The global distribution of cooperatively breeding birds is highly uneven, with hotspots in Australasia and sub-Saharan Africa. The ecological drivers of this distribution remain enigmatic yet could ...yield insights into the evolution and persistence of cooperative breeding. We report that the global distributions of avian obligate brood parasites and cooperatively breeding passerines are tightly correlated and that the uneven phylogenetic distribution of cooperative breeding is associated with the uneven targeting of hosts by brood parasites. With a long-term field study, we show that brood parasites can acquire superior care for their young by targeting cooperative breeders. Conversely, host defenses against brood parasites are strengthened by helpers at the nest. Reciprocally selected interactions between brood parasites and cooperative breeders may therefore explain the close association between these two breeding systems.
Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought ...to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration.
Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases.
In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r=0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification.
Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.
We investigated the feasibility of dose-dense neoadjuvant chemotherapy (NACT) with paclitaxel and carboplatin before radical chemoradiation (CRT) and assessed the response rate to such a regimen.
...CxII is a single-arm phase II trial of 46 patients, with locally advanced cervical cancer (stage Ib2-IVa). Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg m⁻²) weekly for six cycles followed by CRT (40 mg m⁻² of weekly cisplatin, 50.4 Gy, 28 fractions plus brachytherapy). The primary end point was response rate 12 weeks post-CRT.
Baseline characteristics were: median age at diagnosis 43 years; 72% squamous, 22% adenocarcinoma and 7% adenosquamous histologies; FIGO stage IB2 (11%), II (50%), III (33%), IV (7%). Complete or partial response rate was 70% (95% CI: 54-82) post-NACT and 85% (95% CI: 71-94) post-CRT. The median follow-up was 39.1 months. Overall and progression-free survivals at 3 years were 67% (95% CI: 51-79) and 68% (95% CI: 51-79), respectively. Grade 3/4 toxicities were 20% during NACT (11% haematological, 9% non-haematological) and 52% during CRT (haematological: 41%, non-haematological: 22%).
A good response rate is achieved by dose-dense weekly NACT with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible as evidenced by the acceptable toxicity of NACT and by the high compliance to radiotherapy (98%).
Thick molar enamel is among the few diagnostic characters of hominins which are measurable in fossil specimens. Despite a long history of study and characterization of Paranthropus molars as ...relatively 'hyper-thick', only a few tooth fragments and controlled planes of section (designed to be proxies of whole-crown thickness) have been measured. Here, we measure molar enamel thickness in Australopithecus africanus and Paranthropus robustus using accurate microtomographic methods, recording the whole-crown distribution of enamel. Both taxa have relatively thick enamel, but are thinner than previously characterized based on two-dimensional measurements. Three-dimensional measurements show that P. robustus enamel is not hyper-thick, and A. africanus enamel is relatively thinner than that of recent humans. Interspecific differences in the whole-crown distribution of enamel thickness influence cross-sectional measurements such that enamel thickness is exaggerated in two-dimensional sections of A. africanus and P. robustus molars. As such, two-dimensional enamel thickness measurements in australopiths are not reliable proxies for the three-dimensional data they are meant to represent. The three-dimensional distribution of enamel thickness shows different patterns among species, and is more useful for the interpretation of functional adaptations than single summary measures of enamel thickness.
Objectives
Monocyte activation, endothelial dysfunction and platelet activation all potentially contribute to the increased risk of cardiovascular disease (CVD) reported in those with HIV‐1 ...infection. To date, no study has examined how initiation of antiretroviral therapy (ART) affects markers of all three processes. We aimed to compare markers of monocyte, endothelial and platelet function between untreated HIV‐positive subjects and HIV‐negative controls and to examine the early effects of ART initiation on these markers.
Methods
We measured monocyte soluble CD14 (sCD14) and sCD163, endothelial von Willebrand factor (vWF), intercellular adhesion molecule‐1 (ICAM‐1) and vascular adhesion molecule‐1 (VCAM‐1) and platelet soluble P‐selectin (sP‐selectin), soluble CD40 ligand (sCD40L) and soluble glycoprotein VI (sGPVI) biomarkers before and at weeks 4 and 12 post ART initiation in HIV‐positive and well‐matched HIV‐negative controls.
Results
We examined 40 subjects, 25 HIV‐positive subjects and 15 controls, with a median age of 34 years interquartile range (IQR) 31, 40 years, of whom 60% were male and 47.5% Caucasian. Pre‐ART, all biomarkers (monocyte, endothelial and platelet) were significantly higher in HIV‐positive patients versus controls (all P < 0.05) and decreased with ART initiation, except for sCD14, which remained unchanged median 1680 (IQR 1489, 1946) ng/mL at week 12 versus 1570 (IQR 1287, 2102) ng/mL at week 0; P = 0.7. Although platelet activation markers reduced to levels comparable to those in controls, endothelial dysfunction markers remained elevated, as did sCD163 at week 12, median 1005 (IQR 791, 1577) ng/mL in HIV‐positive patients versus 621 (IQR 406, 700) ng/mL in controls; P < 0.0001.
Conclusions
ART initiation resulted in reductions in levels of CVD‐associated biomarkers; however, although they improved, markers of endothelial dysfunction and monocyte activation remained elevated. How these persistent abnormalities affect CVD risk in HIV infection remains to be determined.
PU.1 is a member of the ets family of transcription factors and is expressed exclusively in cells of the hematopoietic lineage. Mice homozygous for a disruption in the PU.1 DNA binding domain are ...born alive but die of severe septicemia within 48 h. The analysis of these neonates revealed a lack of mature macrophages, neutrophils, B cells and T cells, although erythrocytes and megakaryocytes were present. The absence of lymphoid commitment and development in null mice was not absolute, since mice maintained on antibiotics began to develop normal appearing T cells 3–5 days after birth. In contrast, mature B cells remained undetectable in these older mice. Within the myeloid lineage, despite a lack of macrophages in the older antibiotic‐treated animals, a few cells with the characteristics of neutrophils began to appear by day 3. While the PU.1 protein appears not to be essential for myeloid and lymphoid lineage commitment, it is absolutely required for the normal differentiation of B cells and macrophages.
The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal ...debulking surgery in women with epithelial ovarian cancer (EOC).
We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB–IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL).
Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57–1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47–1.35) P = 0.40. The i.p. carboplatin-based regimen was well tolerated with no reduction in QOL or increase in toxicity compared with i.v. administration alone.
In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is well tolerated and associated with an improved PD9 compared with i.v. carboplatin-based chemotherapy.
clinicaltrials.gov, NCT01622543.
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