral, acortar el tiempo de finalización de la acción y mejorar la estabilidad del equilibrio, mejorando la calidad de la acción en los practicantes de esta modalidad de ejercicio. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

ANK2 as a novel predictive biomarker for immune checkpoint inhibitors and its correlation with antitumor immunity in lung adenocarcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to significantly improve the survival of patients with advanced lung adenocarcinoma (LUAD). However, only limited proportion of patients could benefit from ICIs. Novel biomarkers with strong predictability are needed for clinicians to maximize the efficacy of ICIs. Our study aimed to identify potential biomarkers predicting ICIs efficacy in LUAD. METHODS: The Cancer Genome Atlas (TCGA) PanCancer Atlas studies in cBioportal were used to evaluate the mutation frequency of ANK2 across multiple cancers. Clinical and mutational data for LUAD from ICIs-treated cohorts (Hellmann et al. and Rizvi et al.) were collected to explore the correlation between ANK2 mutation and clinical outcomes. In addition, the relationship between ANK2 expression and clinical outcomes was analyzed using LUAD data from TCGA and Gene Expression Omnibus. Furthermore, the impact of ANK2 mutation and expression on the tumor immune microenvironment of LUAD was analyzed using TCGA and TISIDB databases. RESULTS: Patients with ANK2 mutation benefited more from ICIs. In ICIs-treated cohort, prolonged progression-free survival (PFS) (median PFS: NR (not reached) vs. 5.42 months, HR (hazard ratio) 0.31, 95% CI 0.18-0.54; P = 0.0037), improved complete response rate (17.65% vs. 1.85%, P = 0.0402), and improved objective response rate (64.71% vs. 24.07%, P = 0.0033) were observed in LUAD patients with ANK2 mutation compared to their wild-type counterparts. Regarding ANK2 expression, it was observed that ANK2 expression was decreased in LUAD (P < 0.05) and a higher level of ANK2 expression was associated with longer overall survival (HR 0.69, 95% CI 0.52-0.92; P = 0.012) in TCGA LUAD cohort. Moreover, ANK2 mutation or higher ANK2 expression correlated with enhanced antitumor immunity and "hot" tumor microenvironment in LUAD, which could be potential mechanisms that ANK2 mutation facilitated ICIs therapy and patients with higher ANK2 expression survived longer. CONCLUSION: Our findings suggest that ANK2 mutation or increased ANK2 expression may serve as a favorable biomarker for the efficacy of ICIs in patients with LUAD.

Carbon Dot-Anchored Cobalt Oxyhydroxide Composite-Based Hydrogel Sensor for On-Site Monitoring of Organophosphorus Pesticides.

The development of a portable, quantitative, and user-friendly sensor for on-site monitoring of organophosphorus pesticides (OPs) is significantly urgent to guarantee food safety. Herein, a carbon dot/cobalt oxyhydroxide composite (CD/CoOOH)-based fluorescent hydrogel sensor is constructed for precisely quantifying OPs using a homemade portable auxiliary device. As a fluorescence signal indicator, the orange-emissive CD/CoOOH composite is encapsulated into an agarose hydrogel kit for amplifying the detection signals, shielding background interference, and enhancing stability. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the substrate to produce thiocholine, which induces the decomposition of CoOOH and makes the fluorescence enhancement of the hydrogel platform possible. OPs can specifically block the AChE activity to limit thiocholine production, resulting in a decrease in platform fluorescence. The image color of the fluorescent hydrogel kit is transformed into digital information using a homemade auxiliary device, achieving on-site quantitative detection of paraoxon (model target) with a detection limit of 10 ng mL-1. Harnessing CD/CoOOH composite signatures, hydrogel encapsulation, and portable optical devices, the proposed fluorescence hydrogel platform demonstrated high sensitivity and good anti-interference performance in agricultural sample analysis, indicating considerable potential in the on-site application.

Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma.

