Effect of ST36 electroacupuncture on the switch of skeletal muscle fibres in mice with sciatic nerve dissociation.

Skeletal muscle is striated muscle that moves autonomously and is innervated by peripheral nerves. Peripheral nerve injury is very common in clinical treatment. However, the commonly used treatment methods often focus on the regeneration of the injured nerve but overlook the pathological changes in the injured skeletal muscle. Acupuncture, as the main treatment for denervated skeletal muscle atrophy, is used extensively in clinical practice. In the present study, a mouse model of lower limb sciatic nerve detachment was constructed and treated with electroacupuncture Stomach 36 to observe the atrophy of lower limb skeletal muscle and changes in skeletal muscle fibre types before and after electroacupuncture Stomach 36 treatment. Mice with skeletal muscle denervation showed a decrease in the proportion of IIa muscle fibres and an increase in the proportion of IIb muscle fibres, after electroacupuncture Stomach 36. The changes were reversed by specific activators of p38 MAPK, which increased IIa myofibre ratio. The results suggest that electroacupuncture Stomach 36 can reverse the change of muscle fibre type from IIb to IIa after denervation of skeletal muscle by inhibiting p38 MAPK. The results provide an important theoretical basis for the treatment of clinical peripheral nerve injury diseases with electroacupuncture, in addition to novel insights that could facilitate the study of pathological changes of denervated skeletal muscle.

GLUT1 mediates bronchial epithelial E-cadherin disruption in TDI-induced steroid-insensitive asthma.

OBJECTIVE: Down-regulation of bronchial epithelial E-cadherin is an important of feature of severe asthma, including steroid-insensitive asthma. Yet, the mechanisms involved in E-cadherin disruption are not fully understood. This study was aimed to investigate the role of glucose transporter 1 (GLUT1) in dysregulation of E-cadherin in toluene diisocyanate (TDI)-induced steroid-insensitive asthma. METHODS: A murine model of steroid-insensitive asthma was established by TDI sensitization and aerosol inhalation. Selective GLUT1 antagonists WZB117 and BAY876 were given to BALB/c mice after airway challenge. In vitro, primary human bronchial epithelial cells (HBECs) cultured in an airway-liquid interface (ALI) were exposed to TDI. RESULTS: TDI exposure markedly up-regulated GLUT1 in murine lungs and HBECs. Pharmacological inhibition of GLUT1 with BAY876 decreased airway hyperresponsiveness, neutrophil and eosinophil accumulation, as well as type 2 inflammation in vivo. Besides, the TDI-induced down-regulated expression of full-length E-cadherin was also partly recovered, accompanied by inhibited secretion of soluble E-cadherin (sE-cadherin). WZB117 also exhibited mild therapeutic effects, though not significant. In vitro, treatment with GLUT1 inhibitor relieved the TDI-induced disruption of E-cadherin in HBECs. CONCLUSIONS: Taken together, our data demonstrated that GLUT1 modulates bronchial epithelial E-cadherin dysfunction production in TDI-induced steroid-insensitive asthma.

Long-non-coding RNA AK001058: A genetic biomarker in cisplatin sensitivity of non-small-cell lung carcinoma.

Previous evidences have shown that lncRNA AK001058 serves as an oncogene. This study aims to elucidate the expression characteristic of AK001058 in NSCLC samples, and its potential influence on the malignant progression and cisplatin resistance of NSCLC. Relative levels of AK001058 and IGF2 in NSCLC and non-tumoral tissues were detected by qRT-PCR. Proliferation inhibition rate and migratory rate in DDP-induced SPC-A1 and A549 cells were examined by CCK-8 and Transwell assay, respectively. Subsequently, DDP-resistant SPC-A1 and A549 cell lines were generated, and the role of AK001058 in affecting their cell phenotypes was determined. Using dual-luciferase reporter assay, the binding relationship between AK001058 and IGF2 was verified. Their co-regulation on DDP-resistant NSCLC cells was finally explored via rescue experiments. AK001058 was upregulated in NSCLC samples. The proliferative rate was dose-dependently and time-dependently declined in DDP-induced SPC-A1 and A549 cells. Cisplatin induction upregulated AK001058 in NSCLC cells, and attenuated migratory potential. Transfection of sh-AK001058 reduced proliferative and migratory rates in SPC-A1/DDP and A549/DDP cells. IGF2 was the downstream target binding AK001058, which was lowly expressed in NSCLC samples. AK001058 upregulation in NSCLC reduces cisplatin sensitivity and promotes malignant progression by negatively regulating IGF2, leading to cisplatin resistance.

