A review of practical methodologies for the synthesis of indoles is presented. The indole ring system is probably the most ubiquitous heterocycle in nature.
PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived ...glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.
Conspectus Manufacturing process development of new drug substances in the pharmaceutical industry combines numerous chemical challenges beyond the efficient synthesis of complex molecules. ...Optimization of a synthetic route involves the screening of multiple reaction variables with a desired outcome that not only depends on an increased product yield but is also highly influenced by the removal efficacy of residual chemicals and reaction byproducts during the subsequent synthetic route. Consequently, organic chemists must survey a wide array of synthetic variables to develop a highly productive, green, and cost-effective manufacturing process. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. In this regard, conventional “on demand” analytical method development and optimization approaches, traditionally used for guiding synthetic chemistry efforts, become unsustainable. This Account introduces recent efforts to address the aforementioned challenges through the development and implementation of generic or more universal chromatographic methods that can cover a broad spectrum of targeted compound classes. Such generic methods require significant resolving power to enable baseline resolution of multicomponent mixtures in a single experimental run without additional method customization but must be simple enough to allow for routine use by chemists, chemical engineers and other researchers with little experience in chromatographic method development. These powerful analytical methodologies are often employed to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Diverse examples of universal and fit-for-purpose analytical procedures are presented herein, illustrating the power of modern readily available analytical technology for streamlining the development of new drug substances in organic chemistry laboratories across both academic and industrial sectors. With recent advances in analytical instrumentation and column technologies, universal chromatographic methods are quickly becoming a proactive and effective strategy to accelerate the discovery and implementation of new synthetic methodologies, especially but not limited to laboratories where the synthetic process route is undergoing rapid change and optimization. Targets of these generic methods include analysis of organic solvents, acid and basic additives, nucleotide species, palladium scavengers, impurity mapping, enantiopurity, synthetic intermediates, active pharmaceutical ingredients and their counterions, dehalogenation byproducts, and mixtures of organohalogenated pharmaceuticals, among other chemicals used or formed in process chemistry reactions.
Insecticide resistance is a serious threat to the continued effectiveness of insecticide-based malaria vector control measures, such as long-lasting insecticidal nets (LLINs) and indoor residual ...spraying (IRS). This paper describes trends and dynamics of insecticide resistance and its underlying mechanisms from annual resistance monitoring surveys on Anopheles gambiae sensu lato (s.l.) populations conducted across mainland Tanzania from 2004 to 2020.
The World Health Organization (WHO) standard protocols were used to assess susceptibility of the wild female An. gambiae s.l. mosquitoes to insecticides, with mosquitoes exposed to diagnostic concentrations of permethrin, deltamethrin, lambdacyhalothrin, bendiocarb, and pirimiphos-methyl. WHO test papers at 5× and 10× the diagnostic concentrations were used to assess the intensity of resistance to pyrethroids; synergist tests using piperonyl butoxide (PBO) were carried out in sites where mosquitoes were found to be resistant to pyrethroids. To estimate insecticide resistance trends from 2004 to 2020, percentage mortalities from each site and time point were aggregated and regression analysis of mortality versus the Julian dates of bioassays was performed.
Percentage of sites with pyrethroid resistance increased from 0% in 2004 to more than 80% in the 2020, suggesting resistance has been spreading geographically. Results indicate a strong negative association (p = 0.0001) between pyrethroids susceptibility status and survey year. The regression model shows that by 2020 over 40% of An. gambiae mosquitoes survived exposure to pyrethroids at their respective diagnostic doses. A decreasing trend of An. gambiae susceptibility to bendiocarb was observed over time, but this was not statistically significant (p = 0.8413). Anopheles gambiae exhibited high level of susceptibility to the pirimiphos-methyl in sampled sites.
Anopheles gambiae Tanzania's major malaria vector, is now resistant to pyrethroids across the country with resistance increasing in prevalence and intensity and has been spreading geographically. This calls for urgent action for efficient malaria vector control tools to sustain the gains obtained in malaria control. Strengthening insecticide resistance monitoring is important for its management through evidence generation for effective malaria vector control decision.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
5.
Improved Endpoints for Cancer Immunotherapy Trials Hoos, Axel; Eggermont, Alexander M. M.; Janetzki, Sylvia ...
JNCI : Journal of the National Cancer Institute,
09/2010, Letnik:
102, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, ...followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
The perspective of pharmaceutical manufacturers toward key green chemistry research areas, was discussed. The American Chemical Society (ACS) Green Chemistry Institute (GCI) and the global ...pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. A call for research proposals was made in November 2006 and the response from the academic community was outstanding, with 32 research proposals received with 1 month. Development of efficient detergents acceptable for active pharmaceutical ingredient (API) equipment and research toward making vessel-cleaning solvent less in commercial setting would have a major impact on reducing the environmental impact of pharmaceutical processes.
