Circulating eosinophils associated with responsiveness to COVID-19 vaccine and the disease severity in patients with SARS-CoV-2 omicron variant infection.

OBJECTIVE: This study aimed to investigate the longitudinal circulating eosinophil (EOS) data impacted by the COVID-19 vaccine, the predictive role of circulating EOS in the disease severity, and its association with T cell immunity in patients with SARS-CoV-2 Omicron BA.2 variant infection in Shanghai, China. METHODS: We collected a cohort of 1,157 patients infected with SARS-CoV-2 Omicron/BA.2 variant in Shanghai, China. These patients were diagnosed or admitted between Feb 20, 2022, and May 10, 2022, and were classified as asymptomatic (n = 705), mild (n = 286) and severe (n = 166) groups. We compiled and analyzed data of patients' clinical demographic characteristics, laboratory findings, and clinical outcomes. RESULTS: COVID-19 vaccine reduced the incidence of severe cases. Severe patients were shown to have declined peripheral blood EOS. Both the 2 doses and 3 doses of inactivated COVID-19 vaccines promoted the circulating EOS levels. In particular, the 3rd booster shot of inactivated COVID-19 vaccine was shown to have a sustained promoting effect on circulating EOS. Univariate analysis showed that there was a significant difference in age, underlying comorbidities, EOS, lymphocytes, CRP, CD4, and CD8 T cell counts between the mild and the severe patients. Multivariate logistic regression analysis and ROC curve analysis indicate that circulating EOS (AUC = 0.828, p = 0.025), the combination of EOS and CD4 T cell (AUC = 0.920, p = 0.017) can predict the risk of disease severity in patients with SARS-CoV-2 Omicron BA.2 variant infection. CONCLUSIONS: COVID-19 vaccine promotes circulating EOS and reduces the risk of severe illness, and particularly the 3rd booster dose of COVID-19 vaccine sustainedly promotes EOS. Circulating EOS, along with T cell immunity, may have a predictive value for the disease severity in SARS-CoV-2 Omicron infected patients.

Broad-spectrum antibiotics associated gut microbiome disturbance impairs T cell immunity and promotes lung cancer metastasis: a retrospective study.

BACKGROUND: Gut microbiome has been linked to a regulatory role in cancer progression. However, whether broad-spectrum antibiotics (ATB) associated gut microbiome dysbiosis contributes to an impaired T cell immune function, and ultimately promotes lung cancer metastasis is not well known. METHODS: In this study, a retrospective analysis was performed in a cohort of 263 patients initially diagnosed with non-small cell lung cancer (NSCLC) patients, including the ATB group (patients with broad-spectrum antibiotics treatment) (n = 124), and non-ATB group (n = 139) as control. ATB patients were prescribed ATB for over 5 days within 30 days prior to the collection of blood and fecal specimens and followed surgical treatment or first-line therapy. T cell immune function and metastasis-free survival (MFS) were evaluated between the two groups. Gut microbiota was evaluated by 16S rDNA sequencing. The predictive value of T cell immunity for MFS was evaluated by ROC analysis and Cox regression analysis. RESULTS: Our results suggest that broad-spectrum antibiotics (ATB) impair T cell immune function in patients with either early-stage or advanced NSCLC, which likely contribute to the promotion of lung cancer metastasis. Results of the survival analysis show that metastasis-free survival (MFS) is significantly shorter in the ATB patients than that in the non-ATB patients with stage III NSCLC. The 16S rDNA sequencing shows that ATB administration contributes to a significant dysbiosis of the composition and diversity of gut microbiota. Moreover, ROC analysis results of CD4 (AUC 0.642, p = 0.011), CD8 (AUC was 0.729, p < 0.001), CD16 + 56 + (AUC 0.643, p = 0.003), and the combination of CD4, CD8 and CD16 + 56+ (AUC 0.810, p < 0.001), or Cox regression analysis results of CD4 (HR 0.206, p < 0.001), CD8 (HR 0.555, p = 0.009), which is likely regulated by ATB administration, have significantly predictive values for MFS. CONCLUSION: These results provide evidence of gut microbiome disturbance due to ATB administration is involved in the regulation of T cell immunity, and their predictive value for the tumor metastasis in lung cancer patients. Thus, gut microbiota may serve as a therapeutic target for lung cancer. Consequently, caution should be exercised before the long-term administration of broad-spectrum antibiotics in cancer patients.

