Effect of Laryngopharyngeal Reflux and Potassium-Competitive Acid Blocker (P-CAB) on the Microbiological Comprise of the Laryngopharynx.

OBJECTIVE: To probe the microbiota composition progressing from healthy individuals to those with laryngopharyngeal reflux disease (LPRD) and subsequently undergoing potassium-competitive acid inhibitor (P-CAB) therapy. STUDY DESIGN: Prospective case-control study. SETTING: Academic Medical Center. METHODS: Forty patients with LPRD and 51 patients without LPRD were recruited. An 8-week P-CAB therapy was initiated (post-T-LPRD), and 39 had return visits. In total, 130 laryngopharyngeal saliva samples were collected and sequenced by targeting the V3-V4 region of the 16S ribosomal RNA (rRNA) gene using an Illumina MiSeq. Amplicon sequence variants (ASVs) and clinical indices were analyzed. RESULTS: Alpha and beta diversities were compared among the non-LPRD, LPRD, and post-T-LPRD groups, and the Observed_ASVs were not significantly different. At the same time, the Shannon and Simpson indices, unweighted Unifrac, weighted Unifrac, and binary Jaccard distance were significantly different between non-LPRD and LPRD groups. In addition, significant differences were found in the abundance of Streptococcus, Prevotella, and Prevotellaceae in the LPRD versus non-LPRD groups, and Neisseria, Leptotrichia, and Allprevotella in the LPRD versus post-T-LPRD groups. The genera model was used to distinguish patients with LPRD from those without, and a better receiver operating characteristic curve was formed after combining the clinical indices of reflux symptom index, reflux finding score, and pepsin, with an area under the curve of 0.960. CONCLUSION: Laryngopharyngeal microbial communities changed after laryngopharyngeal reflux and were modified further after P-CAB treatment, which provides a potential diagnostic value for LPRD, especially when combined with clinical indices.

Combined exposure to manganese and iron decreases oxidative stress-induced nerve damage by increasing Nrf2/HO-1/NQO1 expression.

BACKGROUND: Manganese (Mn) and iron (Fe) are essential trace elements for humans, yet excessive exposure to Mn or Fe can accumulate in the central nervous system (CNS) and cause neurotoxicity. The purpose of this study was to investigate the effects of Mn and Fe exposure, alone or in combination, on inducing oxidative stress-induced neurological damage in rat cortical and SH-SY5Y cells, and to determine whether combined exposure to these metals increases their individual toxicity. METHODS: SH-SY5Y cells and male Sprague-Dawley rats were used to observe the effects of oxidative stress-induced neurological damage induced by exposure to manganese and iron alone or in combination. To detect the expression of anti-oxidative stress-related proteins, Nrf2, HO-1, and NQO1, and the apoptosis-related proteins, Bcl2 and Bax, and the neurological damage-related protein, α-syn. To detect reactive oxygen species generation and apoptosis. To detect the expression of the rat cortical protein Nrf2. To detect the production of proinflammatory cytokines. RESULTS: We demonstrate that juvenile developmental exposure to Mn and Fe and their combination impairs cognitive performance in rats by inducing oxidative stress causing neurodegeneration in the cortex. Mn, Fe, and their combined exposure increased the expression of ROS, Bcl2, Bax, and α-syn, activated the inflammatory factors IL-6 and IL-12, inhibited the activities of SOD and GSH, and induced oxidative stress-induced neurodegeneration both in rats and SH-SY5Y cells. Combined Mn-Fe exposure attenuated the oxidative stress induced by Mn and Fe exposure alone by increasing the expression of antioxidant factors Nrf2, HO-1, and NQO1. CONCLUSION: In both in vivo and in vitro studies, manganese and iron alone or in combination induced oxidative stress, leading to neuronal damage. In contrast, combined exposure to manganese and iron mitigated the oxidative stress induced by exposure to manganese and iron alone by increasing the expression of antioxidant factors. Therefore, studies to elucidate the main causes of toxicity and establish the molecular mechanisms of toxicity should help to develop more effective therapeutic modalities in the future.

