Effective Therapy Regimens Research Articles

Basis of CD7 molecule and its research progress on immunotherapy in hematologic malignant diseases

CD7 molecule is a 40 kDa single-chain glycoprotein molecule, belonging to the immunoglobulin superfamily. It is an important surface marker on the human immune cell membrane and plays a role in synergistic stimulation of molecular receptors during lymphocyte development and maturation. As an abnormal marker on the surface of hematological malignant cells, it is highly expressed in acute T-lymphocytic leukemia(T-ALL)and T-cell lymphoma. About 30% of patients with acute myeloid leukemia(AML) have been detected the expression of CD7 antigen in tumor cells. CD7 molecule is thought to be involved with disease invasiveness, drug resistance, and poor prognosis. Potent chemotherapy, immunotherapy, hematopoietic stem cell transplantation(HSCT) and other programs have achieved very significant results in the treatment of hematologic malignant diseases. Despite this, there are still some cases of acquired treatment tolerance during the treatment. Molecular targeted therapy provides a safe, effective, and specific therapy regimen that has received increasing attention in recent years. Using of CD7 molecular as a new target for molecular targeted anti-tumor therapy may provide a new therapeutic direction for CD7-positive relapse or refractory hematological malignant diseases. The article intends to review the current progress in the basic and clinical research of CD7 molecules. Key words: Antigens, CD7; Hematologic neoplasms; Immunotherapy; Molecular targeted therapy; Chimeric antigen receptor

Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model

ABSTRACT An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB.

Bismuth, rabeprazole, amoxicillin, and doxycycline as first-line Helicobacter pylori therapy in clinical practice: A pilot study.

Bismuth-containing quadruple therapy (BQT) is a recommended alternative first-line therapy for Helicobacter pylori (H.pylori) infection. We aim to evaluate the efficacy and safety of a new BQT with amoxicillin and doxycycline as a first-line treatment for H.pylori infection in clinical practice. An open, prospective pilot clinical studyincluding H.pylori-positive outpatients who had never received eradication treatment was carried out. An RADB regimen (10mg rabeprazole, 1000mg amoxicillin, 100mg doxycycline, and 220mg colloidal bismuth tartrate, all given bid for 14days) was prescribed by gastroenterologists. H.pylori eradication was confirmed by a 13 C-urea breath test performed at least 6weeks after the end of treatment. Regimen efficacy was evaluated by per-protocol (PP) and intention-to-treat (ITT) analyses. One hundred eighteen patients were included in the study. The eradication rate of RADB was 93.8% (105/112; 95% CI 89.2%-98.3%) in PP analysis and 89.8% (106/118; 95% CI 84.3%-95.4%) in ITT analysis. The patient compliance rate was 97.5% (115/118). The adverse event rate was 6.8% (8/118). Adverse events included asthenia, loss of appetite, dry mouth, heartburn, diarrhea, and abdominal pain. All adverse events disappeared after completionoftherapy. Our results suggest that 14-day BQT with amoxicillin and doxycycline can be an effective and safe eradication regimen for first-line therapy against H.pylori infection in clinical practice.

Pharmacodynamic Drug-Drug Interactions.

Pharmacodynamic drug-drug interactions (DDIs) occur when the pharmacological effect of one drug is altered by that of another drug in a combination regimen. DDIs often are classified as synergistic, additive, or antagonistic in nature, albeit these terms are frequently misused. Within a complex pathophysiological system, the mechanism of interaction may occur at the same target or through alternate pathways. Quantitative evaluation of pharmacodynamic DDIs by employing modeling and simulation approaches is needed to identify and optimize safe and effective combination therapy regimens. This review investigates the opportunities and challenges in pharmacodynamic DDI studies and highlights examples of quantitative methods for evaluating pharmacodynamic DDIs, with a particular emphasis on the use of mechanism-based modeling and simulation in DDI studies. Advancements in both experimental and computational techniques will enable the application of better, model-informed assessments of pharmacodynamic DDIs in drug discovery, development, and therapeutics.

