The Effects of Probiotic Bacillus Spores on Dexamethasone-Treated Rats.

Glucocorticoids are effective anti-inflammatory and immunosuppressive agents. Long-term exposure is associated with multiple metabolic side effects. Spore-forming probiotic bacteria have shown modulatory properties regarding glycolipid metabolism and inflammation. The aim of this study was to evaluate, for the first time, the effects of Bacillus species spores (B. licheniformis, B. indicus, B. subtilis, B. clausii, and B. coagulans) alone and in combination with metformin against dexamethasone-induced systemic disturbances. A total of 30 rats were randomly divided into 5 groups: group 1 served as control (CONTROL), group 2 received dexamethasone (DEXA), group 3 received DEXA and MegaSporeBiotic (MSB), group 4 received DEXA and metformin (MET), and group 5 received DEXA, MSB, and MET. On the last day of the experiment, blood samples and liver tissue samples for histopathological examination were collected. We determined serum glucose, total cholesterol, triglycerides, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), catalase, total antioxidant capacity (TAC), and metformin concentration. DEXA administration caused hyperglycemia and hyperlipidemia, increased inflammation cytokines, and decreased antioxidant markers. Treatment with MSB reduced total cholesterol, suggesting that the administration of Bacillus spores-based probiotics to DEXA-treated rats could ameliorate metabolic parameters.

The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10-IL-10R Pathways in Acute Myeloid Leukemia.

Tumor cells promote the suppression of host anti-tumor type 1 T cell responses by various mechanisms, including the upregulation of surface inhibitory molecules such as programmed death ligand (PD-L)-1, and the production of immunosuppressive cytokines such as interleukin-10 (IL-10). There are over 2000 trials investigating PD-L1 and/or its receptor programmed-death 1 (PD-1) blockade in cancer, leading to the approval of PD-1 or PD-L1 inhibitors in several types of solid cancers and in hematological malignancies. The available data suggest that the molecule PD-L1 on antigen-presenting cells suppresses type 1 T cell immune responses such as cytotoxicity, and that the cytokine IL-10, in addition to downregulating immune responses, increases the expression of inhibitory molecule PD-L1. We hypothesize that the manipulation of both the co-inhibitory network (with anti-PD-L1 blocking antibodies) and suppressor network (with anti-IL-10 blocking antibodies) is an attractive immunotherapeutic intervention for acute myeloid leukemia (AML) patients ineligible for standard treatment with chemotherapy and hematopoietic stem cell transplantation, and with less severe adverse reactions. The proposed combination of these two immunotherapies represents a new approach that can be readily translated into the clinic to improve the therapeutic efficacy of AML disease treatment.

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats.

Acetaminophen (APAP) is one of the most used analgesics and antipyretic agents in the world. Intoxication with APAP is the main cause of acute liver toxicity in both the US and Europe. Spore-forming probiotic bacteria have the ability to resist harsh gastric and intestinal conditions. The aim of this study was to investigate the possible protective effect of Bacillus (B) species (sp) spores (B. licheniformis, B. indicus, B. subtilis, B. clausii, B. coagulans) against hepatotoxicity induced by APAP in rats. A total of 35 rats were randomly divided into seven groups: group I served as control; group II received silymarin; group III received MegaSporeBioticTM (MSB); group IV received APAP and served as the model of hepatotoxicity; group V received APAP and silymarin; group VI received APAP and MSB; group VII received APAP, silymarin and MSB. The livers for histopathological examination and blood samples were collected on the last day of the experiment. We determined aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total antioxidant capacity (TAC) levels and zonula occludens (ZO-1), tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) expression. APAP overdose increased AST and ALT. It slowly decreased TAC compared to the control group, but pretreatment with silymarin and MSB increased TAC levels. Elevated plasma concentrations were identified for ZO-1 in groups treated with APAP overdose compared with those without APAP or receiving APAP in combination with silymarin, MSB or both. The changes were positively correlated with the levels of other proinflammatory cytokines (TNF-α, IL-1ß). In addition, histopathological hepatic injury was improved by preadministration of MSB or silymarin versus the disease model group. Bacillus sp spores had a protective effect on acute hepatic injury induced by APAP. Pretreatment with MSB resulted in a significant reduction in serum AST, ALT, TNF-α, IL-1ß, ZO-1, TAC and also hepatocyte necrosis, similar to the well-known hepatoprotective agent-silymarin.

