Introduction: Pulmonary fibrosis (PF) is a fatal chronic lung disease that causes structural damage and decreased lung function and has a poor prognosis. Currently, there is no medicine that can truly cure PF. Vitamin E (VE) is a group of natural antioxidants with anticancer and antimutagenic properties. There have been a few reports about the attenuation of PF by VE in experimental animals, but the molecular mechanisms are not fully understood. Methods: Bleomycin-induced PF (BLM-PF) mouse model, and cultured mouse primary lung fibroblasts and MLE 12 cells were utilized. Pathological examination of lung sections, immunoblotting, immunofluorescent staining, and real-time PCR were conducted in this study. Results: We confirmed that VE significantly delayed the progression of BLM-PF and increased the survival rates of experimental mice with PF. VE suppressed the pathological activation and fibrotic differentiation of lung fibroblasts and epithelial-mesenchymal transition and alleviated the inflammatory response in BLM-induced fibrotic lungs and pulmonary epithelial cells in vitro. Importantly, VE reduced BLM-induced ferritin expression in fibrotic lungs, whereas VE did not exhibit iron chelation properties in fibroblasts or epithelial cells in vitro. Furthermore, VE protected against mitochondrial dysmorphology and normalized mitochondrial protein expression in BLM-PF lungs. Consistently, VE suppressed apoptosis in BLM-PF lungs and pulmonary epithelial cells in vitro. Discussion: Collectively, VE markedly inhibited BLM-induced PF through a complex mechanism, including improving iron metabolism and mitochondrial structure and function, mitigating inflammation, and decreasing the fibrotic functions of fibroblasts and epithelial cells. Therefore, VE presents a highly potential therapeutic against PF due to its multiple protective effects with few side effects.

Objective: Vitamin D3 has the general properties of a lipid-soluble vitamin, but is also an active steroid hormone that can regulate the proliferation, apoptosis and differentiation of many tumor cells, and exerts anticancer activity against numerous malignancies. However, the mechanism underlying the effects of vitamin D3 on tumors is not fully understood. Here, we used network pharmacology and in vitro experimental approaches to explore the mechanism of vitamin D3 activity in the context of gastric cancer. Methods: The Targetnet, SuperPred, SwissTargetPrediction, and PharmMapper databases were screened for potential drug-related targets, while we used data from the PharmGKB, Drugbank, OMIM, DisGeNET, CTD, and GeneCards databases to identify potential targets associated with gastric cancer. Disease-drug crossover genes were obtained by constructing Venn diagrams. Gene ontology and Kyoto Encyclopedia of Genomes (KEGG) enrichment analyses of crossover genes were conducted and STRING was used to generate protein interaction networks and identify core targets. CCK-8 experiments were performed and apoptosis detected to assess the effect of vitamin D3 on gastric cancer cells. Western blotting was applied to detect p53/AMPK/mTOR signaling, as well as autophagy-, cell cycle-, and apoptosis-related proteins. Results: A total of 485 targets of vitamin D3 activity were obtained and 1200 gastric cancer disease-related targets discovered. Further, 60 potential targets for vitamin D3 in gastric cancer treatment were identified. KEGG analysis indicated that potential targets were mainly involved in the cell cycle, HIF-1 signaling, and the AMPK pathway, among other pathways. These findings were validated using cellular experiments, which demonstrated that the viability of AGS and SGC-7901 cells was impeded by vitamin D3. Further, vitamin D3 promoted apoptosis and inhibited the cell cycle in those cell lines, as well as activating the p53/AMPK/mTOR pathway, which promotes autophagy and inhibits tumor development. Conclusion: Our network pharmacological analyses provide preliminarily data supporting a role for vitamin D3 in promoting autophagy and apoptosis in gastric cancer cells, and in activating the p53/AMPK/mTOR pathway, which inhibits gastric cancer cell proliferation. Our findings demonstrate the molecular mechanism underlying the effect of vitamin D3 in cure of gastric cancer.