Preclinical trial of Bacteriosens used for the photodynamic therapyof malignant tumors, including prostate cancer

Introduction.Bacteriochlorins are the most promising photosensitizers absorbing in the near-infrared spectral region. Their use can enhance the efficiency of photodynamic therapy due to the deeper penetration of radiation into the tumor.Objectiveto conduct a preclinical study of the photoinduced antitumor activity and biodistribution of Bacteriosens.Materials and methods.Bacteriosens is a preparation based on meso-tetra(3-pyridyl)bacteriochlorin absorbing at 747 nm. Photoinduced cytotoxicity was investigated in vitro using human tumor cells: A549, Hep 2, BT-474, MCF-7, SK-BR-3, PC3, and EJ and murine tumor cells: S37, C26, and LLC. In vivo studies were performed in mice with large and small tumors (S37, LLC, and C26).Results.In vitro investigation show that bacteriosens during optical irradiation led to the effective suppression of tumor cell growth in culture (the IC50 value varied from 0,08μМ to 1,21 μМ) and had no toxicity without exposure to light. The effective photodynamic therapy regimen using Bacteriosens in mice with inoculated small and large tumors of different genesis resulted in regression of a primary tumor node on 90–100 % of the animals in the absence of tumor recurrence within 90 days after treatment.Conclusion.Bacteriosens is a promising agent for the photodynamic therapy of small and large tumors; it can be successfully used as an alternative, organ-sparing minimally invasive treatment for malignant tumors, including prostate cancer.

Patterns of Failure Following Postoperative Radiation Therapy Based on “Tumor Bed With Margin” for Stage II to IV Type C Thymic Epithelial Tumor

The study purpose was to report failure patterns in Masaoka-Koga stage II to IV type C thymic epithelial tumor (TET) after postoperative radiation therapy (PORT) and to evaluate the suitability of PORT target volume confined to the "tumor bed only with margin." A retrospective review of 53 patients with stage II to IV type C TET was performed. The clinical outcomes, failure patterns in relation to PORT target volume, and prognostic factors were analyzed. During a median follow-up period of 69months, 14 deaths and 25 recurrences were observed. The 5-year rates of overall survival, disease-specific survival, and freedom from recurrence were 81.0%, 91.5%, and 49.7%, respectively. The failure patterns in relation to PORT target volume were in-field failure in 2 patients (3.8%), marginal in 2 (3.8%), and out of field in 23 (43.4%), respectively. The most common failure site was the pleura (12 patients), followed by the lung parenchyma (8 patients). Relapse involving the regional lymph nodes was observed in 6 patients, of whom 4 had synchronous distant failure and only 2 had isolated ipsilateral supraclavicular lymph node failure. The policy of PORT target volume confined to only the tumor bedseemsreasonable in treating patients with stage II to IV type C TET. The developmentof a more effective systemic therapy regimen is warranted.

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Background:Docetaxel used for first-line treatment of advanced prostate cancer (PCa) is only marginally effective. We previously showed, using the LTL-313H subrenal capsule patient-derived metastatic PCa xenograft model, that docetaxel combined with Aneustat (OMN54), a multivalent plant-derived therapeutic, led to marked synergistic tumour growth inhibition. Here, we investigated the effect of docetaxel+Aneustat on metastasis.Methods:C4-2 cells were incubated with docetaxel, Aneustat and docetaxel+Aneustat to assess effects on cell migration. The LTL-313H model, similarly treated, was analysed for effects on lung micro-metastasis and kidney invasion. The LTL-313H gene expression profile was compared with profiles of PCa patients (obtained from Oncomine) and subjected to IPA to determine involvement of cancer driver genes.Results:Docetaxel+Aneustat markedly inhibited C4-2 cell migration and LTL-313H lung micro-metastasis/kidney invasion. Oncomine analysis indicated that treatment with docetaxel+Aneustat was associated with improved patient outcome. The drug combination markedly downregulated expression of cancer driver genes such as FOXM1 (and FOXM1-target genes). FOXM1 overexpression reduced the anti-metastatic activity of docetaxel+Aneustat.Conclusions:Docetaxel+Aneustat can inhibit PCa tissue invasion and metastasis. This activity appears to be based on reduced expression of cancer driver genes such as FOXM1. Use of docetaxel+Aneustat may provide a new, more effective regimen for therapy of metastatic PCa.