Triplet-drug chemotherapy combined with anti-EGFR antibody as an effective therapy for patients with initially unresectable metastatic colorectal cancer: a meta-analysis.

The meta-analysis aimed to assess the clinical efficacy of chemotherapeutic triplet-drug regimen combined with anti-EGFR antibody in patients with initially unresectable metastatic colorectal cancer (mCRC). A systematic literature search was performed in PubMed Publisher. Studies evaluating FOLFOXIRI combine with panitumumab or cetuximab as the therapy for initially unresectable mCRC were included. The primary outcome was objective response rate (ORR) and rate of R0 resections. The secondary outcomes included overall survival (OS), progression-free survival (PFS), and grades 3 or 4 adverse events. R software (version 4.0.2) and RevMan (version 5.3) were used to analyze the extracted data. The studies included were published between 2010 and 2021, involving four single-arm phase II trials and two randomized phase II trials. A total of 6 studies with 282 patients were included. The data showed a significant benefit for the FOLFOXIRI + anti-EGFR antibody arm compared with FOLFOXIRI arm (RR 1.33; 95% CI, 1.13-1.58; I2 = 0%, P < 0.05). The pooled ORR and pooled rate of R0 resection in patients who receiving FOLFOXIRI + anti-EGFR antibody were 85% (95% CI, 0.78-0.91; I2 = 58%) and 42% (95% CI, 0.32-0.53; I2 = 62%), respectively. The range of median PFS between all the six studies was 9.5-15.5 months, with weighted pooled median PFS mean 11.7 months. The range of median OS between all the four studies was 24.7-37 months, with weighted pooled median PFS mean 31.9 months. The common grades 3 and 4 adverse events were diarrhea and neutropenia. Our findings show that triplet-drug chemotherapy (FOLFOXIRI) combined with anti-EGFR antibody (panitumumab or cetuximab) represents a very effective therapeutic combination associated with a significant ORR and R0 rection rate for patients with molecularly unselected and surgically unresectable metastatic CRC.

CCDC114, DNAI2 and TOP2A involves in the effects of tibolone treatment on postmenopausal endometrium.

BACKGROUND: This study aimed to explore the molecular mechanisms of tibolone treatment in postmenopausal women. METHODS: The gene set enrichment profile, GSE12446, which includes 9 human endometrial samples from postmenopausal women treated with tibolone (tibolone group) and 9 control samples (control group), was downloaded from GEO database for analysis. Differentially expressed genes (DEGs) in tibolone vs. control groups were identified and then used for function and pathway enrichment analysis. Protein-protein interaction (PPI) network and module analyses were also performed. Finally, drug-target interaction was predicted for genes in modules, and then were validated in Pubmed. RESULTS: A total of 238 up-regulated DEGs and 72 down-regulated DEGs were identified. These DEGs were mainly enriched in various biological processed and pathways, such as cilium movement (e.g., CCDC114 and DNAI2), calcium ion homeostasis, regulation of hormone levels and complement/coagulation cascades. PPI network contained 368 interactions and 166 genes, of which IGF1, DNALI1, CCDC114, TOP2A, DNAH5 and DNAI2 were the hue genes. A total of 96 drug-gene interactions were obtained, including 94 drugs and eight genes. TOP2A and HTR2B were found to be targets of 28 drugs and 38 drugs, respectively. Among the 94 obtained drugs, only 12 drugs were reported in studies, of which 7 drugs (e.g., epirubicin) were found to target TOP2A. CONCLUSIONS: CCDC114 and DNAI2 might play important roles in tibolone-treated postmenopausal women via cilium movement function. TOP2A might be a crucial target of tibolone in endometrium of postmenopausal women.

Gene expression changes in arterial and venous endothelial cells exposed to gestational diabetes mellitus.