Purpose: Glutamine synthetase (GS) is the only currently known enzyme responsible for synthesizing endogenous glutamine (Gln). GS exerts a critical role in the oncogenesis of endogenous Gln-dependent cancers, making it an attractive target for anti-tumor therapies. A mixed-function oxidation system consisting of vitamin C (VC), oxygen, and trace metals can oxidize GS and promote its degradation. The current study aims to explore the effect of pharmacological VC treatment on GS. Methods: Endogenous Gln-dependent cancer lines (breast cancer MCF7 and prostate cancer PC3) were selected to establish chronic Gln-deprived MCF7 and PC3 cell models. The expression of GS in parental and chronic Gln-deprived tumor cells exposed to VC treatment and control was determined by Western blot analysis. The anti-cancer effects of VC on parental and chronic Gln-deprived tumor cells were assessed by CCK-8 and annexin V-FITC/PI FACS assays. In addition, changes in cellular reactive oxygen species (ROS), glutathione (GSH) levels and NADPH/NADP + ratio were analyzed to explore the underlying mechanisms. Moreover, BALB/c nude mice xenografting with parental and chronic Gln-deprived prostate cancer cells were constructed to evaluate the in vivo therapeutic effect of VC. Finally, tumor 13N-ammonia uptake in mice bearing prostate cancer xenografts was analyzed following treatment with VC and the expression of GS in xenografts were detected by immunohistochemistry. Results: Cells overexpressing GS were obtained by chronic Gln deprivation. We found that the cytotoxic effect of VC on cancer cells was positively correlated with the expression of GS. Additionally, VC treatment led to a significant increase in ROS production, as well as GSH depletion and NADPH/NADP + reduction. These changes could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). Furthermore, pharmacological VC treatment exhibited a more significant therapeutic effect on xenografts of prostate cancer cells overexpressing GS, that could be well monitored by 13N-ammonia PET/CT imaging. Conclusion: Our findings indicate that VC can kill cancer cells by targeting glutamine synthetase to induce oxidative stress. VC could be used as an anti-cancer treatment for endogenous glutamine-dependent cancers.

Background: The drug therapy of venous thromboembolism (VTE) presents a significant economic burden to the health-care system in low- and middle-income countries. To understand which anticoagulation therapy is most cost-effective for clinical decision-making , the cost-effectiveness of apixaban (API) versus rivaroxaban (RIV), dabigatran (DAB), and low molecular weight heparin (LMWH), followed by vitamin K antagonist (VKA), in the treatment of VTE in China was assessed. Methods: To access the quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs), a long-term cost-effectiveness analysis was constructed using a Markov model with 5 health states. The Markov model was developed using patient data collected from the Xijing Hospital from January 1, 2016 to January 1, 2021. The time horizon was set at 30 years, and a 6-month cycle length was used in the model. Costs and ICERs were reported in 2020 U.S. dollars. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were used to test the uncertainties. A Chinese health-care system perspective was used. Results: In the base case, the data of 231 VTE patients were calculated in the base case analysis retrospectively. The RIV group resulted in a mean VTE attributable to 95% effective treatment. API, DAB, and VKA have a negative ICER (-187017.543, -284,674.922, and -9,283.339, respectively) and were absolutely dominated. The Markov model results confirmed this observation. The ICER of the API and RIV was negative (-216176.977), which belongs to the absolute inferiority scheme, and the ICER value of the DAB and VKA versus RIV was positive (110,577.872 and 836,846.343). Since the ICER of DAB and VKA exceeds the threshold, RIV therapy was likely to be the best choice for the treatment of VTE within the acceptable threshold range. The results of the sensitivity analysis revealed that the model output varied mostly with the cost in the DAB on-treatment therapy. In a probabilistic sensitivity analysis of 1,000 patients for 30 years, RIV has 100% probability of being cost-effective compared with other regimens when the WTP is $10973 per QALY. When WTP exceeded $148,000, DAB was more cost-effective than RIV. Conclusions: Compared with LMWH + VKA and API, the results proved that RIV may be the most cost-effective treatment for VTE patients in China. Our findings could be helpful for physicians in clinical decision-making to select the appropriate treatment option for VTE.