The efficiency of treatment of cryoglobulinemic vasculitis associated with hepatitis C virus: analysis of 60
 cases

Aim. To evaluate the results of immunosuppressive and/or antiviral treatment of patients with hepatitis C virus (HCV)-induced mixed cryoglobulinemic (MC) vasculitis. Material and methods. This prospective study included 60 patients (m/f - 23/49, age - 45,9±11,1) with HCV-MC vasculitis. The Birmingham vasculitis activity score (BVAS) was used before the treatment and during follow-up (3,5±4,1 years). The rate of clinical and immunological responses to the treatment, the frequency of relapses and the influence of different treatment approaches on the prognosis of the disease were evaluated. Logistic regression analysis was used to assess factors influencing the effectiveness of treatment. Results. 23 (38%) patients had liver cirrhosis. BVAS scores before treatment ranged from 2 to 36. 25 (41,6%) patients had BVAS≥15. 6 (10%) patients presented with B-cell non-Hodgkin lymphomas. The antiviral treatment resulted in the elimination of the virus in 48.0% of the cases, complete clinical and immunological responses were achieved in 68,0% and 32,0% respectively. It had an advantage over immunosuppressive therapy in terms of long-term results of the treatment. We established the superiority of anti-CD monoclonal antibodies (rituximab) over conventional immunosuppressive drugs: complete clinical response 73% vs 13% (p=0,001). Combined therapy (rituximab and antiviral treatment) was more effective in patients with severe vasculitis (BVAS≥15). A case of successful treatment using direct-acting antivirals (DAAs) is reported. Causes of MC-vasculitis relapses after achieving sustained viral response are discussed. Conclusion. Antiviral therapy is the treatment of choice in all patients with HCV- HCV-MC vasculitis. Preference should be given to highly effective and safe modern therapy regimens with the use of DAAs. The antiviral treatment of severe forms of vasculitis must be combined with rituximab therapy.

Faces of Frailty in Aging with HIV Infection.

The number of adults who are aging successfully and have HIV infection is increasing. More effective antiretroviral therapy (ART) regimens are preventing individuals infected with HIV from reaching end stages of the HIV infection and developing AIDS (acquired immunodeficiency syndrome). However, even at lower viral loads, chronic HIV infection appears to have consequences on aging processes, including the development of frailty. Frailty is a term used to describe vulnerability in aging. Frailty indices such as the Fried Frailty Index (FFI), the Veterans Aging Cohort Study (VACS) Index, and the Center for Epidemiologic Studies Depression scale (CES-D), an index of emotional frailty, associate with or predict clinical outcomes and death. However, even among existing frailty definitions, components require rigorous and consistent standardization. In the Women's Interagency HIV Study (WIHS), we have shown that frailty does not exist in isolation, even in midlife, and we use frailty to predict death. Frailty indices should be systematically used by health professionals to evaluate health and future risks for adverse events. Frailty prevention efforts, especially among those with HIV infection, appear to be essential for "successful aging" or aging without disability or loss of independence and may prevent HIV transmission. Taking care of elderly people is one of the major challenges of this century, and we must expect and be prepared for an increase in the number of aging adults, some of whom are patients with many co-morbidities and HIV infection.

Pattern-based sensing of triple negative breast cancer cells with dual-ligand cofunctionalized gold nanoclusters.

Early detection of breast cancer is a critical component in patient prognosis and establishing effective therapy regimens. Here, we developed an easily accessible yet potentially powerful sensor to detect cancer cell targets by utilizing seven dual-ligand cofunctionalized gold nanoclusters (AuNCs) as both effective cell recognition elements and signal transducers. On the basis of this AuNC multichannel sensor, we have successfully distinguished healthy, cancerous and metastatic human breast cells with excellent reproducibility and high sensitivity. Triple negative breast cancer cells (TNBCs), which exhibit low expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2, were identified. The high accuracy of the blind breast cell sample tests further validates the practical application of the sensor array. In addition, the versatility of the sensor array is further justified by identifying amongst distinct cell types, different cell concentrations and cell mixtures. Notably, the drug-resistant cancer cells can also be efficiently discriminated. Furthermore, the dual-ligand cofunctionalized AuNCs can efficiently differentiate different cells from the peripheral blood of tumor-free and tumor-bearing mice. Taken together, this fluorescent AuNCs based array provides a powerful cell analysis tool with potential applications in biomedical diagnostics.

