DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited ...for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and
deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G
cells leading to G
arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis.
xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need. SIGNIFICANCE: ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.
The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).
We ...identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic LEP, acinar or papillary ACI/PAP, and micropapillary or solid MIP/SOL). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.
MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).
These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
In a randomized trial, sublobar resection was noninferior to lobectomy for disease-free survival among patients with peripheral clinical stage T1aN0 (≤2 cm) non–small-cell lung cancer.
Summary
The Green Revolution successfully increased food production but in doing so created a legacy of inherently leaky and unsustainable agricultural systems. Central to this are the problems of ...excessive nutrient mining. If agriculture is to balance the needs of food security with the delivery of other ecosystem services, then current rates of soil nutrient stripping must be reduced and the use of synthetic fertilisers made more efficient.
We explore the global extent of the problem, with specific emphasis on the failure of macronutrient management (e.g. nitrogen, phosphorus) to deliver continued improvements in yield and the failure of agriculture to recognise the seriousness of micronutrient depletion (e.g. copper, zinc, selenium).
Nutrient removals associated with the relatively immature, nutrient‐rich soils of the UK are contrasted with the mature, nutrient‐poor soils of India gaining insight into the emerging issue of nutrient stripping and the long‐term implications for human health and soil quality. Whilst nutrient deficiencies are rare in developed countries, micronutrient deficiencies are commonly increasing in less‐developed countries. Increasing rates of micronutrient depletion are being inadvertently accomplished through increasing crop yield potential and nitrogen fertiliser applications.
Amongst other factors, the spatial disconnects caused by the segregation and industrialisation of livestock systems, between rural areas (where food is produced) and urban areas (where food is consumed and human waste treated) are identified as a major constraint to sustainable nutrient recycling.
Synthesis and applications. This study advocates that agricultural sustainability can only be accomplished using a whole‐systems approach that thoroughly considers nutrient stocks, removals, exports and recycling. Society needs to socially and environmentally re‐engineer agricultural systems at all scales. It is suggested that this will be best realised by national‐scale initiatives. Failure to do so will lead to an inevitable and rapid decline in the delivery of provisioning services within agricultural systems.
This study advocates that agricultural sustainability can only be accomplished using a whole‐systems approach that thoroughly considers nutrient stocks, removals, exports and recycling. Society needs to socially and environmentally re‐engineer agricultural systems at all scales. It is suggested that this will be best realised by national‐scale initiatives. Failure to do so will lead to an inevitable and rapid decline in the delivery of provisioning services within agricultural systems.
Historically, the prognosis for individuals diagnosed with lung cancer has been bleak. However, the past 10 years have seen important advances in treatment and diagnosis which have translated into ...the first improvements seen in lung cancer survival. This review highlights the major advances in treatments with curative intent, systemic targeted therapies, palliative care and early diagnosis in lung cancer. We discuss the pivotal research that underpins these new technologies/strategies and their current position in clinical practice.
Background: Low doses of some persistent organic pollutants (POPs) associate cross-sectionally with type 2 diabetes, whereas associations with high POP exposures are inconsistent. Objectives: We ...investigated whether several POPs prospectively predict type 2 diabetes within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Methods: Participants in this nested case—control study were diabetes free in 1987-1988. By 2005-2006, the 90 controls remained free of diabetes, whereas the 90 cases developed diabetes. Using serum collected in 1987-1988, we measured 8 organochlorine pesticides, 22 polychlorinated biphenyl congeners (PCBs), and 1 polybrominated biphenyl (PBB). We compared POP concentrations from CARDIA and the National Health and Nutrition Examination Survey (NHANES) in 2003-2004. We computed odds ratios (ORs) for incident diabetes using logistic regression analysis. Results: Chlorinated POPs in CARDIA in 1987-1988 were much higher than corresponding NHANES 2003-2004 concentrations. POPs showed nonlinear associations with diabetes risk. The highest risk was observed in the second quartiles of trans-nonachlor, oxychlordane, mirex, highly chlorinated PCBs, and PBB153—a finding that suggests low-dose effects. We concentrated risk by summing these POPs and isolated very low concentrations of multiple POPs in the lowest sextile of the sum. The adjusted OR in the second sextile vs. the lowest sextile was 5.3 overall and 20.1 for body mass index ≥ 30 kg/m². Conclusions: Several POPs at low doses similar to current exposure levels may increase diabetes risk, possibly through endocrine disruption. Certain POPs may a play a role in the current epidemic of diabetes, which has been attributed to obesity.
Food web ecologists have long sought to characterize the trophic niches of animals using stable isotopic analysis. However, distilling trophic position from isotopic composition has been difficult, ...largely because of the variability associated with trophic discrimination factors (inter-trophic isotopic fractionation and routing). We circumvented much of this variability using compound-specific isotopic analysis (CSIA). We examined the (15)N signatures of amino acids extracted from organisms reared in pure culture at four discrete trophic levels, across two model communities. We calculated the degree of enrichment at each trophic level and found there was a consistent trophic discrimination factor (~7.6‰). The constancy of the CSIA-derived discrimination factor permitted unprecedented accuracy in the measurement of animal trophic position. Conversely, trophic position estimates generated via bulk-(15)N analysis significantly underestimated trophic position, particularly among higher-order consumers. We then examined the trophic hierarchy of a free-roaming arthropod community, revealing the highest trophic position (5.07) and longest food chain ever reported using CSIA. High accuracy in trophic position estimation brings trophic function into sharper focus, providing greater resolution to the analysis of food webs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Thymic carcinoma outcomes and prognosis: Results of an international analysis Ahmad, Usman, MD; Yao, Xiaopan, PhD; Detterbeck, Frank, MD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
2015, January 2015, 2015-Jan, 2015-01-00, 20150101, Letnik:
149, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Objectives The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free ...survival (RFS). Methods Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures. Results In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval CI, 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS. Conclusions R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS.
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