We investigated the molecular changes in fetoplacental blood vessel endothelial cells in gestational diabetes mellitus (GDM). Raw gene expression profile data of arterial and venous endothelial cells from GDM complicated pregnancies and healthy controls were downloaded and used for bioinformatic analysis. There were two differentially expressed genes (DEGs) in venous endothelial cells and 178 DEGs in arterial endothelial cells induced by GDM. The altered genes were clustered to pathways associated with cell cycle, p53 signaling pathway, and cellular senescence. The disease associated gene-pathway network that was constructed comprised eight down-regulated genes (including FBXO5, CCNB1, and CDK1), one up-regulated gene (CCND2), hsa04068: FoxO signaling pathway and hsa04114: Oocyte mitosis pathway. CCND2 was a significant node in the microRNA (miRNA)-target network, which was regulated by seven miRNAs that included hsa-miR-1299, hsa-miR-1200, and hsa-miR-miR-593-5p. FBXO5 was a significant node regulated by two miRNAs. CCND2 and FBXO5 were also the significant nodes in the transcriptional factors-target network and integrated regulatory network. The cell cycle pathway was significantly altered in arterial endothelial cells during GDM, which was involved with the differential expression of CCND2 and FBXO5.

HMGB1-induced asthmatic airway inflammation through GRP75-mediated enhancement of ER-mitochondrial Ca2+ transfer and ROS increased.

Imbalanced T-helper (TH)1/Th2 response contributes significantly to asthma pathogenesis. Our study indicated that HMGB1 play an important role in the release of Th2-associated cytokines of asthma. However, the specific mechanism about HMGB1-induced imbalanced TH1/Th2 response is not known. In vivo, an OVA-induced asthma mouse model was set up and mice treated with anti-HMGB1 IgG. The mice treated with the anti-HMGB1 IgG ameliorated airway hyper-reactivity, disruption of Th1/Th2 balance and the upregulation of GRP75 induced by OVA. In vitro, the exposure of normal human bronchial epithelial cells to HMGB1 resulted in the upregulation of GRP75, proinflammatory cytokine production, enhanced ER-Mitochondrial Ca2+ transfer, and enhancement of reactive oxygen species (ROS). While HMGB1-induced these changes were attenuated by GRP75 siRNA treatment. Sequentially, pretreatment with 2-APB, SKF960365 (SKF) and Ru360 which inhibit ER-Mitochondrial Ca2+ transfer significantly lowered HMGB1-induced the generation of ROS and the release of Th2 cytokines in 16HBE cells. Meanwhile, N-acetylcysteine (NAC) significantly attenuated the HMGB1-mediated pro-inflammatory cytokines release. Therefore, these results indicate that GRP75-mediated ER-Mitochondrial Ca2+ transfer may be an important contributor in imbalanced of Th1/Th2 balance of asthma. Moreover, HMGB1 specifically induces the release of Th2 cytokines through GRP75-mediated enhancement of ER-Mitochondrial Ca2+ transfer and ROS increased.

Silencing of an aphid carboxylesterase gene by use of plant-mediated RNAi impairs Sitobion avenae tolerance of Phoxim insecticides.

RNA interference (RNAi) describes the ability of double-stranded RNA (dsRNA) to inhibit homologous gene expression at the RNA level. Its specificity is sequence-based and depends on the sequence of one strand of the dsRNA corresponding to part or all of a specific gene transcript. In this study we adopted plant-mediated RNAi technology that targets Sitobion avenae (S. avenae) to enable gene silencing in the aphid and to minimize handling of the insects during experiments. S. avenae was selected for this study because it causes serious economic losses to wheat throughout the world. The carboxylesterase (CbE E4) gene in S. avenae was homologously cloned, which increased synthesis of a protein known to be critical to the resistance (tolerance) this species has developed to a wide range of pesticides. A plant RNAi vector was constructed, and transgenic Triticum aestivum (dsCbE1-5 and dsCbE2-2 lines) expressing CbE E4 dsRNA were developed. S. avenae were fed on dsCbE1-5 and dsCbE2-2 lines stably producing the CbE E4 dsRNA. CbE E4 gene expression in S. avenae was reduced by up to 30-60%. The number of aphids raised on dsCbE1-5 and dsCbE2-2 was lower than the number raised on non-transgenic plants. A solution of CbE E4 enzyme from S. avenae fed on dsCbE1-5 and dsCbE2-2 plants hydrolyzed only up to 20-30% Phoxim solution within 40 min whereas a solution of the enzyme from CbE E4 fed on control plants hydrolyzed 60% of Phoxim solution within 40 min. CbE E4 gene silencing was achieved by our wheat-mediated RNAi approach. This plant-mediated RNAi approach for addressing degradation-based pesticide resistance mechanisms in aphids and may prove useful in pest management for diverse agro-ecosystems.

