Comparative Efficacy of Budesonide/Formoterol Versus Fluticasone/Salmeterol in Patients With Moderate-to-Severe Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: To compare the efficacy of budesonide/formoterol (BF) versus fluticasone/salmeterol (FS) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for studies comparing BF versus FS in the treatment of COPD from inception to July 17, 2023. Outcomes, including exacerbations, hospitalizations, pneumonia, emergency department (ED) visits for COPD, length of hospitalization, and number of exacerbations, were compared using risk ratio (RR) with corresponding 95% confidence interval (CI) or weighted mean difference (WMD) with 95% CI. All statistical analyses were performed using Stata version 12.0. RESULTS: Ten studies comprising a total of 136,369 participants were included. Compared with those treated with FS, patients with COPD treated with BF experienced a reduced number of exacerbations (RR 0.91 [95% CI 0.83-1.00]; p = 0.040), hospitalizations (RR 0.77 [95% CI 0.67-0.88]; p < 0.001), and frequency of pneumonia (RR 0.77 [95% CI 0.64-0.92]; p = 0.05). However, no significant difference was observed between BF and FS in terms of ED visits for COPD (RR 0.87 [95% CI 0.69-1.10]; p = 0.243), length of hospitalization (WMD -0.18 [95% CI -0.62-0.27]; p = 0.437), and number of exacerbations (WMD -0.06 [95% CI -0.28-0.16]; p = 0.602). Notably, no significant heterogeneity was noted in length of hospitalization between the two groups, whereas clear heterogeneity was observed in other outcomes (I2 > 50%, p < 0.05). CONCLUSION: Compared with FS, BF therapy appears to be a more promising treatment strategy for patients with moderate-to-severe COPD; however, this should be verified in further high-quality studies.

The proteolytic activity in inflammatory bowel disease: insight from gut microbiota.

Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease caused by the destruction of the intestinal mucosal epithelium that affects a growing number of people worldwide. Although the etiology of IBD is complex and still elucidated, the role of dysbiosis and dysregulated proteolysis is well recognized. Various studies observed altered composition and diversity of gut microbiota, as well as increased proteolytic activity (PA) in serum, plasma, colonic mucosa, and fecal supernatant of IBD compared to healthy individuals. The imbalance of intestinal microecology and intestinal protein hydrolysis were gradually considered to be closely related to IBD. Notably, the pivotal role of intestinal microbiota in maintaining proteolytic balance received increasing attention. In summary, we have speculated a mesmerizing story, regarding the hidden role of PA and microbiota-derived PA hidden in IBD. Most importantly, we provided the diagnosis and therapeutic targets for IBD as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.

Clinicopathological characteristics and treatment outcomes of advanced SMARCA4-deficient thoracic tumors.

PURPOSE: SMARCA4-deficient thoracic tumors, characterized by distinct clinicopathological, morphological, immunohistochemical, and genetic features, differ significantly from conventional non-small-cell lung carcinomas (NSCLCs). This group encompasses both SMARCA4-deficient NSCLCs (SMARCA4-NSCLCs) and SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs). The efficacy of PD-1 inhibitors in treating SMARCA4-deficient thoracic tumors remains uncertain. METHODS: Medical records of 36 patients diagnosed with stage IIIB, IIIC, or IV SMARCA4-deficient thoracic tumors were analyzed. We assessed the clinical, pathological, and genetic features of these patients through immunohistochemistry (IHC) and a 68-gene panel next-generation sequencing (NGS). We compared the differences between SMARCA4-NSCLCs and SMARCA4-UTs, and evaluated the impact of chemotherapy and immunotherapy on patient outcomes. RESULTS: The majority of patients with SMARCA4-deficient thoracic tumors were heavy-smoking males, averaging 64.6 years in age. IHC predominantly showed weak or negative staining for markers such as TTF-1, CK5/6, p40, synaptophysin, chromogranin A, and CD56, which are often associated with adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors. The most common genetic mutations identified via NGS included TP53, CDKN2A, KRAS, STK11, NF1, and PTEN. No significant overall survival (OS) difference was observed between SMARCA4-NSCLCs and SMARCA4-UTs (p = 0.366). The median OS for patients treated with chemotherapy (n = 9) was 447 days, while the median OS for patients undergoing PD-1-inhibitor-based therapy (n = 16) was not reached (p = 0.105). CONCLUSION: SMARCA4-deficient thoracic tumors exhibit distinct characteristics from conventional NSCLCs, and PD-1 inhibitors show promise in treating advanced SMARCA4-deficient thoracic tumors.