MicroRNAs Associated With a Good Prognosis of Acute Myeloid Leukemia and Their Effect on Macrophage Polarization.

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue.

Are Community Acquired Respiratory Viral Infections an Underestimated Burden in Hematology Patients?

Despite a plethora of studies demonstrating significant morbidity and mortality due to community-acquired respiratory viral (CRV) infections in intensively treated hematology patients, and despite the availability of evidence-based guidelines for the diagnosis and management of respiratory viral infections in this setting, there is no uniform inclusion of respiratory viral infection management in the clinical hematology routine. Nevertheless, timely diagnosis and systematic management of CRV infections in intensively treated hematology patients has a demonstrated potential to significantly improve outcome. We have briefly summarized the recently published data on CRV infection epidemiology, as well as guidelines on the diagnosis and management of CRV infections in patients intensively treated for hematological malignancies. We have also assessed available treatment options, as well as mentioned novel agents currently in development.

A Review of Macrophage MicroRNAs' Role in Human Asthma.

There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma.

Berberine: Botanical Occurrence, Traditional Uses, Extraction Methods, and Relevance in Cardiovascular, Metabolic, Hepatic, and Renal Disorders.

Berberine-containing plants have been traditionally used in different parts of the world for the treatment of inflammatory disorders, skin diseases, wound healing, reducing fevers, affections of eyes, treatment of tumors, digestive and respiratory diseases, and microbial pathologies. The physico-chemical properties of berberine contribute to the high diversity of extraction and detection methods. Considering its particularities this review describes various methods mentioned in the literature so far with reference to the most important factors influencing berberine extraction. Further, the common separation and detection methods like thin layer chromatography, high performance liquid chromatography, and mass spectrometry are discussed in order to give a complex overview of the existing methods. Additionally, many clinical and experimental studies suggest that berberine has several pharmacological properties, such as immunomodulatory, antioxidative, cardioprotective, hepatoprotective, and renoprotective effects. This review summarizes the main information about botanical occurrence, traditional uses, extraction methods, and pharmacological effects of berberine and berberine-containing plants.

Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies.

The co-inhibitory receptor programmed cell death (PD)-1, expressed by immune effector cells, is credited with a protective role for normal tissue during immune responses, by limiting the extent of effector activation. Its presently known ligands, programmed death ligands (PD-Ls) 1 and 2, are expressed by a variety of cells including cancer cells, suggesting a role for these molecules as an immune evasion mechanism. Blocking of the PD-1-PD-L signaling axis has recently been shown to be effective and was clinically approved in relapsed/refractory tumors such as malignant melanoma and lung cancer, but also classical Hodgkin's lymphoma. A plethora of trials exploring PD-1 blockade in cancer are ongoing. Here, we review the role of PD-1 signaling in lymphoid malignancies, and the latest results of trials investigating PD-1 or PD-L1 blocking agents in this group of diseases. Early phase studies proved very promising, leading to the clinical approval of a PD-1 blocking agent in Hodgkin's lymphoma, and Phase III clinical studies are either planned or ongoing in most lymphoid malignancies.

VKORC1-1639 G>A Polymorphism and the Risk of Non-Variceal Upper Gastrointestinal Bleeding.

BACKGROUND AND AIMS: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists. METHODS: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism. RESULTS: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p<0.001), use of NSAIDs (OR 4.542, CI95% 2.502-8.247, p<0.001) or of low-dose aspirin (OR 2.390, CI95% 1.326-4.310), and the VKORC1 -1639 G> A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, p<0.001). CONCLUSION: Patients with non-variceal UGIB caused by the use of NSAIDs or low-dose aspirin are more frequent carriers of the VKORC1 -1639 G>A AA genotype, as compared to those without UGIB.

Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers.

PURPOSE: To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers. METHODS: An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods. RESULTS: Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively. CONCLUSIONS: These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Assessment of a Potential Pharmacokinetic Interaction between Nebivolol and Bupropion in Healthy Volunteers.

BACKGROUND/AIMS: The study aimed at investigating the effects of multiple-dose bupropion (potent inhibitor of CYP2D6) on the pharmacokinetics (PKs) of single-dose nebivolol (CYP2D6 substrate) and to evaluate the clinical relevance of this potential drug interaction. METHODS: This open-label, nonrandomized clinical study had a 2-period design: during period 1 (reference), a single dose of 5 mg nebivolol was administered, while during period 2 (test), 5 mg nebivolol + 300 mg bupropion were ingested concomitantly, after a pretreatment regimen with bupropion (7 days). The PK parameters of nebivolol and its active metabolite were analyzed by noncompartmental modeling, while the pharmacodynamic (PD) parameters (blood pressure and heart rate) were assessed at rest. RESULTS: Bupropion plus nebivolol increased the mean peak plasma concentrations (Cmax) of nebivolol (1.67 ± 0.69 vs. 3.80 ± 1.70 ng/ml) and its active metabolite (0.68 ± 0.22 vs. 1.13 ± 0.38 ng/ml) compared to nebivolol alone. After bupropion pretreatment, the exposure to nebivolol was increased by 7.2-fold for the parent drug and 4-fold for the hydroxylated active metabolite. The difference between the PD parameters measured during the 2 periods was not significant. CONCLUSION: The study concluded that bupropion influenced the PKs of nebivolol in healthy volunteers, but a clinical relevance was not established. However, this latter aspect requires further investigation.

Late relapsing mantle cell lymphoma showing preserved sensitivity to single-agent lenalidomide.

Mantle cell lymphoma is a hematologic malignancy characterized by poor therapeutic outcomes. Immunomodulatory drugs are a focus of attention in this disease, especially for the elderly and frail patients not able to tolerate the typically intensive therapeutic approaches used in fitter patients. We here present the case of refractory mantle cell lymphoma of the elderly that achieved complete remission following the use of single-agent lenalidomide, and a second complete response to the same regimen on relapse 5 years later.

Alkaline reflux esophagitis in patients with total gastrectomy and Roux en Y esojejunostomy.

BACKGROUND AND AIMS: Alkaline reflux esophagitis is a complication that might develop in patients with total gastrectomy. The aim of the study was to analyze the prevalence and severity of reflux esophagitis and the occurence of complications (Barrett's esophagus and esophageal stenosis) in patients with total gastrectomy and Roux en Y esojejunostomy. METHODS: 92 patients with total gastrectomy performed for gastric cancer were included in the study. None of the patients had esophagitis prior to gastrectomy. The patients were assessed clinically and endoscopically after a certain interval from surgery. RESULTS: An important number of patients (14 out of 92, 15.22%) had reflux esophagitis; 5.43% of the patients had also complications of reflux esophagitis (Barrett's esophagus and benign esophageal stenosis) and 6.52% had local tumor recurrence. Of the 14 patients with reflux esophagitis, the majority (9/14) had Los Angeles (LA) grade C esophagitis. The mean interval between surgery and the endoscopic evaluation was 4.43 years. Barrett's esophagus and benign stenosis were diagnosed after a longer period of time (10.33 and 8 years, respectively) as compared to reflux esophagitis (5.29 years). More than half of the esophagitis patients had reflux symptoms. CONCLUSIONS: Although Roux en Y esojejunostomy is a reconstructive technique which prevents the reflux, an important percentage of our patients developed alkaline reflux esophagitis. In most cases, the esophagitis was moderate or severe. Complications of alkaline reflux, i.e. benign stenosis and Barrett's esophagus, also occurred after longer periods of time (8 to 10 years) in a small percentage of patients.