Endoscopic ultrasonography-related diagnostic accuracy and clinical significance on small rectal neuroendocrine neoplasms.

This research aimed to examine the diagnostic accuracy and clinical significance of endoscopic ultrasonography (EUS) in the context of small rectal neuroendocrine neoplasms (NENs). A total of 108 patients with rectal subepithelial lesions (SELs) with a diameter of < 20 mm were included in the analysis. The diagnosis and depth assessment of EUS was compared to the histology findings. The prevalence of NENs in rectal SELs was 78.7% (85/108). The sensitivity of EUS in detecting rectal NENs was 98.9% (84/85), while the specificity was 52.2% (12/23). Overall, the diagnostic accuracy of EUS in identifying rectal NENs was 88.9% (96/108). The overall accuracy rate for EUS in assessing the depth of invasion in rectal NENs was 92.9% (78/84). Therefore, EUS demonstrates reasonable diagnostic accuracy in detecting small rectal NENs, with good sensitivity but inferior specificity. EUS may also assist physicians in assessing the depth of invasion in small rectal NENs before endoscopic excision.

GLUT1 mediates the release of HMGB1 from airway epithelial cells in mixed granulocytic asthma.

Asthma is quite heterogenous and can be categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic. Clinically, mixed granulocytic asthma (MGA) often tends to be severe and requires large doses of corticosteroids. High mobility group box 1 (HMGB1) is one of the epithelium-derived alarmins that contributes to type 2 inflammation and asthma. This study was aimed to investigate the role of glucose transporter 1 (GLUT1) in modulation of airway epithelial HMGB1 production in MGA. Induced sputum and bronchial biopsy specimens were obtained from healthy subjects and asthma patients. BALB/c mice, the airway epithelial cell line BEAS-2B, or primary human bronchial epithelial cells (HBECs) were immunized with allergens. Intracellular and extracellular HMGB1 were both detected. The role of GLUT1 was assessed by using a pharmacological antagonist BAY876. MGA patients have a significant higher sputum HMGB1 level than the health and subjects with other inflammatory phenotypes. Nuclear-to-cytoplasmic translocation of HMGB1 was also observed in the bronchial epithelia. Allergen exposure markedly induced GLUT1 expression in murine lungs and cultured epithelial cells. Pharmacological antagonism of GLUT1 with BAY876 dramatically decreased airway hyperresponsiveness, neutrophil and eosinophil accumulation, as well as type 2 inflammation in murine models of MGA. Besides, the allergen-induced up-regulation of HMGB1 was also partly recovered by BAY876, accompanied by inhibited secretion into the airway lumen. In vitro, treatment with BAY876 relieved the allergen-induced over-expression and secretion of HMGB1 in airway epithelia. Taken together, our data indicated that GLUT1 mediates bronchial epithelial HMGB1 release in MGA.

Invasive pulmonary aspergillosis in non-neutropenic patients with and without underlying disease: a single-centre retrospective analysis of 52 subjects.

BACKGROUND AND OBJECTIVE: Invasive pulmonary aspergillosis (IPA) remains a life-threatening infection in patients with prolonged neutropenia. Few data are available on IPA in non-neutropenic patients without underlying immunocompromising conditions. METHODS: All non-neutropenic patients managed at the institution for a proven and probable IPA over the last 10 years were reviewed retrospectively, and the difference between non-neutropenic patients with and without underlying disease was investigated. RESULTS: Among 52 cases of IPA analysed here, 33 were histologically proven; 19 were probable. Forty-two (80.8%) patients had underlying diseases; 10 (19.2%) patients had no any underlying diseases. There is a significant difference in seasonal distribution among patients with underlying conditions (P = 0.026), but no seasonal difference was found in the other group (P = 0.622). The only significant difference in symptoms between the two groups was fever (P = 0.015). Radiological findings were non-specific in the two groups. Despite treatment, the overall crude mortality rate among 52 patients was 39%. The overall mortality rate in patients with underlying disease was 45%, while that in patients without underlying conditions was 11%. A Cox multivariate analysis showed that organ failure (hazard ratios: 8.739, 95% CI: 3.770-20.255; P = 0.000) was independently associated with overall mortality. CONCLUSIONS: Clinical features of IPA are not well known in non-neutropenic patients, especially in those without underlying conditions. In this study, organ failure was associated with a lower rate of survival of non-neutropenic patients with IPA.