Background: In postthyroidectomy patients, hypocalcemia is the most common complication to prolong hospital stay and decrease patients' satisfaction. Based on current evidence, it is recommended to supply vitamin D to patients with high risk of developing hypocalcemia. However, how to stratify the risk of patients remains challenging. Aim: We conducted a prospective study to evaluate the effect of vitamin D supplement (calcitriol) on high-risk hypocalcemia patients based on relative decline of parathyroid hormone (RDP). Method: RDP was calculated by the difference between preoperative and postoperative first-day PTH divided by preoperative PTH and presented as percentage. Patients who underwent total thyroidectomy in addition to bilateral central compartment dissection were enrolled prospectively and were divided into two cohorts: Cohort I: patients with RDP ≤70% and Cohort II: patients with RDP >70%. Patients in Cohort I were then randomly assigned to Group A or B, and patients in Cohort II were randomly assigned to Group C or D. All groups received oral calcium, and patients in Groups B and D also received calcitriol. All patients were followed for one year. In the study, standard procedure dictates that only oral calcium is given to patients whose RDP ≤70% and that oral calcium and calcitriol are given to patients whose RDP >70%. Therefore, Cohort I Group A and Cohort II Group D are controls in this study. Results: The incidence of clinical hypocalcemia in Groups A and D (the controls) was 11.0% (10/91), and 17.6% (16/91) required additional intravenous calcium. Of note, no patients developed permanent hypocalcemia. Furthermore, calcitriol supplement did not have significant impact on clinical outcomes between Group A and B in Cohort I. By contrast, calcitriol supplement distinctly improved clinical outcome by comparing Groups C and D (Cohort II), as marked by clinical hypocalcemia, need of requiring intravenous calcium, and long-termed decreased levels of PTH. Conclusion: Supplying calcitriol based on RDP cutoff of 70% may be a wise practice in thyroidectomy patients, and RDP 70% may be a useful predictor to stratify high-risk patients.

Boldenone Undecylenate (BLD) is a synthetic derivative of testosterone and a widely used anabolic androgenic steroid. The health risk of BLD use as a pharmaceutical or dietary supplement is still underestimated and under-reported. Vitamin C (VC) has been recognized as an antioxidant with prominent hepatorenal protective effects. This study investigated the possible preventive activity of VC against BLD-induced hepatorenal damage. Forty adult male Wistar rats were classified into five groups: control, vehicle control, VC (orally given 120 mg/kg b. wt./day), BLD (intramuscularly injected 5 mg/kg b. wt./week), and BLD + VC-treated groups. The experiment continued for eight weeks. Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. Serum contents of total protein (TP), albumin (ALB), globulin, total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and very-low-density lipoprotein-cholesterol (VLDL-C) were also assayed. Urea, creatinine, and uric acid levels were determined together with sodium and potassium electrolytes measuring. Moreover, oxidative stress indicators including reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GSR) as well as malondialdehyde (MDA) levels were measured in both hepatic and renal tissues. Corresponding histological examination of renal and hepatic tissues was conducted. Besides, immunohistochemical evaluations for androgen receptors protein (AR) and heat shock protein 90 (Hsp 90) expressions were performed. BLD caused significant rises in serum ALT, AST, TP, ALB, TC, TG, LDL-C, VLDL-C, urea, creatinine, uric acid, potassium, and MDA levels. Further, BLD-injected rats showed significant declines in the serum levels of HDL-C, sodium, GSH, GPx, GST, and GSR. Besides, distinct histopathological perturbations were detected in renal and hepatic tissues of BLD-injected rats. AR and Hsp 90 immunoexpression were increased in hepatic and renal tissues. In contrast, VC significantly reversed the BLD-induced hepatorenal damage in co-treated rats but not ameliorated AR protein overexpression. VC could be an efficient preventive supplement for mitigating BLD-induced hepatorenal damage, possibly via controlling oxidative stress events.

Age-related macular degeneration (AMD) is a degenerative retinal disease and one of major causes of irreversible vision loss. AMD has been linked to several pathological factors, such as oxidative stress and inflammation. Moreover, Aβ (1-42) oligomers have been found in drusen, the extracellular deposits that accumulate beneath the retinal pigmented epithelium in AMD patients. Hereby, we investigated the hypothesis that treatment with 1,25(OH) 2D3 (vitamin D3) and meso-zeaxathin, physiologically present in the eye, would counteract the toxic effects of three different insults on immortalized human retinal pigmented epithelial cells (ARPE-19). Specifically, ARPE-19 cells have been challenged with Aβ (1-42) oligomers, H2O2, LPS, and TNF-α, respectively. In the present study, we demonstrated that the combination of 1,25(OH)2D3 and meso-zeaxanthin significantly counteracted the cell damage induced by the three insults, at least in these in vitro integrated paradigms of AMD. These results suggest that combination of 1,25(OH)2D3 and meso-zeaxathin could be a useful approach to contrast pathological features of AMD, such as retinal inflammation and oxidative stress.