Simultaneous quantification of donafenib, sorafenib, and their N-oxide metabolites in rat plasma using a HPLC-MS/MS method.

Donafenib and sorafenib are small molecule chemotherapy drugs for the management of hepatocellular carcinoma, with donafenib being a deuterated derivative of sorafenib. To date, a high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that quantify donafenib, sorafenib, and their main metabolites has not yet been developed. The objective of this study was to establish a HPLC-MS/MS method for the simultaneous detection of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide and for the pharmacokinetic studies in rat. The extraction of all analytes was achieved by simple protein precipitation utilizing acetonitrile. The Waters XBridge C18 column (2.1 × 100 mm, 3.5 µm) was selected, and the analytes could be efficiently separated and quantitated during a 2.8 min gradient elution procedure. The method was linear within the predefined quantification ranges and provided acceptable precision (%CV < 9.4%), reproducible extraction recovery (99.4%-111.5%), and low matrix effect (88.1%-98.6%). The hemolysis effect did not interfere with the quantification of all analytes, and similar results were obtained by changing the anticoagulant K2-EDTA to heparin or sodium citrate. Plasma pharmacokinetics revealed that the values of t1/2, Cmax, and AUC0-t of donafenib were 1.4-, 6.2-, and 3.1-fold higher than those of sorafenib, respectively. In conclusion, the proposed bioassay was successfully applied to pharmacokinetic studies in rat after administration of donafenib and sorafenib. Our work not only improves the bioanalytical method for determining the plasma concentrations of donafenib, sorafenib, and their N-oxide metabolites, but also provides a scientific reference for clinical pharmacokinetic studies.

Depressive symptoms and sleep duration in relation to chronic kidney disease: Evidence from the China health and retirement longitudinal study.

OBJECTIVE: Nowadays, the joint effects of depressive symptoms and sleep duration on the risk of chronic kidney disease (CKD) are still unclear. We aimed to prospectively assess the combined effect of depressive symptoms and sleep duration on the incidence of CKD in middle-aged and elderly Chinese population. METHODS: A total of 10,953 participants from the China Health and Retirement Longitudinal Study (CHARLS) were included. Depressive symptoms were measured using the 10-item Center for Epidemiological Studies Depression scale (CESD-10). Sleep duration was evaluated by self-reported. CKD events were based on self-reported physicians' diagnosis or personal estimate glomerular filtration rate level (eGFR <60 mL/min/1.73 m2). Cox regression models were established to analyze the correlation between depressive symptoms, sleep duration and the risk of CKD. RESULTS: Over a mean follow-up time was 6.76 ± 0.98 years, 851 (7.8%) participants had reported CKD events during the follow-up. Elevated depressive symptoms (HR = 1.65, 95% CI = 1.43-1.90) and short sleep duration (HR = 1.48, 95% CI = 1.27-1.72) were independently associated with an increased CKD risk after adjusting for potential confounding factors. Participants with short sleep duration (< 6 h)/elevated depressive symptoms (HR = 2.24, 95% CI = 1.89-2.65) were associated with the highest risk of CKD than those with normal sleep duration/low depressive symptoms. CONCLUSIONS: Elevated depressive symptoms and short sleep duration were independent risk factors for CKD. There was a combined effect between depressive symptoms and sleep duration in increasing the risk of CKD.

[Retracted] SB-T-121205, a next-generation taxane, enhances apoptosis and inhibits migration/invasion in MCF-7/PTX cells.