Clinical characteristics and risk factors predictive of pulmonary embolism complicated in bronchiectasis patients: a retrospective study.

OBJECTIVE: Pulmonary embolism (PE) is a rare complication in bronchiectasis (BE) patients associated with a high rate of mortality and morbidity. However, data regarding bronchiectasis patients complicated with PE are limited. Early diagnosis of PE in bronchiectasis patients can improve the prognosis, this study aimed to investigate the clinical features and potential risk factors for early diagnosis of PE in bronchiectasis patients. METHODS: Data of Patients were collected from Tongji Hospital of Tongji University of China. Bronchiectasis patients complicated with pulmonary embolism were named as BE/PE group (n = 63), as well as contemporaneous aged- and sex-matched bronchiectasis patients without pulmonary embolism named as BE group (n = 189), at a ratio of 1:3(cases to controls). Clinical parameters and risk factors were analyzed. RESULTS: Univariate analysis shows that long-term bed rest, chronic lung disease, autoimmune disease, peripheral artery disease (PAD), tuberculosis history, dyspnea, blood homocysteine, CD4/CD8 ratio, or SIQIIITIII syndrome were closely correlated with the incidence of PE in the bronchiectasis patients (p < 0.05). Multivariate logistic regression analysis of significant variables showed that CD4/CD8 ratio (OR 1.409, 95% CI 1.045-1.901) and autoimmune disease (OR 0.264, 95% CI 0.133-0.524) are independent risk factors for BE/PE patients, compared with the BE patients. 53 out of 189 (28.0%) BE patients had hemoptysis, and 15 out of 63 (23.8%) BE/PE patients had hemoptysis (p > 0.05). CONCLUSIONS: The coexistence of pulmonary embolism and bronchiectasis are rarely encountered and easily to be ignored. Early identification of the clinical characteristic and potential risk factors of pulmonary embolism in bronchiectasis patients may help optimize the treatment strategies.

Landscape of tumoral ecosystem for enhanced anti-PD-1 immunotherapy by gut Akkermansia muciniphila.

Gut Akkermansia muciniphila (Akk) has been implicated in impacting immunotherapy or oncogenesis. This study aims to dissect the Akk-associated tumor immune ecosystem (TIME) by single-cell profiling coupled with T cell receptor (TCR) sequencing. We adopted mouse cancer models under anti-PD-1 immunotherapy, combined with oral administration of three forms of Akk, including live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc_1100 (Amuc). We show that live Akk is most effective in activation of CD8 T cells by rescuing the exhausted type into cytotoxic subpopulations. Remarkably, only live Akk activates MHC-II-pDC pathways, downregulates CXCL3 in Bgn(+)Dcn(+) cancer-associated fibroblasts (CAFs), blunts crosstalk between Bgn(+)Dcn(+) CAFs and PD-L1(+) neutrophils by a CXCL3-PD-L1 axis, and further suppresses the crosstalk between PD-L1(+) neutrophils and CD8 T cells, leading to the rescue of exhausted CD8 T cells. Together, this comprehensive picture of the tumor ecosystem provides deeper insights into immune mechanisms associated with gut Akk-dependent anti-PD-1 immunotherapy.

