The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and ...traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
Non‐oxidative, regioselective, and convergent access to densely functionalized oxazoles is realized in a functional‐group tolerant manner using alkynyl thioethers. Sulfur‐terminated alkynes provide ...access to reactivity previously requiring strong donor‐substituted alkynes such as ynamides. Sulfur does not act in an analogous donor fashion in this gold‐catalyzed reaction, thus leading to complementary regioselective outcomes and addressing the limitations of using ynamides.
Taking a different path: The first gold‐catalyzed annulations with alkynyl thioethers are reported. This transformation provides ready and convergent access into densely functionalized 1,3‐oxazole motifs. The sulfur substituent is integral to accessing the desired reactivity and provides a useful synthetic handle for later elaboration. In contrast with recent reports, the reaction does not follow a ketenethionium pathway.
The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We ...therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application ( https://www.obgyn.cam.ac.uk/placentome/ ).
Recent changes in the seasonal timing (phenology) of familiar biological events have been one of the most conspicuous signs of climate change. However, the lack of a standardized approach to ...analysing change has hampered assessment of consistency in such changes among different taxa and trophic levels and across freshwater, terrestrial and marine environments. We present a standardized assessment of 25 532 rates of phenological change for 726 UK terrestrial, freshwater and marine taxa. The majority of spring and summer events have advanced, and more rapidly than previously documented. Such consistency is indicative of shared large scale drivers. Furthermore, average rates of change have accelerated in a way that is consistent with observed warming trends. Less coherent patterns in some groups of organisms point to the agency of more local scale processes and multiple drivers. For the first time we show a broad scale signal of differential phenological change among trophic levels; across environments advances in timing were slowest for secondary consumers, thus heightening the potential risk of temporal mismatch in key trophic interactions. If current patterns and rates of phenological change are indicative of future trends, future climate warming may exacerbate trophic mismatching, further disrupting the functioning, persistence and resilience of many ecosystems and having a major impact on ecosystem services.
The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. ...Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St George's Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term "minimum worthwhile incremental advantage" to describe this parameter.
The physical, chemical and biological attributes of a soil combined with abiotic factors (e.g. climate and topography) drive pedogenesis and some of these attributes have been used as proxies to soil ...quality. Thus, we investigated: (1) whether appropriate soil quality indicators (SQIs) could be identified in soils of Great Britain, (2) whether conventional soil classification or aggregate vegetation classes (AVCs) could predict SQIs and (3) to what extent do soil types and/ or AVCs act as major regulators of SQIs. Factor analysis was used to group 20 soil attributes into six SQI which were named as; soil organic matter (SOM), dissolved organic matter (DOM), soluble N, reduced N, microbial biomass, DOM humification (DOMH). SOM was identified as the most important SQI in the discrimination of both soil types and AVCs. Soil attributes constituting highly to the SOM factor were, microbial quotient and bulk density. The SOM indicator discriminated three soil type groupings and four aggregate vegetation class groupings. Among the soil types, only the peat soils were discriminated from other groups while among the AVCs only the heath and bog classes were isolated from others. However, the peat soil and heath and bog AVC were the only groups that were distinctly discriminated from other groups. All other groups heavily overlapped with one another, making it practically impossible to define reference values for each soil type or AVC. The two-way ANOVA showed that the AVCs were a better regulator of the SQIs than the soil types. We conclude that conventionally classified soil types cannot predict the SQIs defined from large areas with differing climatic and edaphic factors. Localised areas with similar climatic and topoedaphic factors may hold promise for the definition of SQI that may predict the soil types or AVCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This trial involving more than 6000 patients with chronic obstructive pulmonary disease (COPD) compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and ...fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate; this fell short of the study's prespecified goals. There were improved clinical outcomes among patients treated with the combination regimen.
This trial involving more than 6000 patients with COPD compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate, which fell short of the prespecified goal.
Chronic obstructive pulmonary disease (COPD) is a major cause of illness, death, and the use of health care resources globally.
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The disease causes approximately 2.75 million deaths annually, and the number is projected to increase.
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Treatment for COPD is focused on minimizing risk factors, improving symptoms, and preventing exacerbations.
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With the exception of smoking-cessation programs for patients with early disease,
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home oxygen treatment for persistent hypoxemia,
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and lung-reduction surgery for selected patients with emphysema,
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no treatment has been shown to reduce mortality.
Pulmonary inflammation is prominent in COPD.
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Antiinflammatory drugs such as inhaled corticosteroids have little or no . . .
The 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document recommends assessment of chronic obstructive pulmonary disease (COPD) using symptoms and future exacerbation ...risk, employing two score cut-points: COPD Assessment Test (CAT) score ≥ 10 or modified Medical Research Council dyspnoea scale (mMRC) grade ≥ 2. To explore the equivalence of these two symptom cut-points, the relationship between the CAT and the mMRC and St George's Respiratory Questionnaire (SGRQ), the Short-form Health Survey and the Functional Assessment of Chronic Illness Therapy Fatigue scores were retrospectively analysed using a primary care dataset. Data from 1817 patients (mean ± SD forced expiratory volume in 1 s 1.6 ± 0.6 L) showed a significant association between mMRC grades and all health status scores (ANOVA p<0.0001). mMRC grade 1 was associated with significant levels of health status impairment (SGRQ 39.4 ± 15.5 and CAT 15.7 ± 7.0); even patients with mMRC grade 0 had modestly elevated scores (SGRQ 28.5 ± 15.1 and CAT 11.7 ± 6.8). An mMRC grading ≥ 2 categorised 57.2% patients with low symptom (groups A and C) versus 17.2% with the CAT. Using the mMRC cut-point (≥ 1) resulted in similar GOLD group categorisations as the CAT (18.9%). The mMRC showed a clear relationship with health status scores; even low mMRC grades were associated with health status impairment. Cut-points of mMRC grade ≥ 1 and CAT score ≥ 10 were approximately equivalent in determining low-symptom patients. The GOLD assessment framework may require refinement.
Contemporary cancer diagnostics are becoming increasing reliant upon sophisticated new molecular methods for analyzing genetic information. Limiting the scope of these new technologies is the lack of ...adequate solid tumor tissue samples. Patients may present with tumors that are not accessible to biopsy or adequate for longitudinal monitoring. One attractive alternate source is cancer cells in the peripheral blood. These rare circulating tumor cells (CTC) require enrichment and isolation before molecular analysis can be performed. Current CTC platforms lack either the throughput or reliability to use in a clinical setting or they provide CTC samples at purities that restrict molecular access by limiting the molecular tools available.
Recent advances in magetophoresis and microfluidics have been employed to produce an automated platform called LiquidBiopsy®. This platform uses high throughput sheath flow microfluidics for the positive selection of CTC populations. Furthermore the platform quantitatively isolates cells useful for molecular methods such as detection of mutations. CTC recovery was characterized and validated with an accuracy (<20% error) and a precision (CV<25%) down to at least 9 CTC/ml. Using anti-EpCAM antibodies as the capture agent, the platform recovers 78% of MCF7 cells within the linear range. Non specific recovery of background cells is independent of target cell density and averages 55 cells/mL. 10% purity can be achieved with as low as 6 CTCs/mL and better than 1% purity can be achieved with 1 CTC/mL.
The LiquidBiopsy platform is an automated validated platform that provides high throughput molecular access to the CTC population. It can be validated and integrated into the lab flow enabling CTC enumeration as well as recovery of consistently high purity samples for molecular analysis such as quantitative PCR and Next Generation Sequencing. This tool opens the way for clinically relevant genetic profiling of CTCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory ...Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management.
Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified.
Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus.
Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.
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