An Amphiphilic Multiblock Polymer as a High-Temperature Gelling Agent for Oil-Based Drilling Fluids and Its Mechanism of Action.

Oil-based drilling fluids are widely used in challenging wells such as those with large displacements, deepwater and ultra-deepwater wells, deep wells, and ultra-deep wells due to their excellent temperature resistance, inhibition properties, and lubrication. However, there is a challenging issue of rheological deterioration of drilling fluids under high-temperature conditions. In this study, a dual-amphiphilic segmented high-temperature-resistant gelling agent (HTR-GA) was synthesized using poly fatty acids and polyether amines as raw materials. Experimental results showed that the initial decomposition temperature of HTR-GA was 374 °C, indicating good thermal stability. After adding HTR-GA, the emulsion coalescence voltage increased for emulsions with different oil-to-water ratios. HTR-GA could construct a weak gel structure in oil-based drilling fluids, significantly enhancing the shear-thinning and thixotropic properties of oil-based drilling fluids under high-temperature conditions. Using HTR-GA as the core, a set of oil-based drilling fluid systems with good rheological properties, a density of 2.2 g/cm3, and temperature resistance up to 220 °C were constructed. After aging for 24 h at 220 °C, the dynamic shear force exceeded 10 Pa, and G' exceeded 7 Pa, while after aging for 96 h at 220 °C, the dynamic shear force exceeded 4 Pa, and G″ reached 7 Pa. The synthesized compound HTR-GA has been empirically validated to significantly augment the rheological properties of oil-based drilling fluids, particularly under high-temperature conditions, showcasing impressive thermal stability with a resistance threshold of up to 220 °C. This notable enhancement provides critical technical reinforcement for progressive exploration endeavors in deep and ultra-deep well formations, specifically employing oil-based drilling fluids.

Decoding SEC24 Homolog D, COPII coat complex component accuracy as a signature gene in three human cancers.

Although an increasing body of evidence supports the crucial role of the SEC24 Homolog D, COPII Coat Complex Component (SEC24D) gene in the initiation and progression of cancer, a comprehensive pan-cancer analysis of this gene is still lacking. In this study, we conducted an extensive investigation of SEC24D, aiming to elucidate its potential role and underlying mechanisms across multiple human tumors. Our analysis relied on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To validate our findings, we employed RNA sequencing (RNA-seq), targeted bisulfite sequencing (bisulfite-seq) molecular techniques. Our findings revealed elevated mRNA (Messenger RNA) and protein levels of SEC24D in different tumor tissues. However, the up-regulation of SEC24D was significantly correlated with shorter overall survival (OS), metastasis, and various clinical parameters in esophageal cancer (ESCA), lung adenocarcinoma (LUAD), and kidney renal papillary cell carcinoma (KIRP). Expression validation analysis via RNA-seq and targeted bisulfite-seq analyses, further confirmed the higher expression of SEC24D in LUAD cancer cell lines as compared to normal controls. The DNA methylation level of SEC24D was found to be decreased in ESCA, LUAD, and KIRP samples. DNA methylation analysis via bisulfite-seq analysis also validate the lower promoter methylation level of SE24D in LUAD cell lines relative to controls. Moreover, we observed a significant association between the elevated expression of SEC24D and the levels of infiltrating cells, such as B cells, neutrophils, macrophages, CD8+ T cells, and CD4+ T cells. Analysis of SEC24-related genes revealed that "Protein processing in endoplasmic reticulum, SNARE interaction in vesicular transport, Legionellosis, Pathogenic Escherichia coli infection" were mainly involved in the functional mechanism of SEC24D in ESCA, LUAD, and KIRP. Moreover, we also suggested a few valuable drugs (Acetaminophen, Acteoside, Cyclosporine, Polydatin, Estradiol, Estradiol, Quercetin) for treating ESCA, LUAD, and KIRP patients with respect to overexpressed SEC24D. To summarize, this comprehensive pan-cancer study investigated the association between SEC24D expression and clinical parameters in ESCA, LUAD, KIRP. The study provides valuable insights for further exploring the functional and therapeutic aspects of SEC24D and underscores its predictive significance in the carcinogenesis and prognosis of these specific cancer types.