Following the publication of this paper, and subsequently to a corrigendum that was published to take account of errors that had been made concerning the Transwell invasion assay data in Fig. 4B (doi: 10.3892/ijo.2022.5463), it was drawn to the Editor's attention by a concerned reader that the western blots shown in Figs. 3C and 6B shared the same control data; moreover, potential anomalies were identified in the flow cytometric plots shown in Fig. 2A. Although the authors proposed to publish a corrigendum to account for these errors, including new data after having performed certain of the experiments again, given the number of problems that have been identified concerning the assembly of various of the figures in the published paper, the Editor of International Journal of Oncology has decided not to publish a further corrigendum, and has, in fact, determined that this paper should be retracted from the Journal on account of an overall lack of confidence in the originally presented data. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 50: 893-902, 2017; DOI: 10.3892/ijo.2017.3871].

Comprehensive analysis of the lncRNAs-related immune gene signatures and their correlation with immunotherapy in lung adenocarcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified. METHODS: We screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients. RESULTS: We observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups. CONCLUSIONS: Overall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.

Novel cell subtypes of SPP1 + S100P+, MS4A1-SPP1 + S100P+ were key subpopulations in intrahepatic cholangiocarcinoma.

BACKGROUND: In this study, we integrated single-cell RNA sequencing (scRNA-seq) data to investigate cell heterogeneity and utilized MSigDB and CIBERSORTx to explore the pathways of major cell types and the relationships between different cell subtypes. Subsequently, we explored the correlation of cell subtypes with survival and used Gene Set Enrichment Analysis (GSEA) analyses to assess the pathways associated with the infiltration of specific cell subtypes. Finally, multiplex immunohistochemistry in tissue microarray cohort were performed to validate differences in protein level and their correlation with survival. RESULTS: iCCA presented a unique immune ecosystem, with increased proportions of Epi (epithelial)-SPP1-2, Epi-S100P-1, Epi-DN (double negative for SPP1 and S100P expression)-1, Epi-DN-2, Epi-DP (double positive for SPP1 and S100P expression)-1, Plasma B-3, Plasma B-2, B-HSPA1A-1, B-HSPA1A-2 cells, and decreased proportions of B-MS4A1. High level of Epi-DN-2, Epi-SPP1-1, Epi-SPP1-2, B-MS4A1, and low level of Epi-DB-1, Epi-S100P-1, and Epi-S100P-2 was significantly associated with longer overall survival (OS), and high level of B-MS4A1_Low_Epi-DN-2_Low was associated with the shortest OS. Moreover, the results of MsigDB and GSEA suggest that bile acid metabolism is a crucial process in iCCA. Finally, we found that S100P+, SPP1+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ were highly expressed, whereas MS4A1 was lowly expressed in iCCA, and patients with high level of S100P+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ exhibited shorter survival. CONCLUSIONS: We identified the cell heterogeneity of iCCA, found that iCCA is a unique immune ecosystem with many cell subtypes, and showed that the novel cell subtypes of SPP1 + S100P+ and MS4A1-SPP1 + S100P+ were key subpopulations in iCCA.

Source apportionment and human health risk of PAHs accumulated in edible marine organisms: A perspective of "source-organism-human".

Most PAHs produced by human activities can be absorbed and accumulated by edible organisms and pose a potential hazard to human health. However, the source apportionment and human health risk of PAHs accumulated in edible organisms remains largely unknown. Therefore, we conducted source analysis and health risk assessment based on the PAH concentrations in ten marine fish from coastal areas of Guangdong, China. Results showed that the pollution of PAHs in fish organisms was at "Minimally polluted" level, and that all marine fish had the ability to accumulate PAHs. Risk assessment indicated Carcinogenic risk of PAHs in four populations was at a "Cautionary risk" level, with urban children suffered the highest risk. Petroleum pollution, Coal and biomass combustion, and Marine transport emissions were identified as the main anthropogenic sources for PAHs in organisms, and Marine transport emissions accounted for the highest Carcinogenic risk. The Acceptable daily intake for all populations were far below their actual daily intake without causing "Cautionary risk". Our findings provide new insights into the source apportionment and health risk of PAHs from a "source-organism-human" perspective, and suggested that joint management of three anthropogenic sources would be an effective way to prevent the health risks of PAHs.

