Efficacy Of Suppression Research Articles

Tri-stimuli-responsive biodegradable theranostics for mild hyperthermia enhanced chemotherapy.

The combination of hyperthermia and chemotherapy is able to greatly enhance the treatment efficacy mainly due to the synergistic interactions between these two treatments. In this study, we propose a new concept of mild hyperthermia enhanced chemotherapy to explore and validate the synergistic mechanism invitro and invivo. To do this, a novel kind of biodegradable nanotheranostics based on copper sulfide doped periodic mesoporous organosilica nanoparticles (CuS@PMOs) was constructed via an in situ growth method for light-triggered mild hyperthermia and drug delivery. The as-prepared CuS@PMOs exhibit a high doxorubicin (DOX) loading capacity of 470mg/g. The DOX release from CuS@PMOs can be precisely controlled by three stimuli, including intracellular glutathione (GSH), acidic environment in tumor cells, and external laser irradiation. Most intriguingly, mild hyperthermia induced by laser-irradiated CuS nanoparticles can dramatically improve the cell uptake of nanotheranostics both invitro and invivo, thus significantly enhancing the chemotherapeutic efficacy for complete tumor growth suppression without recurrence. Meanwhile, the fluorescence recovery following the DOX release can be used as an indicator to monitor the chemotherapeutic progress.

Isolation and Characterization of Plant Growth Promoting Rhizobacteria Enterobacter hormaechei and their Suppression Efficacy against Colletotrichum falcatum in Combination with Chitosan

Isolation and Characterization of Plant Growth Promoting Rhizobacteria Enterobacter hormaechei and their Suppression Efficacy against Colletotrichum falcatum in Combination with Chitosan

Influence of vitamin D levels on the treatment of premature ventricular complexes in patients with chronic kidney disease

IntroductionRecent studies have shown that in chronic kidney disease (CKD) 25(OH)D deficiency or insufficiency is a significant risk factor for cardiovascular diseases (CVDs), sudden cardiac death (SCD) and mortality. Premature ventricular complexes (PVCs) are very common in patients with CKD, hypertension, obesity, sleep apnea, and structural heart disease. Often PVCs in the structurally normal heart are considered benign, although they seem to be associated with a more than two-fold higher risk of cardiovascular complications, including stroke disease and death. AimIn the present study we aimed to evaluate the influence of different 25(OH)D levels on the changes of the numbers of PVCs in all patients, assessed by 24-hour-Holter monitoring 3months after β-blocker onset. Methods and resultsWe conducted a prospective, longitudinal study of 824 patients with PVCs and CKD (estimated glomerular filtration rate measured by MDRD equation, between 16 and 59mL/min/1.73m2). All patients were treated with a β-blocker (bisoprolol 10mg daily). We observed that the 3 groups presented a significant decrease in the number of PVCs from baseline 26,091±3327 (25(OH)D deficiency group), 25,902±3501 (25(OH)D insufficiency group), and 25,554±3637 (25(OH)D sufficiency group) to 20,554±3782, 19,885±3945 and 15,433±4059, respectively, after 3months of β-blocker therapy (P<0.0001 for the comparisons between time points in the same group). However at the 3rd month after bisoprolol onset, comparisons between 25(OH)D deficiency vs. 25(OH)D sufficiency groups showed a mean difference of 5121 PVCs (P<0.0001), and comparisons between 25(OH)D insufficiency vs. 25(OH)D sufficiency groups showed a mean difference of 4452 PVCs (P<0.0001). No difference was observed between 25(OH)D deficiency vs. 25(OH)D insufficiency groups (P=0.3181). ConclusionsWe suggest that the effectiveness of β-blocker treatment for PVCs in CKD patients was observed in all 25(OH)D levels. However, the responsiveness was higher in patients with a normal range of 25(OH)D in comparison to patients with deficiency or insufficiency in 25(OH)D levels. Whether vitamin D supplementation increases the efficacy of beta-blocker mediated suppression of PVCs requires further evaluation.

A Co-culture Assay to Determine Efficacy of TNF-α Suppression by Biomechanically Induced Human Bone Marrow Mesenchymal Stem Cells.