Neoadjuvant Chemoimmunotherapy Increases Tumor Immune Lymphocytes Infiltration in Resectable Non-small Cell Lung Cancer.

BACKGROUND: Neoadjuvant chemoimmunotherapy treatment (NCIT) has achieved great success for non-small cell lung cancer (NSCLC); however, the intrinsic mechanism underlying this treatment remains unclear. METHODS: Thirty-two patients with stage IIA-IIIC NSCLC who underwent surgery after NCIT were included in this retrospective study. Multiplex immunofluorescence (mIF) staining and image analysis assays were performed on the samples collected before and after NCIT for each patient. RNA analyses was applied to confirm the mIF results. RESULTS: Among the enrolled patients, 14 achieved major pathological response or pathological complete response (pCR) and were defined as the 'response' group, whereas 18 patients did not respond well to NCIT and were defined as the 'nonresponse' group. The results of the mIF assays revealed an overall increase in tumor immune lymphocytes (TILs) after NCIT in the stroma area (p = 0.03) rather than the tumor area (p = 0.86). The percentage of CD8+ T cells and tertiary lymphoid structure counts in both the response and nonresponse groups increased significantly after NCIT compared with before NCIT. CD3+ T cells and FOXP3+ cells decreased significantly in the response group but remained unchanged or increased in the nonresponse group. A comparison of the response and nonresponse groups showed that CD3, FOXP3+ and CD8+/PD-1+ cells before NCIT may serve as predictors of the response to neoadjuvant immunotherapy. The RNA analyses confirmed the mIF results that TILs were elevated after NCIT. CONCLUSIONS: The infiltration of immune cells before NCIT was correlated with pathologic complete response, which enhanced the TILs as a promising predictor for selecting patients who were more likely to benefit from NCIT.

A case report of a young boy with low renin and high aldosterone levels induced by Liddle syndrome who was previously misdiagnosed with primary aldosteronism.

OBJECTIVES: Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalemia. CASE PRESENTATION: This report describes a 17-year-old male with hypertension and hypokalemia. We performed Captopril inhibition and postural stimulation test to diagnose and type primary aldosteronism. The plasma renin activity was consistently low, and aldosterone levels were high, hence the patient was initially diagnosed with primary aldosteronism. After genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of a p. Pro617Ser mutation in the SCNN1B gene. After diagnosis, the patient was prescribed one tablet of amiloride twice a day. The patient's blood pressure (average in 120-135/70-80 mmHg) and serum potassium levels (3.6-4.0 mmol/L) returned to normal and was well-controlled after treatment. CONCLUSIONS: Adolescent hypertension may be secondary to underlying medical conditions affecting the heart, kidneys, or endocrine system or primary with no known underlying disease process. Although in an adolescent with hypertension, hyperaldosteronism, and low plasma renin activity, the initial diagnosis suggested primary hyperaldosteronism, the failure of aldosterone receptor antagonist's therapy led to the diagnosis of Liddle syndrome. Increased aldosterone levels should always be evaluated with caution before a definitive diagnosis to prevent misdiagnosis. Genetic testing is the gold standard for the diagnosis of Liddle syndrome. Early diagnosis and early precise treatment can restore normal blood pressure and prevent severe sequelae of chronic hypertension in patients.

Liddle syndrome: A case report.