A mobile phone short message service improves perceived control of asthma: a randomized controlled trial.

OBJECTIVE: Mobile phone short message service (SMS) has been suggested as a potentially powerful tool to improve asthma outcomes, and it can overcome external barriers such as time and distance to participate education programs. We wanted to know whether SMS can help to overcome intrinsic barriers such as perceived control of asthma (PCA). SUBJECTS AND METHODS: One hundred fifty outpatients with asthma were randomly assigned to the control, traditional, and SMS groups. Patients in all groups received verbal education based on the Global Initiative for Asthma, and patients in the traditional group received additional individualized asthma action plan for self-management with peak expiratory flow monitoring and recording asthma diary, while patients in the SMS group received additional daily SMS reminders on their mobile phone. The six-item PCA Questionnaire (PCAQ-6), Standard Asthma-Specific Quality of Life [AQLQ(S)], spirometry, blood and induced sputum cell count, follow-up compliance rate, medicine compliance rate, and emergency department (ED) visits data were collected at the initial visit and at 12 weeks. RESULTS: In total, 71 participants completed the trial for analysis. Patients' PCAQ-6 score was significantly increased in the SMS and traditional groups (p<0.001) after 12 weeks, and the change of patients' PCAQ-6 score in the SMS group was higher than in the traditional group (p=0.018). Patients in the SMS group had the highest AQLQ(S) score and follow-up rate after 12 weeks. The change in PCAQ-6 score was associated with change in AQLQ(S) score (r=0.442). Patients in all groups had better forced expiratory volume in 1 s (FEV1%) and fewer ED visits after 12 weeks, but no significant differences were found among the three groups in the changes of FEV1% and blood and induced sputum eosinophil counts and neutrophil counts. CONCLUSIONS: SMS can improve PCA, and it has a greater advantage in improving follow-up rate and asthma-specific quality of life than traditional programs.

Lung adenocarcinoma harboring complex EML4-ALK fusion and BRAF V600E co-mutation responded to alectinib.

RATIONALE: The echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) is the most frequent fusion variant of ALK rearrangements in non-small cell lung cancer (NSCLC). With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations of EML4-ALK have been discovered. Complex co-mutation of EML4-ALK fusions together with BRAF V600E, though rarely occurred, also deserves attention to determine the standard of caring these patients. Herein, we report a case of lung adenocarcinoma harboring a complex ALK fusion that coexisted with a BRAF mutation, as tested by DNA-NGS prior to treatment. PATIENT CONCERNS: A 51-year-old non-smoking man, without any symptoms, was admitted to hospital due to small pulmonary nodules and enlarged supraclavicu larlymph nodes found in health checkup. DIAGNOSIS: He was diagnosed with stage IVB (T4N3M1c) lung adenocarcinoma. BRAF V600E (abundance 3.75%) mutation and a novel thus little-understood EML4-ALK (E13, A5; abundance 2.16%) fusion were identified by DNA-NGS analysis of lymph node biopsy tissue in December 2019. INTERVENTIONS: Darafenib plus trametinib targeted therapy and chemotherapy were given firstly, but tumor progression was not inhibited. The ALK inhibitor alectinib was prescribed then. OUTCOMES: The patient exhibited a rapid disease response to ALK tyrosine kinase inhibitors alectinib with a complete remission of widespread metastatic disease and progression-free survival of more than 26 months, but not to darafenib plus trametinib targeted BRAF V600E therapy. Re-analyzed the patient's DNA-NGS original data, showed it is a rare and complex EML4-ALK (E13, A5, A20) fusion in fact. Additional RNA-NGS analysis showed it verified to be a canonical EML4-ALK (E13, A20) fusion transcript and coexisting with a BRAF V600E mutation. LESSONS: This case suggests that for patients with rare or complex EML4-ALK fusions at DNA level, additional RNA-NGS is necessary to verify its functionality as early as possible. Targeting EML4-ALK firstly may be more preferable despite the coexisting of BRAF V600E.

Tislelizumab combined with anlotinib in the second-line treatment of malignant pleural mesothelioma.