Background and Objective: Minor dental surgery is invasive and hemorrhagic. Thus, in patients treated with anticoagulants, the bleeding risk related to these invasive procedures is concerning. The aim of this meta-analysis is to evaluate this risk by comparing the post-operative bleeding rates of oral anticoagulation treatment (OAT) patients (without interrupted or altered anticoagulant intake) with non-OAT patients. Methods: PubMed, Embase and the Cochrane Library were searched for eligible studies that compared the post-operative (following minor dental surgery) bleeding rates of OAT patients without interrupted or altered therapy with those of non-OAT patients. Relative risk (RR) and 95% confidence interval (CI) were calculated. Subgroup analyses were used to identify the association between the bleeding rate and different dental surgeries or anticoagulants. Results: Thirty two full text articles were assessed for eligibility and 20 studies were excluded according to the selection criteria. Finally, 12 studies and a total of 2102 OAT patients and 2271 non-OAT patients were included. A pooled analysis indicated that the post-operative bleeding risk in OAT patients is higher than that of non-OAT patients (RR: 2.794, 95% CI: 1.722-4.532, P = 0.000). The pooled RRs in the dental implant surgery and dental extraction subgroups were 2.136 (95% CI: 0.825-5.531, P = 0.118) and 2.003 (95% CI: 0.987-4.063, P = 0.054), respectively. As for the different oral anticoagulants, the pooled RR in the subgroup of new oral anticoagulants (NOACs) was 1.603 (95% CI: 0.430-5.980, P = 0.482), while the pooled RR in the vitamin K antagonists subgroup was 3.067 (95% CI: 1.838-5.118, P = 0.000). Conclusion: Under current evidence, OAT patients were under a higher post-operative bleeding risk than the non-OAT patients following minor dental surgery. For the dental implant surgeries and dental extractions, our study failed to demonstrate a higher risk of bleeding in the OAT patients compared with the non-OAT patients. Besides, The NOACs might be safer than the vitamin K antagonists in dental implant surgery. However, more well-designed studies are required for future research.

Growing evidence suggests that trimethylamine N-oxide (TMAO) is recognized as a biomarker of increased cardiovascular risk. So far, the evaluation of TMAO serum levels in the clinical practice is limited due to the lack of developing new facile methods with reduced limitations. However, few approaches were achieved to determine TMAO in serum by using mass spectrometry-based technique, some limitations were reported including the use of internal standards. Therefore, in this work, a liquid chromatography-mass spectrometry (LC/MS) based-assay was developed to evaluate the effect of grape pomace extract (Taurisolo®, group A) or Taurisolo®+pectin (group B) on TMAO serum levels in a cohort of overweight/obese subjects. The serum levels of TMAO have been assessed before and after treatment, through LC/MS analysis. After 8-week treatment, in both intervention groups TMAO serum levels significantly decreased (-78.58% p = 0.006 and -76.76% p = 0.001, group A and group B, respectively). Moreover, we performed several analyses aimed to validate the LC/MS method we used. The method has high precision (% C.V = from 12.12 to 3.92% and from 8.25 to 1.07% for intraday and interday, respectively) and accuracy (% bias = from -5.52 to 0.5% and from -1.42 to 3.08% for intraday and interday, respectively). TMAO recoveries from serum ranged from 99 to 97%; LOD: 2 ng/ml and LOQ: 6 ng/ml. In conclusion, we demonstrated the efficacy of a novel nutraceutical formulation in reducing TMAO serum levels in high cardiovascular risk-subjects, and proposed a useful, versatile and rapid LC/MS method for identification and quantization of TMAO, without the use of marked/isotopic internal standards. It, thus, may represent a novel and practical method with applications in clinical practice and nutraceutical research. Clinical Trial Registration: This study is listed on the ISRCTN registry with ID ISRCTN10794277 (doi: 10.1186/ISRCTN10794277).

Regulatory molecules have recently been recognized for their beneficial effects in the treatment of immune-mediated diseases, rather than using cytotoxic immune-suppressing drugs, which are associated with many unwanted side effects. Semaphorin3A (sema3A), a unique regulatory master of the immune system, was shown to be decreased in the serum of systemic lupus erythematosus (SLE) patients, in association with disease severity. Later, we were able to show its extremely beneficial effect in treating lupus nephritis in the NZB/W mice model. The mechanisms by which sema3A maintains its regulatory effect is by binding the regulatory receptor CD72 on B cells, thereby reducing the threshold of BCR signaling on B cells and reducing the production of pro-inflammatory cytokines. The aim of this study was to generate a stable sema3A molecule, easy to produce with a higher binding capacity to CD72 receptor rather than to Neuropilin-1 (NRP-1) receptor, which is expressed in many cell types. Using the crystallographic structure of parental sema3A, we synthesized a new secreted (shorter) sema3A derivative, which we called truncated sema3A (T-sema3A). The new molecule lacked the NRP-1 binding domain (the C-terminal site) and has an artificial dimerization site at position 257 (serine residue was exchanged with a cysteine residue). To facilitate the purification of this molecule we added Histidine epitope tag in frame upstream to a stop codon. This construct was transfected using a viral vector to 293HEK cells to generate cells stably expressing T-sema3A. T-sema3A is shown to be with a higher binding ability to CD72 than to NRP-1 as demonstrated by a homemade ELISA. In addition, T-sema3A was shown to be a regulatory agent which can induce the expression of IL-10 and TGF-β and reduce the secretion of pro-inflammatory cytokines such as IL-6, IFN-γ, and IL-17A from human T and B-lymphocytes. Keeping this in mind, T-sema3A is highly effective in maintaining immune homeostasis, therefore, becoming a potential agent in restoring the regulatory status of the immune system in immune-mediated diseases.