The beneficial effects of mesenchymal stem cell (MSC)-based cellular therapies are believed to be mediated primarily by the ability odansf MSCs to suppress inflammation associated with chronic or acute injury, infection, autoimmunity, and graft-versus-host disease. To specifically address the effects of frictional force caused by blood flow, or wall shear stress (WSS), on human MSC immunomodulatory function, we have utilized microfluidics to model WSS at the luminal wall of arteries. Anti-inflammatory potency of MSCs was subsequently quantified via measurement of TNF-α production by activated murine splenocytes in co-culture assays. The TNF-α suppression assay serves as a reproducible platform for functional assessment of MSC potency and demonstrates predictive value as a surrogate assay for MSC therapeutic efficacy.

Effect of nozzle type on the fungicide efficacy for fusarium head blight suppression on wheat

Effect of fungicide treatments on Fusarium head blight (FHB) and grain yield of wheat depending on application technique i.e. use of different nozzle types, was evaluated in the study. Nozzles types TJ 11004, Albuz ATR 8004 and Arag TFA 11004 were used for application of systemic fungicide Duett Ultra (0.5 l/ha). FHB intensity (%) was determined on the basis of a visual assessment of the number of infected heads and the perecentage of the disease symptoms on the individual head. Differences in grain yield between the treated variants, as well as between the treated and untreated variants, were determined after hand threshing. The lowest percentage of FHB development in wheat and the highest yield were recorded in variants where fungicides were applied by nozzle type ATR 8004. Application technique directly affects the reduction of fusarium head blight in wheat and indirectly it also reduces yield loss.

THE ROLE OF IMMUNITY SUPPRESSION IN TREATMENT OF MYOCARDITIS

Regardless the common consensus on the benefits of immunity suppression in eosinophilic, granulomatous, giant cell and lymphocyte myocarditis, associated with systemic connective tissue diseases, and in rejection of transplanted heart, role of immune suppression therapy (IST) in treatment of lymphocyte inflammatory cardiomyopathy remains controversial. Previous retrospective studies revealed clinical improvement in 90% of patients with virus-negative inflammatory cardiomyopathy and absence of response or worsening of heart function in 85% of virus-positive inflammatory cardiomyopathy after immunity suppression. Other studies identified the enhanced expression of HLA in cardiomyocytes as an additional indicator of sensitivity of inflammatory cardiomyopathy to IST. Recently, the singlecenter randomized study was performed with double blind application of prednisone and azatioprin as addition to maintenance therapy in 85 patients with virus-negative inflammatory cardiomyopathy. The results of the study showed significant improvement of the left ventricle ejection fraction and decrease of the left ventricle dimensions in 88% patients among 43 of treated comparing to 42 patients on placebo demonstrated worsening of cardiac functioning in 83% cases (the TIMIC study). This data confirms the efficacy of immunity suppression in virus-negative inflammatory cardiomyopathy. Insufficiency of response in 12% cases undermines existence of non-revealed viruses and mechanisms of damage and inflammation, non-sensitive to immunity suppression. Restoring of cardiac function in patients actively responded to immunity suppression, was determined by inhibition of cardiomyocytes death and increase of cells proliferation with ad novo synthesized contractile material.

Subcutaneous and Sublingual Immunotherapy in a Mouse Model of Allergic Asthma.

Allergic asthma, caused by inhaled allergens such as house dust mite or grass pollen, is characterized by reversible airway obstruction, associated with an eosinophilic inflammation of the airways, as well as airway hyper responsiveness and remodeling. The inhaled allergens trigger a type-2 inflammatory response with involvement of innate lymphoid cells (ILC2) and Th2 cells, resulting in high production of immunoglobulin E (IgE) antibodies. Consequently, renewed allergen exposure results in a classic allergic response with a distinct early and late phase, both resulting in bronchoconstriction and shortness of breath. Allergen specific immunotherapy (AIT) is the only treatment that is capable of modifying the immunological process underlying allergic responses including allergic asthma and both subcutaneous AIT (SCIT) as well as sublingual AIT (SLIT) have proven clinical efficacy in long term suppression of the allergic response. Although these treatments are very successful for rhinitis, application of AIT in asthma is hampered by variable efficacy, long duration of treatment, and the risk of severe side-effects. A more profound understanding of the mechanisms by which AIT achieves tolerance to allergens in sensitized individuals is needed to improve its efficacy. Mouse models have been very valuable as a preclinical model to characterize the mechanisms of desensitization in AIT and to evaluate novel approaches for improved efficacy. Here, we present a rapid and reproducible mouse model for allergen-specific immunotherapy. In this model, mice are sensitized with two injections of allergen absorbed to aluminum hydroxide to induce allergic sensitization, followed by subcutaneous injections (SCIT) or sublingual administrations (SLIT) of the allergen as immunotherapy treatment. Finally, mice are challenged by three intranasal allergen administrations. We will describe the protocols as well as the most important read-out parameters including measurement of invasive lung function measurements, serum immunoglobulin levels, isolation of broncho-alveolar lavage fluid (BALF), and preparation of cytospins. Moreover, we describe how to restimulate lung single cell suspensions, perform flow cytometry measurements to identify populations of relevant immune cells, and perform ELISAs and Luminex assays to measure the cytokine concentrations in BALF and lung tissue.