INTRODUCTION: Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalaemia and can be treated using ENaC blockers (amiloride and aminopterin). PATIENTS AND METHODS: This report describes a 17-year-old male with hypertension and hypokalaemia. We performed a Captopril inhibition test and a postural stimulation test for the diagnosis and typing of primary aldosteronism. RESULTS: The serum renin was low, and aldosterone was high, so the patient was initially misdiagnosed as primary aldosteronism. After a genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of an SCNN1B p.Pro617Ser mutation. After diagnosis, the patient was administered one tablet of amiloride twice a day (each tablet contains 2.5mg of amiloride hydrochloride and 25mg of hydrochlorothiazide 25mg). The patient's blood pressure (average of 120-135/70-80mmHg) and serum potassium levels (3.6-4.0mmol/L) returned to normal and were well-controlled after treatment. DISCUSSION: The patient is an atypical case of Liddle syndrome; genetic analysis is helpful and essential for diagnosis.

Synergistic cardioptotection by tilianin and syringin in diabetic cardiomyopathy involves interaction of TLR4/NF-κB/NLRP3 and PGC1a/SIRT3 pathways.

Diabetic cardiomyopathy (DCM) is a chronic multifactorial complication of type-2 diabetes mellitus, leading to heart failure. A combination of multifaceted therapeutics for the management of DCM is needed. Here, we investigated the combined effect of syringin and tilianin on DCM by evaluating cardiac function, inflammation, oxidative stress, apoptosis and mitochondrial function, and explored the contribution of TLR4/NF-κB/NLRP3 and PGC1α/SIRT3 pathways in diabetic rats and hyperglycemic-H9c2 cells. Syringin and tilianin (50 and 60 mg/kg, i.p, respectively) were administered for eight weeks, individually or in combination, to healthy and type-2 diabetic Sprague-Dawley rats. Myocardial function was recorded using a carotid catheter, mitochondrial and histopathological changes were evaluated by fluorometric and staining methods, cardiac markers and signaling pathways' proteins expression were measured through ELISA and immunoblotting. In comparison to individual treatments, combination of syringin and tilianin effectively exerted antidiabetic effects and improved cardiac function and DCM markers, reduced NLRP3/IL-6/IL-1ß/TNF-α expression, and suppressed diabetes/hyperglycemia­induced oxidative stress in rats' heart and H9c2 cells, as demonstrated by decreased 8-isoprostane, and increased superoxide dismutase-2 levels. Mitochondrial membrane depolarization and ROS production were inhibited, and caspase-3 and Bax/Bcl2 expression downregulated by combination therapy. Combined treatment markedly inhibited up-regulation of TLR4, MyD88 and NF-κB in diabetic rats. Finally, inhibition of PGC1α/SIRT3 pathway by 3-TYP in hyperglycemic H9c2-cells reversed the beneficial effects of combination therapy on cardiomyocytes injury and NF-κB/NLRP3/IL-1ß expression, without affecting TLR4/MyD88 expression. Syringin plus tilianin synergistically inhibited the diabetes-induced cardiac functional, biochemical and histopathological changes in DCM. Crosstalk between TLR4/NF-κB/NLRP3 and PGC1α/SIRT3/mitochondrial pathways contributed to this protection.

Prognostic Value of ANXA8 in Gastric Carcinoma.

Gastric carcinoma (GC) remains one of the most common and deadly cancers worldwide. In China, the incidence and mortality rates related to GC were quite high. Annexin A8 (ANXA8) is a member of the annexins family of calcium-dependent membrane phospholipid binding proteins. According to recent research, the up-regulation of ANXA8 is closely associated with various types of tumors. However, the specific role of ANXA8 in GC remains unclear. In our study, we explored the prognostic value of ANXA8 in GC. Here, with the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE19826 and GSE13861) analyzed, we further performed quantitative real-time polymerase chain reaction (qRT-PCR) using 58 pairs of fresh-frozen tissues. We also subjected 152 pairs of formalin-fixed, paraffin-embedded GC tumor tissues from patients, and the adjacent normal gastric tissues (ANGTs) to immunohistochemical (IHC) analysis. Hence, we found an elevated expression of ANXA8 in tumor tissues with bioinformatics analyses, qRT-PCR, western blot and IHC. Over-expression of ANXA8 was strongly correlated with TNM stages and differentiation grades. Kaplan-Meier and cox proportional-hazard analyses showed that the increased expression of ANXA8 was strongly associated with overall survival (OS) and disease-free survival (DFS) in GC patients. Moreover, we found that ANXA8 is an independent prognostic factor of GC patients' OS and DFS. In brief, those results suggest that ANXA8 can act as an oncogene of GC development and can serve as a potential prognostic biomarker for GC treatment.