Objectives: We intend to conduct a meta-analysis on the systematic evaluation of traditional Chinese medicine (TCM) in the treatment of ventricular remodeling following acute myocardial infarction (AMI). Our findings may provide certain references for the clinical treatment of ventricular remodeling. Methods: A systematic literature search was conducted in PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wanfang Data, CQVIP, and CBM before 20 July 2020. Data were analyzed using a random/fixed-effect model. Primary outcomes included the effectiveness and TCM syndrome score (TCMSS). Secondary outcomes included 1) echocardiography data, including the left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (LVEF), E/A, stroke volume (SV), and wall motion score (WMS); 2) serum indicators, including the B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) or high sensitivity CRP (hs-CRP); (3) major adverse cardiovascular events (MACE) and other adverse events Results: Forty RCTs involving 3,659 subjects were recruited. Our findings proved that a combination of TCM or TCM preparations with conventional Western medicine for preventing and reversing ventricular remodeling at post-AMI could remarkably enhance the total effectiveness and reduced TCMSS. Moreover, myocardial functions (LVEF, E/A, and SV), ventricular remodeling (LVEDVi, LVESVi, LVEDV, LVESV, LVEDD, LVESD, LVPWT, and WMS), serum levels of BNP and CRP, and MACE were significantly improved by the combination of TCM or TCM preparations with conventional Western medicine. Nevertheless, IVST and the incidence of other adverse events were comparable between control and experimental groups Conclusion: The combination of TCM or TCM preparations and conventional Western medicine can alleviate the process of ventricular remodeling, enhance cardiac function, and reduce the incidence of MACE in AMI patients.

Background: Off-target effects in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) are associated with cardiovascular toxicity. Hypertension represents an important cardiovascular complication and, if not appropriately managed, can contribute to developing thrombotic events. Third-generation TKI ponatinib is associated with hypertension development, and its use is more restricted than in the past. Few data are reported for second-generation TKI, nilotinib, dasatinib, and bosutinib. The aim of this article was to evaluate with a systematic review and meta-analysis the real incidence of hypertension in CML patients treated with second- or third-generation TKI. Methods: The PubMed database, Web of Science, Scopus, and ClinicalTrials.gov were systematically searched for studies published between January 1, 2000, and January 30, 2021; the following terms were entered in the database queries: Cardiovascular, Chronic Myeloid Leukemia, CML, Tyrosine kinases inhibitor, TKI, and Hypertension. The study was carried out according to the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement. Results: A pooled analysis of hypertension incidence was 10% for all new-generation TKI, with an even higher prevalence with ponatinib (17%). The comparison with the first-generation imatinib confirmed that nilotinib was associated with a significantly increased risk of hypertension (RR 2; 95% CI; 1.39-2.88, I2=0%, z=3.73, p=0.0002). The greatest risk was found with ponatinib (RR 9.21; 95% CI; 2.86-29.66, z=3.72, p=0.0002). Conclusion: Hypertension is a common cardiovascular complication in CML patients treated with second- or third-generation TKI.

Wernicke's encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder its main risk factor. WE patients present limiting motor, cognitive, and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed to be one of the phenomena that contribute to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR)4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet [TDD] and receiving pyrithiamine). Nevertheless, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. In addition, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or combined treatment (CA + TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its coreceptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFκB p65 and IκBα, in the postmortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer's disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NF-ĸB and IĸBα in the CA + TDD animal model. In the patient diagnosed with alcohol-induced WE, we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Hence, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in alcohol consumption-related WE.