Nghiên cứu điều kiện tồn trữ và hiệu quả của chất bảo vệ sự tồn tại thực khuẩn thể trong quản lý bệnh cháy bìa lá lúa do vi khuẩn Xanthomonas oryzae pv. oryzae trong điều kiện nhà lưới

Study on additives to help recovery of phages after lyophylization, Glucose 10% showed the best effectiveness, following Mannitol 5% and 10%. Study on storage durations of three formulations, lyophilized formulation at room temperature showed maintaining phage density stable up to 5 months storage, while liquid formulation in 40C and in room temperature showed significant reduction phage density after 3 months and 1 month storage, respectively. Study on additives to help phage surviving on foliar of rice under sunlight conditions, phage density maintained equally among treatments after 24 hours spraying phage on foliar rice. Treatment phage + skimmilk showed better effect in maintaining phage density up to 5 days after spraying, while other treatments showed critical declined of phage density. However, the disease suppression efficacy did not correlate with phage density on rice foliars. Disease reduction was determined by phage density contact with bacterial pathogens in first several hours, therefore the reduction of phage density after 24 hours had no effect on disease reduction. Specially, treatments phage + mungbean or soybean powder expressed better in reduction of percentage of leaf infection than other treatments, there results could be involved with the effect of these additives in enhancing rice resistance beside phage effects.

Microfluidic membrane suppressor module design and evaluation for capillary ion chromatography

A microfluidic ion-suppression module for use in ion-exchange chromatography has been developed and evaluated. The device consists of an ion-exchange membrane clamped between two polymer chips featuring a 200×100μm (width×depth) eluent channel (l=60mm), and a 300×150μm regenerant channel (60mm), respectively. The suppression efficacy using a Nafion membrane was compared with that of a styrene-sulfonate grafted fluorinated ethylene propylene (FEP) membrane. The latter was found to outperform Nafion in terms of lowest attainable background signal (suppression efficacy) and dynamic suppression range. Increasing the suppressor temperature or the sulfuric acid regenerant concentration led to an extension of the operational suppression range, this however at the cost of an increased background signal due to enhanced diffusion, inducing sulfate bleed. Under optimized operating conditions, the microfluidic suppressor provided a dynamic capacity of 0.35μEq./min, being compatible with gradient separations applying up to 70mM KOH in combination with 400μm i.d. capillary columns operated at the optimal flow velocity. The applicability of the miniaturized suppressor is demonstrated for both isocratic and gradient separations of mixtures of inorganic anions. Band-broadening characteristics of the suppressor were optimized with respect to a commercial capillary hollow-fiber suppressor, yielding comparable overall system efficiency, e.g., 8500 plates for nitrate recorded on a 150mm long capillary column. A second chip device was also constructed, featuring suppression at both sides of the eluent flow path. This double-sided suppressor allowed to increase sample throughput and operate at eluent flow rates of 10μL/min, while maintaining efficient suppression characteristics.

Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer

IntroductionAndrogen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards.MethodsData of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42–96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2–12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl.ResultsAfter 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80–92%, from 83–93%, and from 65–97% with median (interquartile range) serum testosterone values of 2.9 (2.9–6.5), 5.0 (2.9–8.7), and 8.7 (5.8–14.1) ng/dl at study end, respectively.ConclusionIn the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0466-7) contains supplementary material, which is available to authorized users.

Probiotic Diversity Enhances Rhizosphere Microbiome Function and Plant Disease Suppression.

