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The lack of adequate anti-leishmanial therapies has led to the continued suffering of millions of people from developing nations. Moreover, optimism for a therapeutic intervention by fexinidazole was dashed due to the inability to maintain cures and control unwanted side effects. To solve these shortcomings, the structural elements of fexinidazole responsible for anti-leishmanial activity and toxicities were explored. Accordingly, a systematic analog design approach was taken for the synthesis of 24 novel analogs. We established the structural features important for activity and identified modifications that improved the hERG receptor safety and liver microsomal metabolic stability. Compared to fexinidazole, the S-configured imidazolooxazole analog 51exhibited 25-fold greater potency against miltefosine resistant L. donovaniamastigotes, greater metabolic stability and little hERG receptor inhibition. Replacement of the toxicophore nitro group for a cyano group resulted in a complete loss of anti-leishmanial activity. The SAR findings should be useful in the further development of this important class of anti-leishmanial agents.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3–6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

Infections by Staphylococcus aureushave been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureusby acquisition of the blaand mecoperons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4is covalently engaged with the active-site serine of BlaR. Compound 4potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureusstrains. The combination of 4with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

Background: Extraction is an important step to obtain phytochemical compounds from natural materials. Among different extraction techniques, microwave-assisted extraction (MAE) is an advanced method with high extraction efficiency and low energy consumption. Objective: This study aimed to optimize the MAE parameters for obtaining the highest levels of phenolic compounds and antioxidant activity from cacao pod husk (CPH). Methods: The dried CPH was prepared using a microwave drying method. The CPH extract was prepared using a microwave-assisted extraction method. The powdered CPH extract was prepared using vacuum evaporation and freeze-drying methods. Phytochemical compounds and antioxidant capacity of CPH extracts were analyzed using spectrophotometric methods. Results: The optimal MAE parameters were 600 W microwave power, 5 s/min irradiation time, 30 min extraction time, and 50 mL/g solvent to sample ratio. Under these MAE parameters, total phenolic content (TPC), phenolic extraction efficiency (PEE), saponin content (SC), and DPPH radical scavenging capacity (DRSC) were achieved from the CPH to be 10.97 mg GAE/g dried sample, 76.82%, 70.10 mg EE/g dried sample, and 141.18 mg DPPH/g dried sample, respectively, which were not significantly different from the predicted values (10.38 mg GAE/g dried sample, 72.68%, 70.09 mg EE/g dried sample, and 121.49 mg DPPH/g dried sample, respectively). The residual moisture, water activity, density, water-soluble index and pH of powdered CPH extract were 9.72%, 0.38, 0.17 g/ml, 84.93% and 7.68, respectively. TPC, total flavonoid content (TFC) and SC of powdered CPH extract were 15.75 mg GAE/g dried sample, 27.03 mg CE/g dried sample and 133.67 mg EE/g dried sample, respectively. DRSC and ferric reducing antioxidant power (FRAP) of powdered CPH extract were 227.79 mg DPPH/g dried sample and 14.12 mg Fe(II)/g dried sample, respectively. Conclusion: The findings from this study reveal that the powdered extract obtained from the CPH at the optimal MAE parameters is a rich source of phytochemicals possessing great antioxidant activity. Therefore, it is a potential candidate to apply in functional foods.

Glioblastoma (GBM), an aggressive grade IV astrocytoma, is the most common primary malignant adult brain tumor characterized by extensive invasiveness, heterogeneity, and angiogenesis. Standard treatment options such as radiation and chemotherapy have proven to be only marginally effective in treating GBM because of its invasive nature. Therefore, extensive efforts have been put forth to develop tumor‐tropic stem cells as viable therapeutic vehicles with potential to treat even the most invasive tumor cells that are harbored within areas of normal brain. To this end, we discovered a newly described NG2‐expressing cell that we isolated from a distinct pericyte subtype found abundantly in cultures derived from peripheral muscle. In this work, we show the translational significance of these peripherally derived neural‐like stem cells (NLSC) and their potential to migrate toward tumors and act as therapeutic carriers. We demonstrate that these NLSCs exhibit in vitro and in vivo GBM tropism. Furthermore, NLSCs did not promote angiogenesis or transform into tumor‐associated stromal cells, which are concerns raised when using other common stem cells, such as mesenchymal stem cells and induced neural stem cells, as therapeutic carriers. We also demonstrate the potential of NLSCs to express a prototype therapeutic, tumor necrosis factor α‐related apoptosis‐inducing ligand and kill GBM cells in vitro. These data demonstrate the therapeutic potential of our newly characterized NLSC against GBM. StemCellsTranslationalMedicine2017;6:471–481