The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.

INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade. METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel. RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy. CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.

Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with severe pulmonary fibrosis. The main cause of IPF-associated death is acute exacerbation of IPF (AE-IPF). This study aims to develop a rat model of AE-IPF by two intratracheal perfusions with bleomycin (BLM). METHODS: Ninety male Sprague Dawley (SD) rats were randomized into three groups: an AE-IPF model group (BLM + BLM group), an IPF model group (BLM group), and a normal control group. Rats in the BLM + BLM group underwent a second perfusion with BLM on day 28 after the first perfusion with BLM. Rats in the other two groups received saline as the second perfusion. Six rats in each group were sacrificed on day 31, day 35, and day 42 after the first perfusion, respectively. Additional 18 rats in each group were observed for survival. RESULTS: Rats in the BLM + BLM group had significantly worse pulmonary alveolar inflammation and fibrosis than rats in the BLM group. Rats in the BLM + BLM group also developed large amounts of hyaline membrane, showed high levels of albumin (ALB) and various inflammatory factors in the bronchoalveolar lavage fluid (BALF), and had markedly increased lung water content. Furthermore, rat survival was reduced in the BLM + BLM group. The pathophysiological characteristics of rats in the BLM + BLM group resemble those of patients with AE-IPF. CONCLUSIONS: A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats.

Serum Krebs von den Lungen-6 level as a diagnostic biomarker for interstitial lung disease in Chinese patients.

OBJECTIVES: The purpose of this study was to determine the diagnostic and prognostic values of serum KL-6 levels in Chinese patients with interstitial lung disease (ILDs). METHODS: A total of 1084 subjects including 373 cases of ILDs, 584 cases of non-ILD pulmonary diseases, and 127 healthy individuals were recruited from three clinical centers in China between January 2011 and December 2013. A total of 106 patients undergoing treatments for ILDs in Shanghai Pulmonary Hospital between January 2011 and December 2013 were enrolled. Baseline and posttreatment serum KL-6 levels were determined. RESULTS: Serum KL-6 levels in patients with ILDs were significantly higher than those in patients with non-ILD pulmonary diseases or in healthy individuals (1492.09 ± 2230.08 U/mL vs 258.67 ± 268.73 U/mL or 178.73 ± 71.17 U/mL, all P < 0.05). At the cut-off value of 500 U/mL, the sensitivity and specificity of serum KL-6 as a diagnostic marker for ILDs was 77.75% and 94.51%, respectively. The Kappa value was 0.743 (P < 0.001). The area below the receiver operating characteristic curve was 0.922 with a 95% Confidence interval of 0.904-0.941 (P < 0.001). The posttreatment serum KL-6 levels significantly reduced in patients with improved ILDs, whereas markedly increased in patients with exacerbated ILDs (All P < 0.05). CONCLUSIONS: Serum KL-6 levels might be a promising diagnostic biomarker for ILDs in Chinese patients. The prognostic value of serum KL-6 levels for ILDs remains to be verified by large-scaled studies.

Establishment of the mouse model of acute exacerbation of idiopathic pulmonary fibrosis.