Purpose: Cognitive impairment in cancer patients induced, at least in part, by treatment are frequently observed and likely have negative impacts on patient quality of life. Such cognitive dysfunctions can affect attention, executive functions, and memory and processing speed, can persist after treatment, and their exact causes remain unclear. The aim of this review was to create an inventory and analysis of clinical studies evaluating biological markers and risk factors for cognitive decline in cancer patients before, during, or after therapy. The ultimate objectives were to identify robust markers and to determine what further research is required to develop original biological markers to enable prevention or adapted treatment management of patients at risk. Method: This review was guided by the PRISMA statement and included a search strategy focused on three components: "cognition disorders," "predictive factors"/"biological markers," and "neoplasms," searched in PubMed since 2005, with exclusion criteria concerning brain tumors, brain therapy, and imaging or animal studies. Results: Twenty-three studies meeting the criteria were analyzed. Potential associations/correlations were identified between cognitive impairments and specific circulating factors, cerebral spinal fluid constituents, and genetic polymorphisms at baseline, during, and at the end of treatment in cancer populations. The most significant results were associations between cognitive dysfunctions and genetic polymorphisms, including APOE-4 and COMT-Val; increased plasma levels of the pro-inflammatory cytokine, IL-6; anemia; and hemoglobin levels during chemotherapy. Plasma levels of specific hormones of the hypothalamo-pituitary-adrenal axis are also modified by treatment. Discussion: It is recognized in the field of cancer cognition that cancer and comorbidities, as well as chemotherapy and hormone therapy, can cause persistent cognitive dysfunction. A number of biological circulating factors and genetic polymorphisms, can predispose to the development of cognitive disorders. However, many predictive factors remain unproven and discordant findings are frequently reported, warranting additional clinical and preclinical longitudinal cohort studies, with goals of better characterization of potential biomarkers and identification of patient populations at risk and/or particularly deleterious treatments. Research should focus on prevention and personalized cancer management, to improve the daily lives, autonomy, and return to work of patients.

Objective: Resistance to anticancer agents ensures a poor prognosis in patients with lung cancer. Metformin could enhance the anticancer effects of standard antineoplastic agents [traditional chemotherapy drugs, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), or immune checkpoint inhibitors (ICIs)]; however, it is unclear whether metformin can be combined with antineoplastic agents in the treatment of lung cancer. To explore the efficacy of combinational strategies, we performed a systematic review and meta-analysis for diabetic and non-diabetic patients with lung cancer. Method: An electronic literature search was performed to obtain relevant randomized controlled trials (RCTs) and observational cohort studies. Hazard ratios (HR) with 95% confidence intervals (CI) of overall survival (OS) and progression-free survival (PFS) outcomes were extracted. Subgroup analysis by antineoplastic agents, study type, histology and clinical stage were investigated. Results: 14 studies (three RCTs and eleven observational cohort studies) consisting 3,856 patients were included in the meta-analysis. Compared to standard antineoplastic agents alone (traditional chemotherapy drugs, EGFR-TKIs or ICIs), the antineoplastic agents combined with metformin significantly improved OS (HR 0.73, 95% CI 0.66-0.81, p < 0.00001) and PFS (HR 0.72, 95% CI 0.59-0.88, p = 0.001); a similar association was found in observational evidence. Limited data from RCTs showed no differences in OS or PFS. Conclusion: Metformin plus antineoplastic agents may improve survival outcomes of patients with lung cancer. Further investigation is needed.