Phyllanthus amarusis known as a healing herb which has traditionally been used in the treatment of various diseases such as hepatitis, diabetes and cancer. The extraction parameters have great effects on the extraction efficiency of bioactive compounds and pharmacological activity of the extracts. This study sought to optimise the microwave-assisted extraction parameters for phenolic compounds-enriched extracts and antioxidant capacity from P. amarususing response surface methodology (RSM). The results showed that the optimal microwave-assisted extraction parameters were an extraction time of 30 min, an irradiation time of 14 s min−1and a ratio of solvent to sample of 150 mL g−1. The total phenolic content, phenolic extraction efficiency, saponin content, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging capacity, 2,2-diphenyl-1-picryl-hydrazil (DPPH) radical scavenging capacity and ferric reducing antioxidant power of the P. amarusachieved under these optimal parameters were 87.3 mg of gallic acid equivalents (GAE) per gram of dried sample, 69.7 %,134.9 mg of escin equivalents (EE) per gram of dried sample, 997.8, 604.7 and 437.3 all in mg of trolox equivalents (TE) per gram of dried sample, respectively, which were not significantly different from the predicted values (86.9 mg of GAE per gram of dried sample, 67.3 %,123.5 mg of EE per gram of dried sample, 1013.3 mg of TE per gram of dried sample, 530.6 mg of TE per gram of dried sample and 423.5 mg of TE per gram of dried sample, respectively). Accordingly, the optimal microwave-assisted extraction parameters of 30 min, 14 s min−1and 150 mL g−1are recommended for the extraction of enriched phenolics from P. amarusfor potential application in the nutraceutical and pharmaceutical industries.

We report a computer simulation and experimental study of adsorption of methanol on a highly graphitized thermal carbon black over a range of temperatures to investigate the adsorptive capacity, the isosteric heat, and the configuration of molecules in the adsorbed layer. We include coverage beyond the monolayer region, not previously studied in detail. The adsorption is shown to be strongly affected by hydrogen bonding which results in strong fluid–fluid interaction between the adsorbed molecules. The adsorption isotherms are initially sigmoidal, however, and in the multilayer region the isotherms follow typical type II behavior. The isosteric heat of adsorption of methanol is distinctly different from that of simple gases because of the dominance of the strong interactions between adsorbed molecules over the solid–fluid interactions. The configuration of adsorbed molecules in the submonolayer region favors the formation of 2D cyclic clusters of four or five methanol molecules, which maximizes the hydrogen bonding, while near the end of the completion of the first layer methanol molecules form molecular chains with some degree of 2D-zigzag pattern which again maximizes the hydrogen bonding between all molecules. This is in qualitative agreement with the X-ray diffraction measurements obtained by Morishige (Morishige, K.; Kawamura, K.; Kose, A. J. Chem. Phys.1990, 93, 5267). When the second and higher layers are formed above the surface, the adsorbate forms clusters in three-dimensional configurations; however, the molecular chains with some degree of 2D-zigzag pattern in the first layer still remain.

The isosteric heat versus loading of simple fluids (noble gases and nitrogen) adsorbed on a graphitic surface at a range of temperatures is investigated with GCMC simulations. At low temperatures (usually below the bulk triple point) the adsorption isotherms show a distinct 2D-phase transition in the first layer and possibly in higher layers and then has a more complex pattern. For densities less than the gaseous 2D-density, the heat increases linearly with loading. For loadings across the 2D-transition, the isosteric heat is constant, and when loadings are greater than the “liquid-like” density of the 2D-transition the isosteric heat again increases linearly with loading up to monolayer concentration, beyond which the isosteric heat decreases sharply, indicating the onset of adsorption into the second layer. Grand canonical Monte Carlo simulation shows that the constant heat observed in the 2D-transition is because of the increase in the number of clusters of similar size, rather than the increase in the cluster size. At very low temperature, a dense layer forms before the onset of the next layer and there is no heat spike in the plot of the isosteric heat versus loading because there are no gaps large enough in the dense layer for further addition of a particle. Moreover, there is no heat spike in these plots at high temperatures because of the increase in thermal motion of the molecules. Therefore, there is a narrow range of temperature from which we can see an isosteric heat spike, resulting from the squeezing of molecules into the lower layers, which increases both the solid−fluid interaction and the fluid−fluid interaction. We have found that the 2D-critical temperatures of the first three layers correlate well with the well depth of the fluid−fluid interaction, and interestingly the 2D-critical temperature of the third layer is between those of the first and second layers.