Single-cell sequencing analysis fibrosis provides insights into the pathobiological cell types and cytokines of radiation-induced pulmonary fibrosis.

BACKGROUND: Radiotherapy is an essential treatment for chest cancer. Radiation-induced pulmonary fibrosis (RIPF) is an almost irreversible interstitial lung disease; however, its pathogenesis remains unclear. METHODS: We analyzed specific changes in cell populations and potential markers by using single-cell sequencing datasets from the Sequence Read Archive database, PERFORMED from control (0 Gy) and thoracic irradiated (20 Gy) mouse lungs at day 150 post-radiation. We performed IHC and ELISA on lung tissue and cells to validate the potential marker cytokines identified by the analysis on rat thoracic irradiated molds (30 Gy). RESULTS: Single-cell sequencing analysis showed changes in abundance across cell types and at the single-cell level, with B and T cells showing the most significant changes in abundance. And four cytokines, CCL5, ICAM1, PF4, and TNF, were significantly upregulated in lung tissues of RIPF rats and cell supernatants after ionizing radiation. CONCLUSION: Cytokines CCL5, ICAM1, PF4, and TNF may play essential roles in radiation pulmonary fibrosis. They are potential targets for the treatment of radiation pulmonary fibrosis.

Protective Effects of Sodium Para-Aminosalicylic Acid on Lead and Cadmium Co-Exposure in SH-SY5Y Cells.

BACKGROUND: Combined exposure to lead and cadmium is common in occupational environments. However, the effects of co-exposure to Pb-Cd on neurotoxicity have not been fully clarified. Sodium para-aminosalicylic acid (PAS-Na) has previously been shown to protect neurons from Pb-induced toxicity. This study aimed to investigate the beneficial effect of PAS-Na against co-exposure to Pb-Cd-induced neurodegeneration in SH-SY5Y cells. METHODS: The MTT assay was used to detect the effects of Pb and Cd alone, or in combination, on SH-SY5Y cell survival. The effects of Pb and Cd alone or in combination on oxidative stress were assessed by reactive oxygen species (ROS) level. Nrf2, the master switch for antioxidant responses, was detected by immunofluorescence. Protein expression levels of PI3K, Akt, p-Akt, Nrf2 and HO-1 were determined by Western blot analysis. RESULTS: MTT assay results established that the survival rate of SH-SY5Y cells was not significantly affected by exposure to 1 µmol/L lead, 0.25 µmol/L cadmium, and 1-fold Pb-Cd mixture (1 µmol/L Pb + 0.25 µmol/L Cd), while 10-fold Pb-Cd combined exposure (10 µmol/L Pb + 2.5 µmol/L Cd) significantly reduced the survival rate of SH-SY5Y cells. Combined Pb-Cd exposure significantly increased intracellular ROS levels, and N-Acetyl-L-cysteine (NAC) treatment in the 10 µmol/L Pb + 2.5 µmol/L Cd group significantly decreased ROS expression levels, attenuating the levels of oxidative stress. Protein expression of PI3K and p-Akt significantly decreased in the 10 µmol/L Pb + 2.5 µmol/L Cd group, while the expression of PI3K and p-Akt protein increased after PAS-Na intervention. Immunofluorescence analysis showed that levels of Nrf2 in the nucleus increased in the 10 µmol/L Pb + 2.5 µmol/L Cd group, along with Nrf2 protein levels, suggesting that Nrf2 was translocated from the cytoplasm into the nucleus upon combined Pb-Cd exposure. In addition, HO-1 protein expression level, a downstream gene product of Nrf2, was increased. In response to NAC intervention, HO-1 protein expression levels significantly decreased. PAS-Na had the same intervention effect as NAC. CONCLUSION: Combined exposure to Pb-Cd induced oxidative stress and cytotoxicity in SH-SY5Y cells. PAS-Na displayed antagonistic effects on neurodegenerative changes induced by combined Pb-Cd exposure; hence, it may afford a novel treatment modality for exposure to these metals.