PURPOSE: To explore and establish an animal model of AE-IPF. METHODS: An animal model of idiopathic pulmonary fibrosis (IPF) was established using bleomycin (BLM). Then, BLM was administered a second time on day 21 to induce AE-IPF (which mimics human AE-IPF). Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of AE-IPF was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid (BALF) and the concentrations of six cytokines (IL-4, IL-6, IL-10, IL-17A, MIG, and TGF-ß1) in BALF supernatants, which were closely associated with IPF and AE-IPF. The intervention role of IL-17A antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the AE-IPF group was significantly greater (45%, 9/20) than that in stable-IPF group (0/18) (P = .0017). The average body weight in AE-IPF group was significantly lower than that in stable group (P < .0001). In AE-IPF group, inflammation and fibrosis were severer by histopathology analysis. In BALF, IL-17A, MIG (CXCL-9), IL-6, and TGF-ß1 levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group (P < .01; P = .0281). IL-17A antibody could attenuated the lung inflammation induced by twice BLM challenges. CONCLUSION: A mouse model of AE-IPF can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of AE-IPF.

Blood glucose fluctuations in hemodialysis patients with end stage diabetic nephropathy.

OBJECTIVE: To characterize blood glucose fluctuation during hemodialysis in patients with end stage diabetic nephropathy (ESDN) by a continuous glucose monitoring system (CGMS), and aim to improve blood glucose control in this patient population. METHODS: Forty-six patients with or without type 2 diabetes mellitus (T2DM), receiving hemodialysis, were recruited in this study. Thirty-six patients had end stage diabetic nephropathy (ESDN group), the other ten patients had end stage renal disease without diabetes (ESRD group). A continuous glucose monitoring system (CGMS) was employed to monitor glycemic fluctuation for 72 hours. Blood samples were collected and analyzed. RESULTS: Mean, standard deviation (SD), maximum, and mean amplitude glycemic excursion (MAGE) of blood glucose and the ratio of blood glucose readings that was greater than 13.9 mmol/L of ESDN group, were significantly greater than those of ESRD group (p<0.01 for all) during 72 hours of observation. The mean blood glucose was significantly lower, while SD and MAGE were significantly higher in ESDN group on hemodialysis day than on days off hemodialysis (p<0.05), while these were not been observed in ESRD group. Though mean, SD, and MAGE of blood glucose during hemodialysis were significantly lower than those of peri-hemodialysis in both groups (p<0.01 or p<0.05, respectively), they were significantly higher in ESDN group than that in ESRD group (p<0.05). The mean blood glucose value calculated from HbA1c did not reflect the actual mean blood glucose measured by CGM in both groups, and gave an inaccurate impression of a significantly lower mean glucose. CONCLUSIONS: ESDN patients had larger glycemic fluctuations as compared with ESRD patients. Hemodialysis caused reduction in mean, SD, and MAGE, which in turn caused bigger glycemic fluctuations on hemodialysis day. The HbA1c in ESDN patients gave an inaccurate value, which did not truly reflect blood glucose status for a prolonged period.

A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway.

D-cyclins are universally dysregulated in multiple myeloma and frequently overexpressed in leukemia. To better understand the role and impact of dysregulated D-cyclins in hematologic malignancies, we conducted a high-throughput screen for inhibitors of cyclin D2 transactivation and identified 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161), which inhibited the expression of cyclins D1, D2, and D3 and arrested cells at the G(0)/G(1) phase. After D-cyclin suppression, S14161 induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of leukemia, S14161 inhibited tumor growth without evidence of weight loss or gross organ toxicity. Mechanistically, S14161 inhibited the activity of phosphoinositide 3-kinase in intact cells and the activity of the phosphoinositide 3-kinases α, ß, δ, and γ in a cell-free enzymatic assay. In contrast, it did not inhibit the enzymatic activities of other related kinases, including the mammalian target of rapamycin, the DNA-dependent protein kinase catalytic subunit, and phosphoinositide-dependent kinase-1. Thus, we identified a novel chemical compound that inhibits D-cyclin transactivation via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Given its potent antileukemia and antimyeloma activity and minimal toxicity, S14161 could be developed as a novel agent for blood cancer therapy.