Background: The emergence of immune checkpoint inhibitors (ICIs) has significantly improved the clinical outcomes of patients with metastatic melanoma. However, survival benefits are only observed in a subset of patients. The fibroblast growth factor receptor (FGFR) family genes are frequently mutated in melanoma, yet their impacts on the efficacy of ICIs remain unclear. Our study aimed to explore the association of FGFR mutations with ICIs efficacy in metastatic melanoma. Methods: The Cancer Genome Atlas (TCGA) data (PanCancer Atlas, skin cutaneous melanoma (SKCM), n = 448) in cBioPortal were collected as a TCGA cohort to investigate the association between FGFR mutations and prognosis of melanoma patients. To explore the impact of FGFR mutations on the efficacy of ICIs in melanoma, clinical and tumor whole-exome sequencing (WES) data of four ICI-treated studies from cBioPortal were consolidated as an ICIs-treated cohort. Moreover, the relationship between FGFR mutations and immunogenicity (tumor mutation burden (TMB), neo-antigen load (NAL), mismatch repair (MMR)-related genes and DNA damage repair (DDR)-related genes) of melanoma was evaluated utilizing data from the ICIs-treated cohort. The influence of FGFR mutations on the tumor immune microenvironment (TIME) of melanoma was also analyzed using the TCGA cohort. Results: In the TCGA cohort, survival in melanoma patients with or without FGFR mutations was nearly equivalent. In the ICIs-treated cohort, patients with FGFR mutations had better survival than those without (median overall survival: 60.00 vs. 31.00 months; hazard ratio: 0.58, 95% CI: 0.42-0.80; P = 0.0051). Besides, the objective response rate was higher for patients harboring FGFR mutations (55.56%) compared to wild-type patients (22.40%) (P = 0.0076). Mechanistically, it was revealed that FGFR mutations correlated with increased immunogenicity (e.g., TMB, NAL, MMR-related gene mutations and DDR-related gene mutations). Meanwhile, FGFR mutant melanoma tended to exhibit an enhanced antitumor TIME compared with its wild-type counterparts. Conclusions: Our study demonstrated that FGFR mutations is a promising biomarker in stratifying patients with advanced melanoma who might benefit from ICIs therapy.

Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors.

Background: Although immune checkpoint inhibitors (ICIs) generally show poor therapeutic efficacy in patients with epidermal growth factor receptor (EGFR) mutations, certain research indicate that a small proportion of these patients do respond to ICIs. The present study sought to identify the features of patients with EGFR mutations who might benefit from ICIs from multiple studies and discussed the optimal treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. Methods: The profiles of 114 advanced NSCLC patients with EGFR mutations who received ICIs treatment were retrospectively reviewed. EGFR subtypes, programmed cell death ligand 1 (PD-L1) expression, and clinical characteristics regarding their impact on the efficacy of ICIs were investigated. Results: Patients with major EGFR mutations (L858R or 19Del) had a shorter progression-free survival (PFS) and a lower objective response rate (ORR) as compared to patients with rare (20ins or G719X) and other EGFR mutations. Although not statistically significant, median overall survival (OS) tended to be longer in patients with negative (<1%) PD-L1 expression than with positive (≥1%) PD-L1 expression (15.61 vs. 7.40 months, p = 0.138). Median PFS and OS were significantly shorter in heavily treated patients (prior lines of therapy ≥3 lines vs. <3 lines: mPFS, 1.80 vs. 2.50 months, p = 0.003; mOS, 6.70 vs. 14.00 months, p = 0.031). ORR was also lower in patients who had received ≥3 prior lines of therapy compared to in those <3 prior lines of therapy (0.00% vs. 21.67%, p = 0.002). Conclusion: Patients with major EGFR mutations showed poorer responses to ICIs than those with rare EGFR mutations. EGFR-mutated patients with lower PD-L1 expression showed a trend towards a longer OS after receiving ICIs. ICIs should be administered as early as possible to previously treated EGFR-mutated NSCLC patients. ICI-based combined therapies may be a direction for treatment of these patient subtypes in the future.

Tumor-infiltrating neutrophils and peripheral neutrophil-to-lymphocyte ratio conversely predicted the prognosis of patients with non-small cell lung cancer.

Increasing evidence indicates that neutrophil-associated prognostic markers, such as, tumor-associated neutrophils (TANs), neutrophil-to-T cell ratio (NTR) and neutrophil-to-lymphocyte ratio (NLR), are strongly correlated with the survival of patients with non-small cell lung cancer (NSCLC). However, either the association or the difference in their predictive efficacies remains unknown. To this aim, we investigated the influence of intratumoural TANs and peripheral NLR on the clinical outcome of NSCLC patients using tumor tissues, peripheral blood indexes, and clinicopathological data of 133 patients diagnosed with NSCLC. Additionally, Kendall correlation analysis was performed to identify the association between TANs and NLR. Our results revealed that intratumoural TANs were effective prognostic factors for favorable overall survival (OS), but were not associated with disease-free survival (DFS) in the subgroup analysis of 84 postoperative patients and progression-free survival (PFS) in 49 non-resectable NSCLC patients. Elevated NTR also indicated favorable prognosis, with high intratumoural NTR being correlated with prolonged OS and high stromal NTR being correlated with prolonged DFS. In contrast, peripheral NLR predicted dismal OS and DFS of patients receiving curative surgery. Furthermore, neither intratumoural nor stromal TANs were found to be associated with NLR, indicating that they were independent inflammatory indexes in predicting the prognosis of NSCLC. In conclusion, we discovered that TANs and NLR independently and oppositely predicted the clinical outcome of NSCLC patients, providing new sights on the role of neutrophil in tumor biology and survival prediction.