Research progress on non-protein-targeted drugs for cancer therapy.

Non-protein target drugs, especially RNA-based gene therapies for treating hereditary diseases, have been recognized worldwide. As cancer is an insurmountable challenge, no miracle drug is currently available. With the advancements in the field of biopharmaceuticals, research on cancer therapy has gradually focused on non-protein target-targeted drugs, especially RNA therapeutics, including oligonucleotide drugs and mRNA vaccines. This review mainly summarizes the clinical research progress in RNA therapeutics and highlights that appropriate target selection and optimized delivery vehicles are key factors in increasing the effectiveness of cancer treatment in vivo.

[Corrigendum] SB­T­121205, a next­generation taxane, enhances apoptosis and inhibits migration/invasion in MCF­7/PTX cells.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that Fig. 4B on p. 899, showing the results of Transwell invasion assay experiments, contained a pair of apparently overlapping panels, such that they may have been derived from the same original source, even though they were intended to show the results from differently performed experiments. After having re­examined their original data, the authors were able to identify that Fig. 4B had been inadvertently assembled incorrectly. The revised version of Fig. 4, featuring the correct data for the SB­T­121205, 10 nM data panel (the lower­left panel in Fig. 4B), is shown on the next page. The authors confirm that these data continue to support the main conclusions presented in their paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum. They also apologize to the readership for any inconvenience caused. [International Journal of Oncology 50: 893­902, 2017; DOI: 10.3892/ijo.2017.3871].

Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial.

INTRODUCTION: Long COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, postexertional malaise and cognitive dysfunction. There is currently no effective treatment and the underlying mechanisms are unknown, although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in long COVID-19. This randomised, placebo-controlled clinical trial will explore HBOT as a potential treatment for long COVID-19. The primary objective is to evaluate if HBOT improves health-related quality of life (HRQoL) for patients with long COVID-19 compared with placebo/sham. The main secondary objective is to evaluate whether HBOT improves endothelial function, objective physical performance and short-term HRQoL. METHODS AND ANALYSIS: A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to long COVID-19, with low HRQoL. Clinical data, HRQoL questionnaires, blood samples, objective tests and activity metre data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over 6 weeks. Assessments for safety and efficacy will be performed at 6, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND 36-Item Health Survey) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent data safety monitoring board. ETHICS AND DISSEMINATION: The trial is approved by the Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Products Agency (5.1-2020-36673). Positive, negative and inconclusive results will be published in peer-reviewed scientific journals with open access. TRIAL REGISTRATION NUMBER: NCT04842448.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Identifying and Targeting Prediction of the PI3K-AKT Signaling Pathway in Drug-Induced Thrombocytopenia in Infected Patients Receiving Linezolid Therapy: A Network Pharmacology-Based Analysis.

The pharmacological mechanisms underlying the adverse effects of linezolid on thrombocytopenia have not been conclusively determined. This network pharmacology study aimed at investigating the potential pharmacological mechanisms of linezolid-induced adverse reactions in thrombocytopenia. In this study, target genes for linezolid and thrombocytopenia were compared and analyzed. Overlapping thrombocytopenia-associated targets and predicted targets of linezolid were imported to establish protein-protein interaction networks. Gene Ontology and the Kyoto Encyclopedia of Genes and Genome pathway enrichment analyses were performed to determine the enriched biological terms and pathways. The mechanisms involved in linezolid-induced thrombocytopenia were established to be associated with various biological processes, including T cell activation, peptidyl serine modification, and peptidyl serine phosphorylation. The top five relevant protein targets were obtained, including ALB, AKT1, EGFR, IL6, and MTOR. Enrichment analysis showed that the targets of linezolid were positively correlated with T cell activation responses. The mechanism of action of linezolid was positively correlated with the PI3K-AKT signaling pathway and negatively correlated with the Ras signaling pathway. We identified the important protein targets and signaling pathways involved in linezolid-induced thrombocytopenia in anti-infection therapy, providing new information for subsequent studies on the pathogenesis of drug-induced thrombocytopenia and potential therapeutic strategies for rational use of linezolid in clinical settings.