COVID-19 vaccination is associated with enhanced efficacy of anti-PD-(L)1 immunotherapy in advanced NSCLC patients: a real-world study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccine has played a major role in ending the pandemic. However, little is known about the influence of COVID-19 vaccine on the efficacy of immunotherapy in patients with non-small cell lung cancer (NSCLC). OBJECTIVES: The goal of this study is to explore whether COVID-19 vaccine impacts the efficacy of immune checkpoint inhibitors (ICIs) in NSCLC patients. METHODS: We retrospectively analyzed the survival data of ICI-treated 104 patients with stage III-IV NSCLC, who either received COVID-19 vaccination (n = 25) or no vaccination (n = 79). The potential risk factors, in particular roles of COVID-19 vaccination in the efficacy of ICIs in these patients, were evaluated. RESULTS: Our results showed significantly improved ORR (28.0% vs. 11.39%, p = 0.05) and DCR (88.0% vs. 54.43%, p = 0.005) in the COVID-19 vaccinated group compared with the non-vaccinated group. Regarding the long-term survival benefits, COVID-19 vaccine showed profound influence both on the PFS (HR = 0.16, p = 0.021) and OS (HR = 0.168, p = 0.019) in patients with NSCLC under ICIs treatment. The PFS (p < 0.001) or OS (p < 0.001) was significantly improved in the COVID-19 vaccinated group, compared with the non-vaccinated group. Moreover, CD4 T cell (p = 0.047) level was higher in the COVID-19 vaccinated group than in the non-vaccinated group. CONCLUSIONS: COVID-19 vaccination enhances anti-PD-1 immunotherapy efficacy in patients with stage III-IV NSCLC, suggesting that COVID-19 vaccination may provide additional benefit to NSCLC patients.

Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of gut Akkermansia muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in mice.

Although gut microbiota has been linked to cancer, little is known about the crosstalk between gut- and intratumoral-microbiomes. The goal of this study was to determine whether gut Akkermansia muciniphila (Akk) is involved in the regulation of intratumoral microbiome and metabolic contexture, leading to an anticancer effect on lung cancer. We evaluated the effects of gut endogenous or gavaged exogenous Akk on the tumorigenesis using the Lewis lung cancer mouse model. Feces, blood, and tumor tissue samples were collected for 16S rDNA sequencing. We then conducted spatially resolved metabolomics profiling to discover cancer metabolites in situ directly and to characterize the overall Akk-regulated metabolic features, followed by the correlation analysis of intratumoral bacteria with metabolic network. Our results showed that both endogenous and exogenous gavaged Akk significantly inhibited tumorigenesis. Moreover, we detected increased Akk abundance in blood circulation or tumor tissue by 16S rDNA sequencing in the Akk gavaged mice, compared with the control mice. Of great interest, gavaged Akk may migrate into tumor tissue and influence the composition of intratumoral microbiome. Spatially resolved metabolomics analysis revealed that the gut-derived Akk was able to regulate tumor metabolic pathways, from metabolites to enzymes. Finally, our study identified a significant correlation between the gut Akk-regulated intratumoral bacteria and metabolic network. Together, gut-derived Akk may migrate into blood circulation, and subsequently colonize into lung cancer tissue, which contributes to the suppression of tumorigenesis by influencing tumoral symbiotic microbiome and reprogramming tumoral metabolism, although more studies are needed.

Oral activated charcoal suppresses hyperphosphataemia in haemodialysis patients.

AIM: Hyperphosphataemia is almost inevitable in end stage renal disease (ESRD) patients and is associated with increased morbidity and mortality. In this study we examined whether oral activated charcoal (oAC) reduces serum phosphate level in haemodialysis patients. METHODS: This was an open-label, prospective, uncontrolled study. One hundred and thirty-five haemodialysis patients were included in this study, with cessation of treatment with any phosphate binders during a 2 week washout period. Patients with serum phosphate levels greater than 5.5 mg/dL during the washout period were included for treatment with oAC. oAC was started at a dose of 600 mg three times per day with meals and was administered for 24 weeks. oAC dose was titrated up during the 24 week period to achieve phosphate control (3.5-5.5 mg/dL). A second 2 week washout period followed the end of oAC treatment. RESULTS: In the 114 patients who successfully completed the trial, the mean dose of activated charcoal was 3190 ± 806 mg/day. oAC reduced mean phosphate levels to below 5.5 mg/dL, with mean decreases of 2.60 ± 0.11 mg/dL (P < 0.01) and 103 (90.4%) of the patients reached the phosphate target. After the second washout period the phosphate levels increased to 7.50 ± 1.03 mg/dL (P < 0.01). Serum intact parathyroid hormone (iPTH) levels declined from 338.75 ± 147.77 pg/mL to 276.51 ± 127.82 pg/mL (P < 0.05) during the study. oAC had no influence on serum prealbumin, total cholesterol, triglycerides, serum ferritin, haemoglobin or platelet levels and the levels of 1,25-dihydroxyvitamin D were stable during the study. CONCLUSION: In this open-label uncontrolled study, oAC effectively controls hyperphosphataemia and hyperparathyroidism in haemodialysis patients. The safety and efficacy of oAC needs to be assessed in a randomized controlled trial.