Introduction: Until now, there is no clinically approved specific medicine to treat COVID-19. Prior systematic reviews (SRs) have shown that traditional Chinese medicine (TCM) reduces the number of patients with severe disease and time to fever clearance, promotes clinical effectiveness, and improves chest images and the negativity rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test. Few SRs arrived at a definitive conclusion, and more randomized controlled trials (RCTs) were published. We conducted this study to summarize the latest evidence of TCM in COVID-19. Methods: Eight online databases were searched from December 2019 to July 2020, updated to March 2021. Only RCTs evaluating the clinical efficacy and safety of TCM in the treatment of COVID-19 were included. Primary outcomes were clinical cure and the negativity of the SARS-CoV-2 nucleic acid test. Secondary outcomes included clinical deterioration, ARDS, mechanical ventilation, death, time to fever clearance, duration of hospitalization, and chest imaging improvement. Safety outcomes included adverse events and serious adverse events during treatment. Two reviewers selected the included articles, assessed the risk of bias, and extracted data independently and in duplicate. Results: A total of 25 RCTs involving 2222 participants were selected in the systematic review, and seven RCTs were included in the meta-analysis. The results showed that TCM plus routine treatment was significantly better than routine treatment alone in clinical cure (risk ratio [RR] = 1.20, 95% confidence interval (CI) [1.04, 1.38], P = 0.01) and chest image improvement (RR = 1.22, 95% CI [1.07, 1.39], P = 0.01) and could reduce clinical deterioration (RR = 0.39, 95% CI [0.18, 0.86], P = 0.02), ARDS (RR = 0.28, 95% CI [0.11, 0.69], P = 0.01), mechanical ventilation (RR = 0.30, 95% CI [0.12, 0.77], P = 0.01), or death rate (RR = 0.28, 95% CI [0.09, 0.84], P = 0.02). No significant difference between TCM and routine treatment in the negativity of SARS-CoV-2 nucleic acid test (RR = 1.08, 95% CI [0.94, 1.23], P = 0.29) was observed. Finally, there was no overall significant difference in the incidence of adverse events between the two groups. The summary of evidence showed moderate confidence of a benefit of 11.8% in clinical cure and 14.0% in chest image improvement and a reduction of 5.9% in clinical deterioration, 25.4% in ARDS, 18.3% in mechanical ventilation, and 4.5% in death with TCM plus routine treatment compared to routine treatment alone in patients with COVID-19. A low confidence of a benefit of 5.4% in the negativity of SARS-CoV-2 nucleic acid test was also observed. Conclusions: Synethized evidence of 21 outcomes in 8 RCTs showed moderate certainty that TCM treatment plus routine treatment may promote a clinical cure and chest image improvement compared to routine treatment alone while reducing clinical deterioration, development of ARDS, use of mechanical ventilation, and death in patients with COVID-19. TCM treatment plus routine treatment may not promote the negativity of the SARS-CoV-2 nucleic acid test compared to routine treatment alone. TCM treatment was found to be safe for patients with COVID-19.

Background: In patients with allogenic hematopoietic stem cell transplantation (allo-HSCT), immune-checkpoint inhibitors (ICI) are used to treat malignancy recurrence. However, ICI are also associated with graft vs. host disease (GVHD). In this pharmacovigilance analysis, we aimed to characterize cases of GVHD associated with ICI, drawn from the World Health Organization pharmacovigilance database, VigiBase®, and from literature. Methods: We performed VigiBase® query of cases of GVHD associated with ICI. These cases were combined with those of literature, not reported in VigiBase®. The Bayesian estimate of disproportionality analysis, the information component, was considered significant if its 95% credibility interval lower bound was positive; denoting a significant association between GVHD and the suspected ICI. Time to onset between ICI and GVHD onset and subsequent mortality were assessed. Results: Disproportionality analysis yielded 93 cases of GVHD associated with ICI (61.8% men, median age 38 [interquartile range = 27; 50] years). Cases were mostly associated with nivolumab (53/93, 57.0%), pembrolizumab (23/93, 24.7%) and ipilimumab (12/93, 12.9%) monotherapies. GVHD events occurred after 1 [1; 5.5] injection of ICI, with a time to onset of 35 [IQR = 14; 176] days. Immediate subsequent mortality after GVHD was 24/93, 25.8%. There was no significant difference in mortality depending on the molecule (p = 0.41) or the combination regimen (combined vs. monotherapy, p = 0.60). Previous history of GVHD was present in 11/18, 61.1% in cases reported in literature. Conclusion: In this worldwide pharmacovigilance study, disproportionality yielded significant association between GVHD and ICI, with subsequent mortality of 25.8%. Previous history of GVHD was reported in more than half of cases. Clinicaltrials.gov identifier: NCT03492242.