Importance of the field:In the USA only 35% of patients with hypertension achieve adequate blood pressure control. Non-compliance is one of the main barriers to treatment. Vaccine against hypertension is an innovative treatment, injected every 4 – 6 months, to combat non-compliance.Areas covered in this review:Pathogenesis of hypertension and progress towards developing a hypertension vaccine, including the virus-like-particle-based approach, new adjuvant molecules and the potential toxicity of hypertension vaccine.What the reader will gain:The pathogenesis of hypertension is multifactorial. The most common cause is disruption of the Renin–angiotensin–aldosterone system (RAAS), and the first vaccine study was carried out against renin. While the vaccine reduced blood pressure in animal models, it also caused autoimmune disease. In the last decade, vaccines against angiotensin I, angiotensin II, and angiotensin II-type 1 receptors have demonstrated acceptable safety profiles in animal and human studies.Take home message:Reduction in blood pressure can be achieved by inducing immunity against targets in the RAAS. The target antigen and selection of adjuvant are crucial factors determining effectiveness and safety of the vaccine. CYT006-AngQb (angiotensin II vaccine) reduced blood pressure in humans but the results were not reproducible with more frequent dosing. Vaccines for hypertension are still in the early phase. We hope for an effective vaccine for hypertension in the years to come.

The long arm of human chromosome 14 (14q), an acrocentric chromosome, is estimated to be approximately 93 Mb in length. Genetic maps published to date have included mostly random DNA markers. The map we present here includes 13 genes, as well as 29 random DNA segments, based on typing of the CEPH families. Our map has been placed in context with other published maps. The resulting map of 42 loci has markers on average 5 cM apart and has a total length of 163 cM. The map order differs in the telomeric region from that of other maps previously published. 14q has homology, throughout approximately half its length, with mouse chromosome 12 and has a proximal region of homology with mouse chromosome 14. Copyright 1994, 1999 Academic Press

The present environmental crisis prompts the search for renewable energy sources such as solar-driven production of hydrogen from water. Herein, we report an efficient hybrid photocatalyst for water oxidation, consisting of a ruthenium polypyridyl complex covalently grafted on core/shell Fe@FeOxnanoparticles viaa phosphonic acid group. The photoelectrochemical measurements were performed under 1 sun illumination in 1 M KOH. The photocurrent density of this hybrid photoanode reached 20 μA/cm2(applied potential of +1.0 V vsreversible hydrogen electrode), corresponding to a turnover frequency of 0.02 s–1. This performance represents a 9-fold enhancement of that achieved with a mixture of Fe@FeOxnanoparticles and a linker-free ruthenium polypyridyl photosensitizer. This increase in performance could be attributed to a more efficient electron transfer between the ruthenium photosensitizer and the Fe@FeOxcatalyst as a consequence of the covalent link between these two species through the phosphonate pendant group.

Reddy: Gilead: Other: Speaker; Seattle Genetics: Consultancy; ImmunoGen: Consultancy; PCYC: Consultancy; Celgene: Consultancy, Research Funding.

Reddy: PCYC: Consultancy; ImmunoGen: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.

No relevant conflicts of interest to declare.

Background:Prior studies have demonstrated the utility of involved field radiation therapy to reduce relapse rates and improve local control in Hodgkin Lymphoma (HL). The standard treatment for early stage unfavorable HL is combined modality approach with chemotherapy and radiation therapy (XRT). Despite reduction in the fields of XRT, long term adverse outcomes are associated with the combined modality approach. Recent clinical trials have focused on adapting therapy based on interim PET scans. There is, however, limited data evaluating patient outcomes with chemotherapy alone in unfavorable, bulky HL patients.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.