Association between microalbuminuria and subclinical atherosclerosis evaluated by carotid artery intima-media in elderly patients with normal renal function.

BACKGROUND: Moderate to severe renal insufficiency and albuminuria have been shown to be independent risk factors for atherosclerosis. However, little is known about the direct association between subclinical atherosclerosis evaluated by carotid artery intima-media thickness (IMT) and microalbuminuria in elderly patients with normal renal function. METHODS: Subjects were 272 elderly patients (age ≥ 60 years) with normoalbuminuria (n = 238) and microalbuminuria (n = 34). Carotid IMT was measured by means of high-resolution B-mode ultrasonography. Estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2 was defined as normal renal function. Those who had macroalbuminuria and atherosclerotic vascular disease were not included. RESULTS: Compared to subjects with normoalbuminuria, subjects with microalbuminuria had higher mean carotid IMT (1.02 ± 0.38 vs. 0.85 ± 0.28 mm; P < 0.01) and maximal IMT (1.86 ± 0.86 vs. 1.60 ± 0.73 mm; P = 0.06). By a multiple linear regression, microalbuminuria positively correlated with mean carotid IMT after adjusting for traditional cardiovascular disease risk factors including age, sex, hypertension, diabetes, smoking, total cholesterol, pulse pressure, waist circumference, serum uric acid. As a categorical outcome, the prevalence of the highest mean cariotid IMT quartile (increased IMT ≥ 1.05 mm) was compared with the lower three quartiles. After adjusted for potential confounders, microalbuminuria was associated with increased carotid IMT, with an odds ratio of 2.95 [95 % confidence interval, 1.22 - 7.10]. eGFR was not significantly associated with mean carotid IMT in our analysis. CONCLUSIONS: A slight elevation of albuminuria is a significant determinant of carotid IMT independent of traditional cardiovascular risk factors in our patients. Our study further confirms the importance of intensive examinations for the early detection of atherosclerosis when microalbuminuria is found in elderly patients, although with normal renal function.

Case report: Acute oxalate nephropathy due to traditional medicinal herbs.

Acute oxalate nephropathy (AON), defined as the association between acute kidney injury (AKI) and the deposition of oxalate crystals in the renal parenchyma, is a rare complication of hyperoxaluria. We report a rare case of AON in an adult due to medicinal herbs intake leading to crystal-induced AKI. We recommend that a thorough medication history including the use of medicinal herbs, should be obtained for all patients with a rapid loss of kidney function, especially in the absence of known risk factors for AKI. The use of medicinal herbs with unknown oxalate contents would increase the risk of AON and should be avoided.

Gut microbiota regulate tumor metastasis via circRNA/miRNA networks.