•Wildfire increases water repellency of Sphagnum and feather moss.•Burnt feather moss is more severely water repellent than Sphagnum both pre- and post-wildfire.•Feather moss is severely water ...repellent at a depth of 1–5 cm and only slightly water repellent at the surface.•Water repellency may reduce evaporation, increasing peatland resilience to wildfire within feather moss dominated peatlands.
Water repellency alters soil hydrology after periods of wildfire, potentially modifying the ecosystem recovery to such disturbance. Despite this potential importance, the extent and severity of water repellency within burned peatlands and its importance in regulating peatland recovery to wildfire disturbance remains poorly understood. We characterised the water repellency of peat in a burned (one year post-fire) and unburned peatland in the Western Boreal Plain utilising the water drop penetration time and ethanol droplet molarity tests. Burned Sphagnum moss and feather moss sites had a more severe degree of water repellency than unburned sites, with differences being more pronounced between burned and unburned feather moss sites. Burned feather moss exhibited the most extreme water repellency, followed by unburned feather moss, and burned Sphagnum. The severity of water repellency varied with depth through the near surface of the moss/peat profile. This was most evident within the burned feathermoss where more extreme water repellency was observed at the near-surface compared to the surface, with the most extreme water repellency found at 1 and 5cm depths. Unburned Sphagnum was completely hydrophilic at all depths. We suggest that the extreme water repellency in near-surface feather moss peat acts as a barrier that impedes the supply of water to the surface that replaces that lost via evaporation. This leads to drying of the near-surface vadose zone within feather moss areas and a concomitantly large decrease in peatland evaporation within feather moss dominated peatlands. This negative feedback mechanism likely enhances the resilience of such peatland to wildfire disturbance, maintaining a high water table position, thereby limiting peat decomposition. In comparison, such a feedback is not observed strongly within Sphagnum, leaving Sphagnum dominated peatlands potentially vulnerable to low water table positions post disturbance.
This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma.
Patients with previously ...treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC).
BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6–16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids.
Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.
This analysis was carried out to evaluate the long-term survival of patients with metastatic melanoma who received ipilimumab, a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte ...antigen-4, in clinical trials.
Patients received ipilimumab in one of three completed phase II clinical trials (CA184-008, CA184-022, and CA184-007). Previously treated patients were enrolled in all studies, and treatment-naïve patients were also included in study CA184-007. Patients received ipilimumab at a dose of 10 mg/kg in studies CA184-008 and CA184-007, and at doses of 0.3, 3, or 10 mg/kg in study CA184-022. Ipilimumab was given every 3 weeks for four doses, and eligible patients could receive ipilimumab maintenance therapy every 12 weeks. In study CA184-022, patients could cross over to be retreated with ipilimumab at 10 mg/kg upon disease progression. Ongoing survival follow-up is conducted in a companion study, CA184-025.
Four-year survival rates 95% confidence interval (95% CI) for previously treated patients who received ipilimumab at 0.3, 3, or 10 mg/kg were 13.8% 6.1–22.5, 18.2% 9.5–27.6, and 19.7% 13.4–26.5 to 28.4% 13.9–44.2, respectively. In treatment-naïve patients who received ipilimumab at 10 mg/kg, 4-year survival rates were 37.7% 18.6–57.4 to 49.5% 23.8–75.4.
These results demonstrate durable survival in a significant proportion of patients with metastatic melanoma who received ipilimumab therapy.
Primary cilia are important sites of signal transduction involved in a wide range of developmental and postnatal functions. Proteolytic processing of the transcription factor Gli3, for example, ...occurs in primary cilia, and defects in intraflagellar transport (IFT), which is crucial for the maintenance of primary cilia, can lead to severe developmental defects and diseases. Here we report an essential role of primary cilia in forebrain development. Uncovered by N-ethyl-N-nitrosourea-mutagenesis, cobblestone is a hypomorphic allele of the IFT gene Ift88, in which Ift88 mRNA and protein levels are reduced by 70-80%. cobblestone mutants are distinguished by subpial heterotopias in the forebrain. Mutants show both severe defects in the formation of dorsomedial telencephalic structures, such as the choroid plexus, cortical hem and hippocampus, and also a relaxation of both dorsal-ventral and rostral-caudal compartmental boundaries. These defects phenocopy many of the abnormalities seen in the Gli3 mutant forebrain, and we show that Gli3 proteolytic processing is reduced, leading to an accumulation of the full-length activator isoform. In addition, we observe an upregulation of canonical Wnt signaling in the neocortex and in the caudal forebrain. Interestingly, the ultrastructure and morphology of ventricular cilia in the cobblestone mutants remains intact. Together, these results indicate a critical role for ciliary function in the developing forebrain.
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