Phase 1/2 trial of ixazomib, cyclophosphamide, and dexamethasone for newly diagnosed multiple myeloma (NDMM).

8002Background: Ixazomib (Ixa) is an oral proteasome inhibitor, approved for treatment of relapsed myeloma (MM) in combination with lenalidomide and dexamethasone (Dex). The combination of bortezomib with cyclophosphamide (Ctx) and Dex is an effective regimen for initial therapy of MM. The combination of Ixa, Ctx and Dex could provide an effective, all oral regimen for initial therapy of MM. Methods: NDMM patients (pts) with measurable disease, adequate organ function, and an ECOG PS >=2 were enrolled. The primary objective of the phase 1 was to determine the MTD of Ctx that can be combined with Ixa and Dex. Pts received Ixa 4 mg on days 1, 8, 15, dex 40 mg days 1, 8, 15, 22 and cyclophosphamide 300 or 400 mg/m2 days 1, 8, 15, 22; cycles were 28 days. Patients could continue on ixa alone after 12 cycles. The phase 2 portion was designed to determine the complete plus very good partial response rate (>=VGPR) of ixazomib to be used in combination with cyclophosphamide and dexamethasone in ND MM. Results: Fi...

Effectiveness of an Adjuvant Chemotherapy Regimen for Early-Stage Breast Cancer: A Systematic Review and Network Meta-analysis.

Different adjuvant chemotherapy regimens are available for early-stage breast cancer. Because conventional meta-analysis does not allow comparing all regimens, we performed a network meta-analysis to identify the most effective adjuvant chemotherapy regimen. To find the most effective adjuvant therapy regimen for early-stage breast cancer. We searched MEDLINE, Embase, and the Cochrane Library for articles published before June 2015; the American Society of Clinical Oncology annual meeting abstracts from January 1983 through December 2014; and the American Association for Cancer Research annual meeting abstracts from January 1916 through December 2014. Additionally, we manually searched bibliographies for related references. We included randomized clinical trials of adjuvant treatments for early-stage breast cancer that compared 2 or more of the following: no adjuvant chemotherapy; sequential anthracycline-cyclophosphamide and taxane (AC-T); concurrent anthracycline-cyclophosphamide and taxane (ACT); anthracycline-cyclophosphamide without taxane (AC); docetaxel and cyclophosphamide (TC); cyclophosphamide, methotrexate, and fluorouracil (CMF); and platinum-containing regimens. We followed the PRISMA guidelines. Two investigators independently selected the articles and extracted information. Disagreements were resolved by discussion with another author. Quality was assessed by Cochrane risk-of-bias method. Data were pooled using random-effects models. We used network meta-analysis to test the most effective adjuvant therapy regimen in terms of overall survival (OS) by comparing regimens listed in the National Comprehensive Cancer Network guidelines and platinum-containing regimens. We identified 24 trials. The TC and platinum-containing regimens had OS benefit similar to that of sequential AC-T (TC hazard ratio [HR], 0.93; 95% CI, 0.62-1.40; and platinum HR, 0.93; 95% CI, 0.66-1.31). Patients treated with CMF or AC had significantly worse OS than those treated with sequential AC-T (CMF HR, 1.56; 95% CI, 1.32-1.85; and AC HR, 1.22; 95% CI, 1.10-1.37). Platinum-containing regimens tended to be more toxic than sequential AC-T. The toxicity of TC was similar to or less than that of sequential AC-T. Meta-regression analysis showed that hormone receptor status did not impact the HRs for OS for any regimen. Sequential AC-T is likely to be the most effective adjuvant therapy regimen for early-stage breast cancer regardless of hormone receptor status.

Low-Dose DMC Significantly Enhances the Effect of TMZ on Glioma Cells by Targeting Multiple Signaling Pathways Both In Vivo and In Vitro.

Temozolomide (TMZ) is widely used for treating glioblastoma (GBM), which can effectively inhibit the GBM growth for some months; however, it still cannot prevent the invariable recurrence of GBM. Improving the chemotherapeutic sensitization becomes an urgent agenda. In this study, we found low-dose demethoxycurcumin (DMC) could enhance the sensitivity of TMZ on glioma cells, and high-dose DMC has more significant effects on GBM cells compared with TMZ treatment alone both in vitro and in vivo. And co-administration of DMC and TMZ resulted in a significant increase in GBM apoptosis and a marked inhibition of cell growth pathogenesis of GBM. Mechanistically, DMC and TMZ synergistically increase intracellular level of reactive oxygen species (ROS) production, activate caspase-3-dependent apoptotic pathway, and inactivate of JAK/STAT3 signaling pathway in GBMs, which account for the cell apoptosis and proliferation inhibition. Together, these data implicate that low-dose DMC combined with TMZ represents an effective therapy regimen against GBMs by targeting multiple signaling pathways.