BACKGROUND: Increasing evidence indicates that gut microbiota plays an important role in cancer progression. However, the underlying mechanism remains largely unknown. Here, we report that broad-spectrum antibiotics (ABX) treatment leads to enhanced metastasis by the alteration of gut microbiome composition. METHODS: Cancer LLC and B16-F10 cell metastasis mouse models, and microarray/RNA sequencing analysis were used to reveal the regulatory functions of microbiota-mediated circular RNA (circRNA)/microRNA (miRNA) networks that may contribute to cancer metastasis. RESULTS: The specific pathogen-free (SPF) mice with ABX treatment demonstrated enhanced lung metastasis. Fecal microbiota transplantation (FMT) from SPF mice or Bifidobacterium into germ-free mice significantly suppressed lung metastasis. Mechanistically, gut microbiota impacts circRNA expression to regulate levels of corresponding miRNAs. Specifically, such modulations of gut microbiota inhibit mmu_circ_0000730 expression in an IL-11-dependent manner. Bioinformatics analysis combined with luciferase reporter assays revealed reciprocal repression between mmu_circ_0000730 and mmu-miR-466i-3p. We further showed that both mmu-miR-466i-3p and mmu-miR-466 f-3p suppresses a number of genes involved in epithelial-mesenchymal transition (EMT) and stemness of cancer stem cells such as SOX9. CONCLUSIONS: These results provide evidence of a previously unrecognized regulatory role of non-coding RNAs in microbiota-mediated cancer metastasis, and thus, the microbiome may serve as a therapeutic target.

Regulation of androgen receptor splice variant AR3 by PCGEM1.

The androgen receptor (AR) is required for prostate development and is also a major driver of prostate cancer pathogenesis. Thus androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, castration resistance due to expression of constitutively active AR splice variants is a significant challenge to prostate cancer therapy; little is known why effectiveness of ADT can only last for a relatively short time. In the present study, we show that PCGEM1 interacts with splicing factors heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and U2AF65, as determined by RNA precipitation and Western blot, suggesting a role for PCGEM1 in alternative splicing. In support of this possibility, PCGEM1 is correlated with AR3, a predominant and clinically important form of AR splice variants in prostate cancer. Moreover, androgen deprivation (AD) induces PCGEM1 and causes its accumulation in nuclear speckles. Finally, we show that the AD-induced PCGEM1 regulates the competition between hnRNP A1 and U2AF65 for AR pre-mRNA. AD promotes PCGEM1 to interact with both hnRNP A1 and U2AF65 with different consequences. While the interaction of PCGEM1 with hnRNP A1 suppresses AR3 by exon skipping, its interaction with U2AF65 promotes AR3 by exonization. Together, we demonstrate an AD-mediated AR3 expression involving PCGEM1 and splicing factors.

Lung fluorescence imaging to evaluate tumor metastasis induced by AQP5 expression in murine model.

Our recent study, by up-regulation of AQP5 expression, showed enhanced proliferation and migration potential in lung cancer. However, so far none of the in vivo study of gene silencing of AQP5 has been tested. In this study, we tested roles of AQP5 on lung cancer metastasis potential by gene silencing of AQP5 in two lung cancer cell lines and tried to monitor lung metastases with EGFP marker. Lungs were imaged at different time points and allowed an accurate evaluation of tumor burden over time. Our results showed significantly decreased metastasis potential in AQP5 gene-silencing cells. Lung imaging confirmed the frequency of metastasis in mice. These data provide more evidence that AQP5 plays important roles in the metastasis potential of lung cancer. Lung fluorescence imaging provides rapid monitoring for tumor growth and metastasis, and it also offers quantitative and sensitive analysis of tumor growth and metastasis, compared to the traditional histology technique.

Aquaporin 5 expression increases mucin production in lung adenocarcinoma.

Our recent studies have demonstrated that AQP5 is involved in the metastatic potential of lung cancer. Here, our aim was to explore the effects of AQP5 expression on mucin production in lung adenocarcinoma. We tested MUC5AC and MUC5B mucin production induced by AQP5 expression in lung adenocarcinoma metastasis. Lung adenocarcinoma cells with different levels of AQP5 expression were used in this study. In another set of experiments, deletion of AQP5 was studied using AQP5 (-/-) mice. Significantly increased expression of MUC5AC and MUC5B mucin was found in AQP5 high-expressing tumor cells, which suggested that mucin production induced by AQP5 may contribute to the enhanced metastatic potential in lung adenocarcinoma cells. Our results also showed that AQP5 expression increases MUC5AC and MUC5B mucin production and that this may be partly through the EGFR signaling pathway. In brief, our results provide evidence that mucin production induced by AQP5 expression may play important roles in enhanced metastasis potential in lung adenocarcinoma.