RATIONALE: Malignant pleural mesothelioma (MPM) is a malevolent tumor originated from pleura and often leads to poor prognosis. Chemotherapy of pemetrexed and cisplatin combined with antiangiogenic therapy of bevacizumab is recommended as the first-line regimen by guidelines. However, there are few sustainable second-line anti-tumor theraies that bring distinct survival benefit after the occurrence of drug resistance as the reported mPFS (median progression-free survival) scarcely exceeds 6 months. Immune checkpoint inhibitors are extensively investigated in pan-cancer, and dual immunotherapy has been listed in the first-line recommendation of MPM in several guidelines, while MPM patients benefit modestly from immune checkpoint inhibitors combination or monotherapy in second-line practice. PATIENT CONCERNS AND DIAGNOSIS: We report a 59-year-old male patient who was diagnosed with unresectable MPM in April 2021. INTERVENTIONS: He received firstly pemetrexed combined with platinum and bevacizumab, which barely curbed disease progression; When the first line treatment failed, he was switched to tislelizumab combined with anlotinib. OUTCOMES: Tislelizumab combined with anlotinib significantly relieved his clinical symptoms, and imaging examination further validated the improvement. Until present, the second-line treatment PFS is more than 10 months. LESSONS: The case firstly demonstrated the efficacy of tislelizumab combined with anlotinib in the second-line management of MPM. Thus, immunotherapy combined with small-molecule multi-target anti-angiogenic medication may be alternative for the second-line schemes of MPM.

Clinical characteristics of 14 cases of severe Chlamydia psittaci pneumonia diagnosed by metagenomic next-generation sequencing: A case series.

INTRODUCTION: The objective of this study was to explore the clinical, laboratory, and imaging features of severe Chlamydia psittaci pneumonia in order to improve early diagnosis and treatment success rates. METHODS: We conducted a retrospective record review of 14 cases of severe Chlamydia psittaci pneumonia diagnosed by metagenomic next-generation sequencing technology in our hospital. We extracted and analyzed data on the clinical symptoms and signs, contact history, laboratory investigations, chest computed tomography, treatment, and clinical outcomes. RESULTS: Of the 14 patients, 12 (86%) were male and two (14%) were female, with a mean age of 57 years (SD: 7 years). Eleven patients (79%) had a history of poultry contact. The main clinical manifestations were fever (n = 14, 100%), flu-like symptoms (n = 10, 71%), cough, sputum (n = 9, 64%), and dyspnea (n = 5, 36%). Blood tests revealed marked elevation of neutrophil percentage, C-reactive protein, procalcitonin, brain natriuretic peptide, and creatine kinase levels; slight elevation of aspartate aminotransferase, creatinine, urea, fibrinogen, and D-dimer levels; and decreased albumin, sodium, and calcium levels. Chest computed tomography showed bilateral lesions (n = 7, 50%), middle-lower lobe lesions (n = 10, 71%), lesions in multiple lobes (n = 9, 64%), consolidation shadows (n = 11, 79%), and pleural effusions (n = 11, 79%). The median time from disease onset to hospital admission was 4.5 days (interquartile range: 1-17 days); the mean length of hospital stay was 20.9 ±â€Š8.5 days, and the mean time from admission to diagnosis was 5.1 ±â€Š2.6 days. After diagnosis, patients were either treated with doxycycline alone or doxycycline combined with quinolones. All 14 patients developed respiratory failure and received invasive mechanical ventilation; two (14%) received veno-venous extracorporeal membrane oxygenation, four (29%) received continuous renal replacement therapy, and three (21%) died. DISCUSSION AND CONCLUSION: A poultry contact history and typical flu-like symptoms are early indicators of Chlamydia psittaci pneumonia. Substantial elevations in procalcitonin, creatine kinase, and brain natriuretic peptide indicate severe disease. Metagenomic next-generation sequencing is useful for diagnosis. Early empirical antibiotic therapy with quinolones can reduce the mortality in critically ill patients.

High mobility group protein B1 (HMGB1) in Asthma: comparison of patients with chronic obstructive pulmonary disease and healthy controls.