Comparison of the efficacy and safety of first-line treatments based on clinicopathological characteristics for patients with advanced epidermal growth factor receptor mutated non-small-cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: A growing number of regimens have been approved as first-line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer. However, the optimal regimen has not been determined, especially for patients with different clinicopathological characteristics. Therefore, we performed this meta-analysis to compare the efficacy and safety of first-line treatments for patients with EGFR-mutated NSCLC based on clinicopathological characteristics, thereby providing evidence for individual patient clinical decision-making. METHODS: The PubMed, Embase, Cochrane Library databases, and abstracts of ASCO, ESMO, and WCLC were searched from inception to 3 June 2021 to identify eligible randomized controlled trials (RCTs). The outcomes of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs) were compared and ranked based on various clinicopathological characteristics among 14 regimens by network meta-analysis (NMA) and the surface under the cumulative ranking curve (SUCRA), respectively. RESULTS: 25 RCTs were included, with a total of 6965 patients and 14 treatment regimens. The primary endpoint of all RCTs was PFS, and OS, ORR, and ≥3AEs were secondary endpoints. Regarding overall patients, the most distinct PFS benefit was observed in osimertinib (OSI), with the fewest ≥3AEs, whereas gefitinib plus pemetrexed-based chemotherapy (GEF+PB) provided the greatest benefit for OS. When considering EGFR mutation type, aumolertinib (AUM) and GEF+PB could be the optimal regimens in terms of PFS for patients with EGFR 19DEL and EGFR 21L858R, respectively. Notably, the efficacy of the 14 regimens for PFS varied across clinicopathological characteristics, with GEP+PB ranking first in Eastern Cooperative Oncology Group performance status (ECOG PS)= 1, Asian, age＜65 and smoking subgroups, with AUM ranking first in ECOG PS= 0 and female subgroups, with ICO+PB ranking first in age ≥65 and no smoking subgroups, and with AFA+CET ranking first in the male subgroup. In terms of brain metastases, third-generation EGFR-TKI showed obvious superiority, with AUM and OSI optimally prolonging PFS in patients with and without brain metastases, respectively. In addition, GEF+PB is a superior alternative, ranking second in terms of PFS regardless of the presence of brain metastases. CONCLUSIONS: OSI and GEF+PB were the most two effective first-line regimens for overall patients, ranking first in PFS and OS, respectively. GEF+PB ranked first in terms of PFS in subgroups of EGFR 21L858R, ECOG PS= 1, Asian, age <65, and smoking. Meanwhile, AUM in subgroups of EGFR 19DEL, ECOG PS= 0, female, brain metastasis, OSI in the subgroup of without brain metastasis, ICO+PB in no smoking subgroup, and AFA+CET in male subgroup were the best options as for their evident superiority in PFS.

Recent Advancements of Monotherapy, Combination, and Sequential Treatment of EGFR/ALK-TKIs and ICIs in Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths with high morbidity and mortality. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 85% of all cases. Fortunately, the development of molecular oncology provides a promising and effective therapeutic strategy for lung cancers, including specific gene mutations/translocations and immune checkpoints, with epidermal growth factor receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later as the targeted therapy and immune checkpoint inhibitors (ICIs) as immunotherapy. This review summarized the recent therapy advancements of TKIs and ICIs in NSCLC and focused on the clinical effect of combination or sequential treatment so as to provide the effective advice for the treatment of NSCLC.

CDC25C as a Predictive Biomarker for Immune Checkpoint Inhibitors in Patients With Lung Adenocarcinoma.