Detection of the criteria of prognostication of efficency of chronic acquired toxoplasmosis treatment

The great number of treatment schemes of toxoplasmosis predetermines the question for clinician how to choose the most effective therapy regimen. Aim. Detection of the criteria of prognostication of efficiency of the treatment patients with the chronic acquired toxoplasmosis (CAT) in an acute phase before and after the complex therapy. Methods. For attaining the set aim we examined 143 patients (92 women and 51 men) 18-75 years old with CAT in an acute phase. For evaluation of efficiency of the complex antiparasitic pathogenetic therapy and the character of dynamics of the studying indicators there was carried out the repeat examination of 143 patients in 1-2 and 5-6 month after the end of treatment. Results. An efficiency of considered treatment regimens depends on an initial pathogenetic determinant specific for each of them and its calculation allows prognosticate and individualize the treatment of patients. Conclusions. The immunological parameters, data of clinical blood analysis and biochemical indicators of the liver function and also the clinical-anamnestic indicators have the predictor properties that allows use it for prognosis of efficiency of CAT treatment. An efficiency of the different treatment regimens of toxoplasmosis can be prognosticated on the base of initial values of parameters of homeostasis of patient’s organism. An efficiency of elaborated algorithms of prognosis of efficiency of the different regimens of CAT therapy was 86,7-90% at the reliability ≥95%, that allows recommend it for clinical use. The use of prognostic algorithms allows individualize the treatment of patients with CAT.

Challenges in the Diagnosis and Management of Inflammatory Bowel Disease in the Elderly.

Among inflammatory bowel disease (IBD) patients, 4-12% is diagnosed after the age of 60. Both the rates of elderly and IBD are increasing worldwide. In older patients, the diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) is made more difficult due to polypharmacy and multimorbidity along with disease processes that mimic IBD. The clinical presentation in older-onset IBD differs from younger patients, and there is minimal disease progression over time. The management of the older IBD patient involves a combination of medical and surgical strategies. Few treatment efficacy studies exist in elderly IBD as most authors have focused on the adverse events related to therapy. A vast number of incident CD and UC cases in elderly have been treated with 5-aminosalicylic acid agents and do not require the use of immune modifying agents or biologics. Many other older IBD patients are prescribed long-term corticosteroids despite guidelines recommending more effective and safer maintenance therapy regimens. Serious infections, malignancy, and drug interactions are the most concerning complications of medical therapy. There are particularly important health care maintenance issues in older IBD patients including vaccinations, colorectal cancer screening, and bone loss prevention.

COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway.

Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins ανβ3, α4, β1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1α to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

Major diseases manifesting by vestibular vertigo: Treatment and rehabilitation

Betahistine hydrochloride is the drug of choice for the treatment of vestibular vertigo in the presence of benign paroxysmal positional vertigo, Meniere's disease, and vestibular neuronitis. Effective combination therapy regimens that contain, along with drugs from other pharmacologi- cal groups, betahistine hydrochloride that improves blood circulation in the vestibular structures, accelerates vestibular compensation, and pre- vents recurrent dizzy spells, have been elaborated to treat central vestibular vertigo in migraine-associated dizziness and in acute cerebrovas- cular accident. Of great importance is a combination of drug therapy and the current rehabilitation methods for vestibular diseases, which con- tribute to prompter and complete recovery of vestibular function. Biofeedback instrumental rehabilitation techniques using a stabilographic plat- form are highly effective. Successful treatment depends on the correctness of the established diagnosis. The diagnosis of peripheral and central vestibular vertigo frequently poses challenges. The essential reason for this is physicians' unawareness about outpatient methods for the diag- nosis of major vestibular diseases when the patient is at a doctor. It is important to follow a vestibular system study protocol since the use and correct assessment of diagnostic tests in most cases make it possible to estimate the degree of vestibular analyzer injury and to make an accu- rate diagnosis. The paper describes the diseases that are the most common causes of vestibular vertigo. The most effective methods for their treatment and cur- rent rehabilitation methods are discussed.