High mobility group protein B1 (HMGB1) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, the expression of HMGB1 in plasma and sputum of patients with asthma and COPD across disease severity needs to be defined. The objective of the study was to examine the induced sputum and plasma concentrations of HMGB1 in COPD and asthmatic patients to determine differences in HMGB1 levels between these diseases and their relationship with airway obstruction and inflammatory patterns. A total of 147 participants were enrolled in this study. The participants included 34 control subjects, 61 patients with persistent asthma (according to the Global Initiative for Asthma [GINA] guidelines) and 47 patients with stable COPD (stratified by Global Initiative for Chronic Obstructive Lung Disease [GOLD] status). Spirometry was performed before sputum induction. HMGB1 levels in induced sputum and plasma were determined by enzyme-linked immunosorbent assay. Sputum and plasma concentrations of HMGB1 in patients with asthma and COPD were significantly higher than concentrations in control subjects and were significantly negatively correlated with forced expiratory volume in 1 s (FEV(1)), FEV(1) (% predicted) in all 147 participants. The levels of HMGB1 in induced sputum of COPD patients were significantly higher than those of asthma patients and healthy controls (P < 0.001). This difference was present even after adjusting for sex, age, smoking status, daily dose of inhaled corticosteroids and disease severity. There were no significant differences in HMGB1 levels between patients with eosinophilic and noneosinophilic asthma. HMGB1 levels in asthmatic and COPD patients were positively correlated with neutrophil counts and percentage of neutrophils. In multivariate analysis, the two diseases (asthma and COPD) and disease severity were independent predictors of sputum HMGB1, but not smoking, age or use of inhaled corticosteroids. In conclusion, these data support a potential role for HMGB1 as a biomarker and diagnostic tool for the differential diagnosis of asthma and COPD. The importance of this observation on asthma and COPD mechanisms and outcomes should be further investigated in large prospective studies.

The biological behavior of drug-resistantovarian cancer cells and changes in the CA125 and HE4 levels after CIK interventions.

OBJECTIVE: This study aimed to investigate the biological behavior of drug-resistant ovarian cancer cells and changes in the cancer antigen 125 (CA125) and human epididymal protein 4 (HE4) levels after the application of cytokine-induced killer (CIK) intervention. METHODS: Drug-resistant ovarian cancer cells (namely SKVCR) were treated with CIK at different concentrations to observe the changes in the cell survival and cell morphology and the CA125, HE4, cytokine transforming growth factor-α (TGF-α), and tumor necrosis factor-α (TNF-α) levels in the cell lines before and after intervention. RESULTS: With an increase in the CIK concentration, the survival rate of the SKVCR cell lines showed a decreasing trend. Under a constant CIK concentration, the survival rate of the SKVCR cell lines gradually decreased over time but become stable at 72 h. Before the CIK intervention, the SKVCR cells were full and rounded in shape, but after the CIK intervention, there was remarkable cell shrinkage and an increase in apoptotic cells. Compared with before the CIK intervention, the CA125 and HE4 levels were significantly decreased, but the TGF-α and TNF-α levels were increased (P<0.05). CONCLUSION: After the CIK intervention in the drug-resistant ovarian cancer cells, the cell survival rate decreases with an increase in the CIK concentration or an extension of the intervention time, and the cell morphology will be significantly improved, and the CA125, HE4, and other related cytokine levels will also change significantly, suggesting that CIK can kill drug-resistant ovarian cancer cells.

Planarian gamma-interferon-inducible lysosomal thiol reductase (GILT) is required for gram-negative bacterial clearance.

The powerful regenerative ability of planarians has long been a concern of scientists, but recently, their efficient immune system has attracted more and more attention from researchers. Gamma-interferon-inducible lysosomal thiol reductase (GILT) is related not only to antigen presentation but also to bacteria invasions. But the systematic studies are not yet to be conducted on the relationship between bacterial infection. Our study reveals for the first time that GILT of planarian (DjGILT) plays an essential role in the clearance of Gram-negative bacteria by conducting H2O2 concentration in planarians. In animals that DjGILT was silenced, it persisted for up to 9 days before all bacteria were cleared, compared with 6 days of the control group. When infected with E. coli and V. anguillarum, the level of H2O2 was significantly increased in DjGILT-silenced planarians, and concomitantly, mRNA level of C-type lectin DjCTL, which modulates agglutination and clearance efficiency of invading bacteria, was decreased. Further study showed that the decrease of H2O2 level led to a significant increase in DjCTL transcripts. Collectively, we proposed a mechanism model for the involvement of GILT gene in bacterial elimination. We have for the first time revealed the specific mechanism of GILT in innate immune response against bacterial infection.