The application of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer has significantly improved patient survival. However, most patients fail to respond to ICIs or develop drug resistance during treatment. Therefore, novel biomarkers are needed to predict the efficacy of ICIs or provide clues on how to overcome drug resistance. Here, it was revealed that cell division cycle 25C (CDC25C) expression was upregulated in lung adenocarcinoma (LUAD) compared to that of normal lung tissue in multiple databases. This was further verified by q-PCR. Furthermore, higher CDC25C expression was associated with shorter overall survival and worse pathological stage. Most importantly, a higher CDC25C expression was associated with shorter progression-free survival in LUAD patients treated with nivolumab, suggesting the role of the cell cycle in immunotherapy. In addition, CDC25C expression was significantly associated with immune cell infiltration and immune-related signatures in the LUAD tumor microenvironment. Moreover, CDC25C was differentially expressed and correlated with overall survival in multiple tumors, indicating that CDC25C is a broad-spectrum biomarker. Taken together, our study demonstrates that CDC25C is a prognostic biomarker for LUAD patients, especially for patients treated with ICIs. Our study also provides strong evidence for the role of the cell cycle in ICIs therapy and tumor microenvironment.

MicroRNA-206 inhibits HCV proliferation through depressing ACC1 lipid synthesis signalling pathway.

MicroRNAs are considered to play important roles in cell biological and pathological progress. microRNA-206 (miR-206) was reported to participate in lipogenesis, and lipid droplets were necessary for the life cycle of HCV proliferation. Whether miR-206 was associated with HCV proliferation and the potential mechanism are not clear. In this study, we firstly identified that miR-206 could inhibit HCV proliferation at the RNA and protein level. Bioinformatical prediction of target genes binding to miR-206 was performed to investigate whether inhibiting function was due to a lipogenesis pathway. Then, the acetyl-CoA carboxylase 1 (ACC1) gene was selected as target gene of miR-206. The dual-luciferase reporter assay results showed that luciferase significantly decreased in cells transfected with 3'-UTR of the ACC1 gene and miR-206. The RNA and protein levels of the ACC1 gene and its pathway genes were significantly lower in cells transfected with miR-206 than in controls. Furthermore, the lipid droplet numbers also significantly decreased in cells transfected with miR-206. In conclusion, miR-206 could inhibit HCV proliferation through depressing ACC1 lipogenesis pathway and decreasing the lipid droplet numbers. miR-206 might be used as anti-HCV biochemical drug in the future.

Abnormal interhemispheric functional connectivity in patients with primary dysmenorrhea: a resting-state functional MRI study.

Background: Neuroimaging studies have confirmed that functional connectivity (FC) disruption of pain-related brain networks may contribute to the cerebral pathophysiology of primary dysmenorrhea (PDM). However, it remains unclear whether FC of symmetrical regions of bilateral hemispheres associated with PDM is abnormal. This functional MRI study aimed to explore the changes of voxel-mirrored homotopic connectivity (VMHC) and seed-based FC in patients with PDM. Methods: A cohort comprising patients with PDM (n=35) and healthy controls (HCs) (n=41) underwent resting-state functional MRI scans during their menstrual phase. Interhemispheric FC was compared between the two groups using VMHC analysis. Brain areas with significant group differences in VMHC were selected as seed regions for FC analysis. Correlation analysis was also conducted to examine the relationship between abnormal connectivity of brain regions and clinical measures of pain and anxiety. Results: Compared with healthy individuals, patients with PDM showed significantly enhanced VMHC in the bilateral orbital part of the superior frontal gyrus and the bilateral middle frontal gyrus. Subsequent seed-based FC analysis showed enhanced connectivity between the aforementioned areas and pain-related brain structures. Hyperconnectivity between the left middle frontal gyrus and the right cingulate gyrus in patients was negatively correlated with an increase in the visual analogue score (VAS) for pain (r=-0.341, P<0.05). Conclusions: Our findings indicate that ongoing dysmenorrhea is accompanied by abnormal interhemispheric functional coordination and enhanced connectivity in pain-related regions, attention networks, and the reward system. These findings may provide a novel perspective on the central mechanism of pain caused by PDM.

Echinacoside inhibits the proliferation, migration, invasion and angiogenesis of ovarian cancer cells through PI3K/AKT pathway.