High Glucose and Carbonyl Stress Impair HIF-1-Regulated Responses and the Control of Mycobacterium tuberculosis in Macrophages.

Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), but the mechanisms behind diabetes-TB comorbidity are still undefined. Here, we studied the role of hypoxia-inducible factor-1 (HIF-1), a main regulator of metabolic and inflammatory responses, in the outcome of Mycobacterium tuberculosis infection of bone marrow-derived macrophages (BMM). We observed that M. tuberculosis infection of BMM increased the expression of HIF-1α and HIF-1-regulated genes. Treatment with the hypoxia mimetic deferoxamine (DFO) further increased levels of HIF-1-regulated immune and metabolic molecules and diminished the intracellular bacterial load in BMM and in the lungs of infected mice. The expression of HIF-1-regulated immunometabolic genes was reduced, and the intracellular M. tuberculosis levels were increased in BMM incubated with high-glucose levels or with methylglyoxal (MGO), a reactive carbonyl compound elevated in DM. In line with the in vitro findings, high M. tuberculosis levels and low HIF-1-regulated transcript levels were found in the lungs from hyperglycemic Leprdb/db compared with wild-type mice. The increased intracellular M. tuberculosis growth and the reduced expression of HIF-1-regulated metabolic and inflammatory genes in BMM incubated with MGO or high glucose were reverted by additional treatment with DFO. Hif1a-deficient BMM showed ablated responses of immunometabolic transcripts after mycobacterial infection at normal or high-glucose levels. We propose that HIF-1 may be targeted for the control of M. tuberculosis during DM. IMPORTANCE People living with diabetes who are also infected with M. tuberculosis are more likely to develop tuberculosis disease (TB). Why diabetic patients have an increased risk for developing TB is not well understood. Macrophages, the cell niche for M. tuberculosis, can express microbicidal mechanisms or be permissive to mycobacterial persistence and growth. Here, we showed that high glucose and carbonyl stress, which mediate diabetes pathogenesis, impair the control of intracellular M. tuberculosis in macrophages. Infection with M. tuberculosis stimulated the expression of genes regulated by the transcription factor HIF-1, a major controller of the responses to hypoxia, resulting in macrophage activation. High glucose and carbonyl compounds inhibited HIF-1 responses by macrophages. Mycobacterial control in the presence of glucose or carbonyl stress was restored by DFO, a compound that stabilizes HIF-1. We propose that HIF-1 can be targeted to reduce the risk of developing TB in people with diabetes.

PSMA5 contributes to progression of lung adenocarcinoma in association with the JAK/STAT pathway.

Proteasome dysregulation is a common feature of cancer and a critical risk for tumorigenesis. However, the characteristics of proteasome components in tumor development and metastasis are poorly understood. PSMA5, an α5 subunit of the 20S core proteasome, is associated with the degradation of intracellular proteins. Increasing evidence indicated that it is involved in tumor development, but the underlying mechanism has remained unknown. Here, we show that PSMA5 is upregulated in lung adenocarcinoma (LUAD) cells and clinical LUAD tissues. Moreover, its upregulation is positively associated with lymph node metastasis and the poor prognosis of LUAD patients. PSMA5 knockdown inhibited the proliferation, invasion and metastasis of LUAD cells in vitro and in vivo, induced apoptosis of LUAD cells and sensitized LUAD cells to cisplatin. Furthermore, investigations revealed that PSMA5 overexpression inhibited cell apoptosis by activating the janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway in LUAD cells. In total, our results demonstrate that PSMA5 may function as a prognostic factor in LUAD. In addition, PSMA5 is a promising therapeutic target for LUAD, as its depletion induces cell apoptosis by inhibiting the JAK/STAT pathway.

