Mahkota Dewa (Phaleria Macrocarpa) sebagai Antinefrotoksisitas “Dewa Penyelamat” dalam Penurunan Efek Samping Cisplatin

Cisplatin is one of the most widely used chemotherapeutic agent in cancer treatment, however it possess series of harmful adverse effects, most notably, nephrotoxicity. Due to that reason, a natural chemopreventive agent is needed to minimize cisplatin's toxicity, namely, Mahkota Dewa fruit (Phaleria marcocarpa) extract. This research aim to determine anti nephrotoxic effect of mahkota dewa fruit on Vero cells, model of renal cells. Cytotoxic assay of mahkota dewa's extract and cisplatin both single and combination was determined using MTT assay on HeLa cells and Vero cells. The cytotoxic assay resulted that IC50 value of cisplatin and Mahkota Dewa to HeLa cells were 18µM (5,4 µg/mL) and 845 µg/mL, respectively, whereas the IC50 value of cisplatin and Mahkota Dewa to Vero were 80 µM (24 µg/mL) and 730 µg/mL, respectively. The results indicated that cisplatin was more cytotoxic to HeLa cell in comparison to Vero cell. Combination treatment of mahkota dewa's extract at 183 µg/mL and cisplatin 284 µM showed increased viability of Vero cells. Therefore, combination treatment of cisplatin and mahkota dewa are able to decrease nephrotoxicity of cisplatin to renal cells

Applications and challenges of marker-assisted selection in the Western Australian Wheat Breeding Program

Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the beta1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of beta1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked beta1 integrin function or knockdown of beta1 switched the migratory behavior of human and mouse E-cadherin-positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor-beta (TGFbeta) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box-binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFbeta receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in beta1 integrin-deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that beta1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting beta1 integrins may have undesirable effects in TNBC

Checkpoint inhibition reduces the threshold for Drug-Specific T-Cell priming and increases the incidence of sulfasalazine hypersensitivity

An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring

Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-Desmethyl Naproxen metabolite but not the acyl glucuronide

Background Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug-induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T-cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking. Methods In this work, we identify CD4+ and CD8+ T-cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN-γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP-DILI, were used to explore drug-specific T-cell activation. T-cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T-cell activation. Cells were exposed to NAP, its oxidative metabolite 6-O-desmethyl NAP (DM-NAP), its AG or synthesized NAP-AG human-serum albumin adducts (NAP-AG adduct). Results CD4+ and CD8+ T-cells from patients expressing a range of different Vβ receptors were stimulated to proliferate and secrete IFN-γ and IL-22 when exposed to DM-NAP, but not NAP, NAP-AG or the NAP-AG adduct. Activation of the CD4+ TCC was HLA-DQ-restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM-NAP-pulsed APC, while fixation of APC blocked the T-cell response. Cross-reactivity was not observed with structurally-related drugs. Conclusion Our results confirm hepatic T-cell infiltrations in NSAID-induced DILI, and show a T-cell memory response toward DM-NAP indicating an immune-mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP

Measurement of CD4+ and CD8+ T-Lymphocyte Cytokine Secretion and Gene Expression Changes in p-Phenylenediamine Allergic Patients and Tolerant Individuals

Factors predisposing to individual susceptibility to contact allergic dermatitis are ill defined. This study was designed to characterize the response of allergic and tolerant individuals’ T-lymphocytes after exposure to p-phenylenediamine (PPD). Peripheral blood mononuclear cells (PBMCs) from allergic patients proliferated when treated with PPD and Bandrowski's base (BB) and secreted IL-1α, -1β, -4, -5, -6, -8, -10, and -13; IFN-γ; tumor necrosis factor-α; MIP-1α/β; MCP-1 (monocyte chemotactic protein-1); and RANTES. PBMCs from tolerant individuals were stimulated to proliferate only with BB, and they secreted significantly lower levels of Th2 cytokines. Principal component analysis showed that genes are differentially expressed between the patient groups. A network-based analysis of microarray data showed upregulation of T helper type 2 (Th2) gene pathways, including IL-9, in allergic patients, but a regulatory gene profile in tolerant individuals. Real-time PCR confirmed the observed increase in Th2 cytokine gene transcription in allergic patients. Purified CD4+ and CD8+ T cells from allergic patients were stimulated to proliferate and secrete Th2 cytokines following antigen exposure. Only CD4+ T cells from tolerant individuals were stimulated by BB, and levels of Th2 cytokines were 80% lower. The nature of the antigenic determinant stimulating PBMCs and levels of Th2 cytokines, including IL-9, was confirmed in a validation cohort. These studies show increased activity of Th2 cytokines in CD4+ and CD8+ T cells from individuals with allergic contact dermatitis

Field-adapted sampling of whole blood to determine the levels of amodiaquine and its metabolite in children with uncomplicated malaria treated with amodiaquine plus artesunate combination

<p>Abstract</p> <p>Background</p> <p>Artemisinin combination therapy (ACT) has been widely adopted as first-line treatment for uncomplicated falciparum malaria. In Uganda, amodiaquine plus artesunate (AQ+AS), is the alternative first-line regimen to Coartem^®(artemether + lumefantrine) for the treatment of uncomplicated falciparum malaria. Currently, there are few field-adapted analytical techniques for monitoring amodiaquine utilization in patients. This study evaluates the field applicability of a new method to determine amodiaquine and its metabolite concentrations in whole blood dried on filter paper.</p> <p>Methods</p> <p>Twelve patients aged between 1.5 to 8 years with uncomplicated malaria received three standard oral doses of AQ+AS. Filter paper blood samples were collected before drug intake and at six different time points over 28 days period. A new field-adapted sampling procedure and liquid chromatographic method was used for quantitative determination of amodiaquine and its metabolite in whole blood.</p> <p>Results</p> <p>The sampling procedure was successively applied in the field. Amodiaquine could be quantified for at least three days and the metabolite up to 28 days. All parasites in all the 12 patients cleared within the first three days of treatment and no adverse drug effects were observed.</p> <p>Conclusion</p> <p>The methodology is suitable for field studies. The possibility to determine the concentration of the active metabolite of amodiaquine up to 28 days suggested that the method is sensitive enough to monitor amodiaquine utilization in patients. Amodiaquine plus artesunate seems effective for treatment of falciparum malaria.</p