Background: Mycoplasma pneumoniae pneumonia (MPP) causes flu-like symptoms in children, increasing the burden on the health and education systems. In China, traditional Chinese medicine oral liquids (TCMOLs) combined with azithromycin (TCMOLs + Azithromycin) is commonly used to treat MPP in children. However, TCMOLs with the optimal clinical applicability remain unknown. Here, we evaluated the clinical effectiveness and safety of TCMOLs + Azithromycin in children with MPP. Methods: We searched PubMed, Embase, Cochrane Library, Ovid, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and VIP information resource integration service platform databases for eligible randomized controlled trials (RCTs) published from database inception to October 2020. Two reviewers independently performed data extraction and risk of bias assessment. After Bayesian random effect modeling and surface under the cumulative ranking curve (SUCRA) scoring, we ranked each intervention. We assessed heterogeneity using multivariate meta-regression for potential modifiers and used the Grading of Recommendations, Assessment, Development, and Evaluation to rate pooled evidence's certainty. Results: In the 63 included RCTs with 6,410 children, five different TCMOLs were combined with azithromycin. TCMOLs + Azithromycin had significantly better primary outcomes than did azithromycin alone. Of all TCMOLs, Xiaoer Xiaoji Zhike (XEXJZK)+Azithromycin showed the best effectiveness with respect to the response rate (odds ratio [OR] = 6.5, 95% credible interval [CrI] = 4.3-10; low certainty) and pulmonary rales disappearance time (mean difference [MD] = -2.1, 95% CrI: -2.9 to -1.2; low certainty) with SUCRA 85 and 80%, respectively. Pudilan Xiaoyan + Azithromycin showed the highest effectiveness with respect to cough disappearance time (MD = -2.6, 95% CrI: -3.4 to -1.7; very low certainty) and fever disappearance time (MD = -1.8, 95% CrI: -2.3 to -1.3; very low certainty) with SUCRA 87 and 87%, respectively. The difference in the adverse effects between TCMOLs + Azithromycin and azithromycin alone was nonsignificant. Conclusion: Of the different TCMOLs, XEXJZK may be the best option to combine with azithromycin to treat children with MPP. However, our results should be interpreted with caution due to the low certainty of evidence. In general, TCMOLs' safety remains unclear because of a lack of evidence. More high-quality RCTs are needed to further evaluate efficacy and safety of these TCMOLs.

Background: The incidence of Mycobacterium avium complex (MAC) increases as immunosuppressed conditions become more common. MAC's standard treatment regimen includes a macrolide, ethambutol, and a rifamycin, among which rifampin and rifabutin are the most commonly used. Although current guidelines recommend initial therapy for MAC with rifampin, it has been theorized to be less efficacious than rifabutin. Methods: We reviewed the relevant scientific literature published up to February 18, 2020. Statistical analyses were performed with Comprehensive Meta-Analysis Software Version 2.0 (Biostat, Englewood, NJ). The pooled frequency with 95% confidence intervals (CI) was assessed using a random-effect model. We considered P <0.05 as statistically significant for publication bias. Results: After reviewing 3665 records, we identified 24 studies that satisfied the inclusion criteria. Among these studies, 8 had rifabutin in their regimens (rifabutin group) and 16 had rifampin in their regimens (rifampin group). The estimated pooled treatment success rate was found to be 54.7% (95% CI 41.0-67.0%) in rifabutin groups and 67.5% (95% CI 55.7-77.4%) in rifampin groups. There was no evidence of publication bias among the included studies (Egger's test p-value was 0.7). Conclusion: In this study, it was shown that in comparison to Rifabutin, rifampin has similar treatment success rates in treating MAC. In order to determine the exact preference of each of these drugs, double-blind clinical trial studies are recommended.

Background: Antimicrobial resistance is a serious public health problem that has become a global threat. Special attention should be given to polymyxins (polymyxin B and colistin) which, since their reintroduction into clinical practice, are considered "last resort" drugs. The objective of this study is to perform a bibliometric analysis of scientific research on polymyxin resistance. Methods: Scopus was used to retrieve documents relevant to polymyxin resistance from 2010 to 2019. Data was exported to Microsoft Excel for table presentation. SciVal was used for volume and citation analysis as well as collaboration patterns. Also, we extracted data regarding the top documents, authors, countries, institutions, and the metrics of journals. VantagePoint and VOSviewer were used for geographical distribution of worldwide research and keyword co-occurrence analysis, respectively. Results: A total of 1,409 documents were retrieved. The retrieved documents received 25.0 citations per document. Articles (73.88%) and letters (18.09%) were the most frequent types of documents. During 2010-2019, there was a significant growth in publications (p-value < 0.001). The received citations were 35,209 with a peak in 2016 (11,250 citations). China and the United States led the scientific production with 299 (21.2%) and 238 (16.9%) publications, respectively. Little or no contribution came from central Asia, Sub-Saharan Africa, and Latin America. Chinese institutions have caused the greatest impact, with University of Zhejiang (China) being the most prolific institution on the subject (88 documents). In terms of the most productive journals, Antimicrobial Agents and Chemotherapy ranked first with 196 (13.9%) documents. Most of the documents were published in quartile one journals and only had national collaboration (43.2%). Analysis of keyword co-occurrence revealed that research on polymyxin resistance during the last decade has focused on its relationship with public health, pharmacology, and genetics. Conclusion: The number of documents on polymyxin resistance has increased significantly in the recent years, with a steep growth from 2016 onwards. China and the United States led the scientific production. Most of the documents were published in high-quality journals. Greater joint efforts and more contribution from central Asia, Sub-Saharan Africa, and Latin America are still needed to tackle this global problem.