ABSTRACTBacterial communities associated with plant roots play an important role in the suppression of soil-borne pathogens, and multispecies probiotic consortia may enhance disease suppression efficacy. Here we introduced defined Pseudomonas species consortia into naturally complex microbial communities and measured the importance of Pseudomonas community diversity for their survival and the suppression of the bacterial plant pathogen Ralstonia solanacearum in the tomato rhizosphere microbiome. The survival of introduced Pseudomonas consortia increased with increasing diversity. Further, high Pseudomonas diversity reduced pathogen density in the rhizosphere and decreased the disease incidence due to both intensified resource competition and interference with the pathogen. These results provide novel mechanistic insights into elevated pathogen suppression by diverse probiotic consortia in naturally diverse plant rhizospheres. Ecologically based community assembly rules could thus play a key role in engineering functionally reliable microbiome applications.

Thought Suppression Research Methods: Paradigms, Theories, Methodological Concerns

Abstract It is hard to provide an unequivocal answer to the question of whether or not thought suppression is effective. Two thought suppression paradigms - the “white bear” paradigm and the think/no-think paradigm - give mixed results. Generally, “white bear” experiments indicate that thought suppression is counterproductive, while experiments in the think/no-think paradigm suggest that it is possible to effectively suppress a thought. There are also alternative methods used to study thought suppression, for instance the directed forgetting paradigm or the Stroop task. In the article, I describe the research methods used to explore thought suppression efficacy. I focus on the “white bear” and the think/no-think paradigms and discuss theories proposed to explain the results obtained. I also consider the internal and external validity of the methods used.

Evaluation of Some Trichoderma harzianum Isolates for the Management of Soilborne Diseases of Brinjal and Okra

Present study investigated the efficacy of 6 Trichoderma harzianum isolates against damping off and wilt diseases of brinjal and okra caused by Fusarium oxysporium (FO) and Pythium aphanidermatum (PA), respectively in order to get more effective isolates for disease management. Isolated pathogens from brinjal were named as Fob and Pab and from okra Foo and Pao for F. oxysporum and P. aphanidermatum, respectively. In vitro analysis revealed that T. harzianum isolates inhibited the radial growth of both pathogens and isolate Th-Sks was most effective with 78.44 and 74.16% growth inhibition of Fob and Pab, and 78.19 and 78.11% of Foo and Pao, respectively. Production of volatile and non-volatile metabolites by isolate Th-Sks was more aggressive in mycelial growth inhibition of all test pathogens than that of other isolates. Isolate Th-Sks had highest suppression efficacy i.e. 95.92 and 98.93% for Fob and Pab, 96.43 and 93.33% for Foo and Pao under glasshouse conditions, 96.18 and 95.73% for Fob and Pab, and 94.66 and 96.18% for Foo and Pao in the field conditions, respectively. Additionally, seed treatment of brinjal and okra with isolate Th-Sks gave a significant stimulatory effect on plant height (brinjal 52.9 cm; okra 110.5 cm) and increased fruit yield (brinjal 328.3 g; okra 294.6 g) in comparison to other isolates and control sets during field trials. Thus, it is concluded that isolate Th-Sks can be used as biocontrol agent for management of wilt and damping off diseases of okra and brinjal after multilocation trials.

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification. ASCL1, a transcription factor shown to play a role in SCLC, was also expressed in 11/14 cell lines. All SCLC cell lines were sensitive to JQ1 with GI50 values ≤1.23 μM, with six of them showing GI50 values <0.1 μM. Expression of MYCL as well as MYCN, ASCL1 and other driver oncogenes including CDK6 was reduced by JQ1 treatment, in particular in the cell lines with high expression of the respective genes; however, no association was observed between the sensitivity to JQ1 and the levels of MYCL, MYCN and ASCL1 expression. In contrast, levels of CDK6 expression and its reduction rates by JQ1 were associated with JQ1 sensitivity. Therefore, we concluded that CDK6 is a novel target of JQ1 and predictive marker for JQ1 sensitivity in SCLC cells.

Biological spectrum of Trichoderma harzianum Rifai isolates to control fungal diseases of tomato (Solanum lycopersicon L.)

Three Trichoderma harzianum isolates viz., Th-Sks, Th-Ke and Th-Ar collected from respective states of India viz., Rajasthan, Kerala and Andhra Pradesh were evaluated for the management of six fungal diseases namely damping off, Fusarium wilt, Rhizoctonia wilt, early leaf spot, late blight and Septoria leaf spot in tomato. During in vitro analysis, T. harzianum isolates inhibited the pathogens’ growth. Isolate Th-Sks was the most virulent antagonist against all the test pathogens and exhibited maximum of 79.47% growth inhibition of Phytophthora infestans. Isolate Th-Sks proved most effective at suppression efficacy in the range of 95–100% and 91–100% against all diseases under glasshouse and in the field conditions, respectively. Tomato seeds treatment with isolate Th-Sks also promoted plant height (78.23 cm) and fruits yield (290 g/plant) during field trial and data were found to be not-significantly different from other isolates. Thus, it is concluded that isolate Th-Sks can be utilised as a biocontrol agent for management of fungal diseases in tomato.

Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.

cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.

Tumor-Specific Peptide, Selected from a Phage Peptide Library, Enhances Antitumor Activity of Lactaptin.

A recombinant analogue of lactaptin (RL2), a new potential anticancer molecule, induces apoptosis in cultured tumor cells. The tumor suppression efficacy of RL2 was shown against mouse hepatoma-1 cells and MDA-MB-231 human breast adenocarcinoma cells. The RL2-based therapeutic drug lactaptin is distributed evenly throughout the organism, which reduces its antitumor efficacy. In the current study, we obtained a genetic construct that allows production of the recombinant fusion protein T3-RL2, consisting of RL2 and T3 peptide (YTYDPWLIFPAN), in E. coli cells. T3 peptide was selected from a phage peptide library as a result of two screenings: in vitro using MDA-MB-231 cell culture and in vivo using a mouse xenograft model of breast cancer MDA-MB-231. It was shown that the displayed peptide T3 provides binding and internalization of phage particles by MDA-MB-231 cells and their specific accumulation in MDA-MB-231 tumor tissue. In addition, based on the nucleotide sequences coding RL2 and the known tumor-targeting peptide iRGD, we obtained genetic constructs that provide synthesis of fusion proteins RL2-iRGD and RL-iRGD-His. We studied the cytotoxic activity of fusion proteins T3-RL2, RL2-iRGD and RL-iRGD-His in vitro using MDA-MB-231 and MCF-7 human adenocarcinoma cells. The in vitro results showed that the fusion proteins inhibit proliferation of both cell cultures, and their cytotoxic activity is higher than that of RL2. In vivo experiments on the study of the antitumor efficacy of the obtained fusion proteins demonstrated that T3-RL2 protein significantly inhibits MDA-MB-231 tumor growth in a xenograft model compared with RL2, while the antitumor effect of RL2-iRGD and RL-iRGD-His proteins is comparable to the effect of RL2.

Intramuscular depot formulations of leuprolide acetate suppress testosterone levels below a 20 ng/dL threshold: a retrospective analysis of two Phase III studies.

IntroductionAndrogen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs is a standard treatment for advanced prostate cancer. GnRH analog therapy can reduce testosterone to “castrate” levels, historically defined as <50 ng/dL. With the advent of newer assays, a lower threshold of <20 ng/dL has recently been proposed. We report the results of a retrospective analysis of two Phase III trials of 4- and 6-month depot microsphere formulations of leuprolide acetate (LA), a GnRH agonist that has previously demonstrated efficacy in testosterone suppression to <50 ng/dL in patients on ADT. This analysis investigates the ability of these LA formulations to suppress to ≤20 ng/dL levels.MethodsIn two of five AbbVie/Abbott clinical trials of microsphere formulations of LA for ADT, analytic technology permitting testosterone detection as low as 3 ng/dL was used and thus was selected for this analysis. Both trials were open-label, fixed-dose studies in prostate cancer patients, naïve to ADT. Patients received either 30 mg (4-month formulation; n=49) or 45 mg (6-month formulation; n=151) depot injections of LA microspheres. Treatment duration was up to 32 weeks for the 4-month formulation and 48 weeks for the 6-month formulation. The proportion of patients achieving the 20 ng/dL threshold was determined every 4 weeks.ResultsPooled analysis showed that 152 of 193 (79%) of patients achieved serum testosterone levels of ≤20 ng/dL at 4 weeks, and sustained the improvement at week 24 (169/189, 89%). Additionally, in the 6-month study, 127/135 (94.1%) patients were suppressed to ≤20 ng/dL at 48 weeks.ConclusionBoth 4- and 6-month intramuscular depot formulations of LA achieved and maintained mean serum testosterone levels ≤20 ng/dL in the vast majority of patients as early as 4 weeks following treatment initiation. Additional research on the clinical relevance of this lower testosterone threshold is warranted.