Identification of a Prognostic Signature Composed of GPI, IL22RA1, CCT6A and SPOCK1 for Lung Adenocarcinoma Based on Bioinformatic Analysis of lncRNA-Mediated ceRNA Network and Sample Validation.

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors with high morbidity and mortality in China and worldwide. Long non-coding RNAs (lncRNAs) as the competing endogenous RNA (ceRNA) play an essential role in the occurrence and development of LUAD. However, identifying lncRNA-related biomarkers to improve the accuracy of LUAD prognosis remains to be determined. This study downloaded RNA sequence data from The Cancer Genome Atlas (TCGA) database and identified the differential RNAs by bioinformatics. A total of 214 lncRNA, 198 miRNA and 2989 mRNA were differentially identified between LUAD and adjacent nontumor samples. According to the ceRNA hypothesis, we constructed a lncRNA-miRNA-mRNA network including 95 protein-coding mRNAs, 7 lncRNAs and 15 miRNAs, and found 24 node genes in this network were significantly associated with the overall survival of LUAD patients. Subsequently, through LASSO regression and multivariate Cox regression analyses, a four-gene prognostic signature composed of GPI, IL22RA1, CCT6A and SPOCK1 was developed based on the node genes of the lncRNA-mediated ceRNA network, demonstrating high performance in predicting the survival and chemotherapeutic responses of low- and high-risk LUAD patients. Finally, independent prognostic factors were further analyzed and combined into a well-executed nomogram that showed strong potential for clinical applications. In summary, the data from the current study suggested that the four-gene signature obtained from analysis of lncRNA-mediated ceRNA could serve as a reliable biomarker for LUAD prognosis and evaluation of chemotherapeutic response.

Adverse events of different PD-1 inhibitors in lung cancer patients: a real-world study.

Background: Programmed death-1 (PD-1) inhibitors have been approved and are currently widely used to treat lung cancer patients. However, comparative data on the adverse events (AEs) associated with different PD-1 inhibitors are very limited. Methods: Patients with histologically confirmed lung cancer who had been treated with at least 1 dose of PD-1 inhibitors between January 2017 and December 2019 at a tertiary cancer hospital were included in the study. Data on treatment-related AEs (tr-AEs) were collected from their electronic medical records. Results: A total of 227 lung cancer patients treated with nivolumab (n=83), pembrolizumab (n=65), camrelizumab (n=27), sintilimab (n=31), and toripalimab (n=21) were included. In relation to nivolumab, pembrolizumab, camrelizumab, sintilimab, and toripalimab, the incidence rates of all-grade tr-AEs were 37.34%, 24.62%, 62.96%, 29.03% and 9.52%, respectively (P=0.01), and the incidence rates of grade 3-4 tr-AEs were 2.41%, 3.08%, 22.22%, 3.23% and 0%, respectively (P=0.05). The most common all-grade tr-AEs were capillary hemangioma (22.22%) and abnormal liver function (22.22%) for camrelizumab, pneumonitis for nivolumab (12.05%), pembrolizumab (6.15%) and nausea/vomiting (12.9%) for sintilimab, and pneumonitis (4.76%), rash/pruritus (4.76%) and shingles (4.76%) for toripalimab. Sex, age, PD-1 inhibitors, histology type and PD-1 cycles were significantly associated with tr-AEs. Conclusions: There were significant differences in the incidence and most common tr-AEs among the different PD-1 inhibitors. Different monitoring priorities should be given to different PD-1 inhibitors during treatment cycles.

Pharmacist-Led Management Improves Treatment Adherence and Quality of Life in Opioid-Tolerant Patients With Cancer Pain: A Randomized Controlled Trial.

INTRODUCTION: Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life. METHODS: Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035). RESULTS: In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522). CONCLUSIONS: Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03455023.