APOPTOSIS OF PANCREATIC BETA-CELLS AS A NEW TARGET FOR INSULIN THERAPY OF PATIENTS WITH TYPE 1 AND 2 DIABETES MELLITUS

There is a review of the mechanisms of pancreatic beta-cell programmed death (apoptosis) in type 1 and 2 diabetes mellitus. Based on the evidence of anti-apoptotic physiological effects of insulin the necessity of new therapeutic strategy focused on maximal beta-cell function and mass preserving in diabetic patients using modern effective insulin therapy regimen is ground. The advantages of the both long- and short-acting insulin analogues (Lantus® and Apidra®) for early aggressive and safe glucose lowering therapy warranted to beta-cell preservation are argued.

Progress and prospects for targeting Hsp90 to treat fungal infections

Fungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

FAS-AS1 Intronic Lncrna and Ibrutinib Negatively Regulate Soluble Fas Production and Sensitize B-Cell Lymphomas To Fas-Mediated Apoptosis

IntroductionThe death receptor Fas is responsible for cell homeostasis, elimination of defective cells, and more recently promotion of cancer. Many effective anti-cancer therapies depend on Fas-mediated apoptosis to eradicate tumor cells and ineffective Fas- mediated apoptosis is a recognized basis for primary and acquired resistance to chemotherapy. Impaired Fas-mediated apoptosis is associated with poor clinical outcome and chemoresistance in patients with lymphoma. Evasion of immune surveillance and resistance in Fas apoptosis occur in part through interference with FasL binding either by Fas binding proteins (nucleolin and human herpesvirus 8 K1) or by release of soluble Fas (sFas), which is produced by skipping of exon 6. The first intron of Fas pre-mRNA contains a long-noncoding RNA (lncRNA) termed FAS-AS1 implicated in gene expression. The presence of sFas in serum is associated with poor clinical outcome of patients with non-Hodgkin's lymphoma (NHL). However, the mechanisms that control Fas alternative splicing are incompletely understood. Methods/ResultsThe levels of FAS-AS1 lncRNA are suppressed in primary NHL and B-cell lymphoma cell lines and inversely correlate with production of sFas. ChiP assay revealed hyper- methylation of FAS-AS1 promoter that is responsible for the reduced expression of FAS-AS1 lncRNA.Histone methyltransferase EZH2 is responsible for transcriptional repression via trimethylation of lysine 27 on histone H3. EZH2-mediated hyper-methylation of the FAS-AS1 promoter correlated with production of sFas, which was reversed by the ectopic expression of FAS-AS1 or pharmacological inhibition of EZH2 by DZNep. Inhibition of EZH2 methyltransferase activity elevated FAS-AS1 lncRNA levels and promoted its binding to RBM5 in RNA-Immunoprecipitation assay. Sequestering RBM5 by FAS-AS1 lncRNA inhibited RBM5-mediated skipping of exon 6 and thus sFas production. Decreased production of sFas was accompanied by increased levels of surface Fas and FasL binding in lymphoma cell lines that translated into enhanced Fas-mediated apoptosis.Bruton tyrosine kinase (BTK) is important for B cell receptor signaling and was proposed and demonstrated to be a feasible target for lymphoma treatment. BTK inhibitor ibrutinib decreased levels of EZH2 and RBM5 and correspondingly decreased levels of sFas and enhanced Fas-mediated apoptosis. ConclusionTaken together, we show here for the first time that the FAS-AS1 intronic lncRNA negatively regulates production of sFas. The oncogenic proteins EZH2 and RBM5, overexpressed in lymphoma cells, cooperate to produce sFas through down regulation of FAS-AS1 expression and stimulation of skipping of exon 6 with production of sFas. Targeting of EZH2 by DZNep and ibrutinib reduces sFas expression and sensitizes cells to Fas-mediated apoptosis. We anticipate that these drugs will play a key role in effective therapy regimens by enhancing Fas-signaling and account in part for the enhanced chemotherapy responses in hematologic malignancies. Disclosures:No relevant conflicts of interest to declare.