Abstract 3074: Addition of ARN509 and docetaxel, alone or in combination, to castration demonstrates improved efficacy and heterogeneity of molecular response in prostate cancer patient-derived xenografts

Abstract Results from clinical and preclinical investigations suggest potential survival benefits from more aggressive early treatment of some patients. Our objective was to evaluate in vivo the efficacy of adding docetaxel (DOC) or ARN509, alone or in combination, to primary androgen ablation and to investigate the associated molecular response and resistance. We used hormone-sensitive LuCaP patient-derived prostate cancer xenografts (PDXs) models 35, 77, and 147 that all express AR but differ significantly in responses to castration (CX) and exhibit diverse molecular characteristics. Tumors were grown in intact mice and when established, mice were randomized for CX alone or CX with DOC or ARN-509, or their combination. Tumor volume (TV), and serum PSA responses were monitored. Tumors were harvested 5 days post-treatment (d5) and at end of study (EOS) for analyses. Our results show differential efficacy of the treatments, mimicking the heterogeneity of clinical response. LuCaP 77 progression was inhibited by CX and the additional treatments (TXs) further inhibited TV, with the most decreased TV and PSA detected in the combination group. When compared to CX, CX combined with ARN509 demonstrated the most significantly improved survival benefit (10w vs 16.5w median survival; HR = 0.2, p&amp;lt;0.001), while CX combined with DOC resulted in a smaller survival benefit (10w vs 12.5w, median survival HR = 0.5 p = 0.036). The combination TX did not result in improved survival due to negative health side effects that resulted in early sacrifice. LuCaP 147 exhibited similar responses to CX as LuCaP 77 but only small additional inhibition of TV with the combination TXs and no significant survival improvements over CX alone. LuCaP 35 was the most responsive to CX and the additional treatments did not enhance the TV inhibition, decreases in serum PSA or survival. Preliminary IHC analyses of the early response (d5 tumors) did not show significant decrease in AR or GR in any of the PDXs but decrease in PSA indicated the efficacy of androgen suppression. Decreased proliferation (Ki67) was detected in LuCaP 77 and LuCaP 147 after CX and more pronounced decreases in the combination vs CX groups in LuCaP 77 and ARN509 and the combination vs CX in LuCaP 147 with no difference detected in LuCaP 35. Analyses of early gene expression responses at d5 by qPCR revealed changes specifically associated with single and combination treatment with ARN509 in LuCaP 77 for both AR-regulated genes (FKBP5, PCNA, and AKR1C3) and proliferation-associated genes (UBE2C3 and NUSAP1). Further analyses of the responses and alteration of genes and proteins associated with AR signaling, proliferation and drug resistance at d5 and EOS are ongoing. Citation Format: Ryan McMullin, Himanshu Gupta, Yashoda Rajpurohit, Holly Nguyen, Lisha Brown, Daniel Sondheim, Gormley Michael, Deborah Ricci, Shibu Thomas, Corey Eva. Addition of ARN509 and docetaxel, alone or in combination, to castration demonstrates improved efficacy and heterogeneity of molecular response in prostate cancer patient-derived xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3074.

Optimization of the cultural medium and conditions for production of antifungal substances by Streptomyces platensis 3-10 and evaluation of its efficacy in suppression of clubroot disease (Plasmodiophora brassicae) of oilseed rape

This study was conducted to optimize the cultural medium and conditions for production of antifungal substances by Streptomyces platensis 3-10 and to evaluate its efficacy in suppressing Plasmodiophora brassicae (PB), the causal agent for clubroot of oilseed rape. The optimization was done using the one-factor-at-a-time (OFAT) method, followed by orthogonal designing. The optimized medium contained starch at 3% (w/v), peptone at 0.75%, yeast extract at 0.025%, soybean meal at 1% (w/v) and minor/trace elements (K+, Mg2+, Mn2+, Zn2+), initial pH 6.5. After incubation in this medium at 28°C/150rpm for 72h, isolate 3-10 showed high antifungal activity. The cultural filtrates (CF3-10) produced an average inhibition-zone diameter of 50mm against Aspergillus niger. The live spores and metabolites of 3-10 in CF3-10 or its crude extracts (CE3-10) suppressed PB infection of oilseed rape roots by 3–83%, compared to the treatment with PB alone. The efficacy was positively correlated (correlation co-efficiency: 0.9526–0.9873, P<0.05) to the applied dose of each active component. Germination of PB resting spores was inhibited by 75% and 80% by CE3-10 (1000μg/mL, w/v) and CF3-10 (5%, v/v), respectively. These findings suggest that S. platensis 3-10 is a promising biocontrol agent against PB.