Echinacoside is a group of natural compounds extracted from medicinal plants Cistanche and Echinacea, which has neuroprotective, antiaging, immunomodulatory and anticancer effects, but its specific role and mechanism in tumor remains partially unclear. To our knowledge, it was the first time to reported the effect of Echinacoside in ovarian cancer. Colony formation, TUNEL staining, Transwell and tube formation assays were conducted to analyze the proliferation, apoptosis, invasion and tube formation abilities of serous ovarian carcinoma cells (SKOV3 and OVCAR-3), respectively. The expressions of apoptosis-, invasion- and PI3K/AKT pathway-related proteins were measured by western blotting. In addition, PI3K agonist (740Y-P) was used to assess the regulatory effect of Echinacoside on PI3K/AKT signaling in ovarian cancer. Finally, the anti-tumor effect of Echinacoside on SKOV3-xenografted mice was evaluated by xenograft tumor mouse model. Our results demonstrated Echinacoside concentration-dependently reduced the proliferation, migration and angiogenesis of ovarian cancer cells, whereas promoted apoptosis. Moreover, western blotting revealed that Echinacoside suppressed the growth of ovarian cancer cells by downregulating the phosphorylation levels of PI3K, AKT and mTOR, which could be partially reversed by 740Y-P. Further, in vivo results showed that Echinacoside could effectively alleviate the tumor growth of xenograft mice, accompanied by the decrease of PI3K/AKT signaling. In general, our results demonstrate that Echinacoside could reduce the ovarian cancer progression through inhibition of PI3K/AKT pathway, suggesting that Echinacoside may be a new treatment option for ovarian cancer.

Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors.

INTRODUCTION: Mutations in BRAF occur in 2% to 4% of patients with lung adenocarcinoma. Combination dabrafenib and trametinib, or single-agent vemurafenib is approved only for patients with cancers driven by the V600E BRAF mutation. Targeted therapy is not currently available for patients harboring non-V600 BRAF mutations. METHODS: A lung adenocarcinoma patient-derived xenograft model (PHLC12) with wild-type and nonamplified EGFR was tested for response to EGFR tyrosine kinase inhibitors (TKIs). A cell line derived from this model (X12CL) was also used to evaluate drug sensitivity and to identify potential drivers by small interfering RNA knockdown. Kinase assays were used to test direct targeting of the candidate driver by the EGFR TKIs. Structural modeling including, molecular dynamics simulations, and binding assays were conducted to explore the mechanism of off-target inhibition by EGFR TKIs on the model 12 driver. RESULTS: Both patient-derived xenograft PHLC12 and the X12CL cell line were sensitive to multiple EGFR TKIs. The BRAFG469V mutation was found to be the only known oncogenic mutation in this model. Small interfering RNA knockdown of BRAF, but not the EGFR, killed X12CL, confirming BRAFG469V as the oncogenic driver. Kinase activity of the BRAF protein isolated from X12CL was inhibited by treatment with the EGFR TKIs gefitinib and osimertinib, and expression of BRAFG469V in non-EGFR-expressing NR6 cells promoted growth in low serum condition, which was also sensitive to EGFR TKIs. Structural modeling, molecular dynamic simulations, and in vitro binding assays support BRAFG469V being a direct target of the TKIs. CONCLUSIONS: Clinically approved EGFR TKIs can be repurposed to treat patients with non-small cell lung cancer harboring the BRAFG469V mutation.

Hypoglycemic effect of astragaloside IV via modulating gut microbiota and regulating AMPK/SIRT1 and PI3K/AKT pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Astragali, the dried root of Astragalus mongholicus Bunge, has long been used in traditional Chinese Medicine to treat diabetes. Astragaloside IV (AS-IV), one of the most active ingredients in the root, has been shown to have anti-diabetes ability; however, its underlying mechanism is still unclear. MATERIALS AND METHODS: In this study, we evaluated the hypoglycemic effect and possible mechanisms of AS-IV in diabetic mice and insulin resistance-HepG2 cells. The components of the intestinal microflora in mice with type 2 diabetes mellitus (T2DM) were determined using high-throughput 16S rRNA gene sequencing. Moreover, the molecular mechanisms of specific members of insulin signaling pathways were analyzed. RESULTS: AS-IV significantly reversed the abnormalities in blood lipids, glucose, insulin resistance, as well as oxidative stress levels in T2DM mice. Histological finding showed that AS-IV could protect the cellular architecture of the liver and pancreas. AS-IV also regulated the abundance and diversity of intestinal flora of T2DM mice in a positive direction and increased butyric acid levels. The active role of AS-IV as an anti-diabetic compound by regulating the AMPK/SIRT1 and PI3K/AKT signaling pathways was revealed using a T2DM model and verified through the intervention of inhibitors using insulin-resistance HepG2 cells. CONCLUSION: Our results suggested that AS-IV may be used as an anti-diabetic drug candidate owing to its effects of regulating gut microbiota and AMPK/SIRT1 and PI3K/AKT signaling pathways.