Understanding the crystallographic and nanomechanical properties of bryozoans.

This study examines how microscale differences in skeletal ultrastructure affect the crystallographic and nanomechanical properties of two related bryozoan species: (i) Hornera currieae, which is found at relatively quiescent depths of c. 1000 m, and (ii) Hornera robusta, which lives at depths of 50-400 m where it is exposed to currents and storm waves. Microstructural and Electron Backscatter Diffraction (EBSD) observations show that in both species the secondary walls are composed of low-Mg calcite crystallites that grow with their c-axes perpendicular to the wall. Branches in H. currieae develop a strong preferred orientation of the calcite c-axes, while in H. robusta the c-axes are more scattered. Microstructural observations suggest that the degree of scattering is controlled by the underlying morphology of the skeletons: in H. currieae the laminated branch walls are smooth and relatively uninterrupted, whereas the wall architecture of H. robusta is modified by numerous deflections, forming pustules and ridges associated with microscopic tubules. Modelling of the Young's modulus and measurements of nanoindentation hardness indicate that the observed scattering of the crystallite c-axes affects the elastic modulus and nanohardness of the branches, and therefore controls the mechanical properties of the skeletal walls. At relatively high pressure in deep waters, the anisotropic skeletal architecture of H. currieae is aimed at concentrating elasticity normal to the skeleton wall. In comparison, in the relatively shallow and active hydrographic regime of the continental shelf, the elastically isotropic skeleton of H. robusta is designed to increase protection from external predators and stronger omni-directional currents.

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy.

BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.

Impact of environmental complexity and stocking density on affective states of rainbow trout (Oncorhynchus mykiss).

Environmental condition, such as environmental complexity or stocking density, can directly or indirectly influence animal emotion and ultimately, affective state. Affective states of animals can be assessed through judgement bias tests, evaluating responses to ambiguous situations. In this study, we aimed to determine whether environmental complexity and stocking density impacted rainbow trout affective state. Rainbow trout (n = 108) were housed in recirculating aquaculture systems under commercial conditions while trained at tank-level to discriminate between a positively reinforced chamber (feed) in one location and a negative chamber (positive punishment; chase by net for 1 s) in the opposing location. Fish from successful tanks (two out of five tanks) were then housed in treatment tanks of either high- or low- environmental complexity at either high (165 fish/m3) or low (69 fish/m3) stocking density. Trained fish were tested for latencies to approach three intermediate, ambiguous chambers. Fish housed in high-density tanks were faster to enter all chambers than those housed in low-density tanks (8.5 s vs. 15.2 s; P = 0.001), with faster entries into the positive (7.4 s vs. 15.2 s; P = 0.02) and near-negative chambers (10.2 s vs. 17.4 s; P = 0.006), suggesting that these fish were more optimistic to receive a feed reward. Tank complexity did not affect test outcomes. No differences between treatments were observed between body weight, length, and plasma cortisol. Overall, rainbow trout are capable of discriminating between cues during a judgement bias test and fish housed in high-density environments respond more optimistically in ambiguous situations compared to fish in low-density environments.

"PAUSE": a method for communicating radiological extent of peritoneal malignancy.

Radiology reports of diffuse peritoneal disease should address key findings pertinent to the management of these patients. The reporting of radiology findings in patients with peritoneal malignancy is currently variable and poorly standardised. Using the acronym "PAUSE" we emphasise the key imaging features that a radiology report should include in a patient with peritoneal malignancy, focussing on the key elements determining feasibility and likely prognosis of surgery and potential benefits from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The term "PAUSE" incorporates the following: P, primary tumour and peritoneal carcinomatosis index (PCI) as estimated by imaging; A, ascites and abdominal wall involvement; U, unfavourable sites of involvement; S, small bowel and mesenteric disease; E, extra peritoneal metastases. Thus, "PAUSE" has the potential to standardise radiology reporting in this field.

Increased stomach cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. METHODS: In a cohort of 22,269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. RESULTS: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). CONCLUSIONS: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

High-density aggregations of rodlet cells in the gonads of Greenland halibut Reinhardtius hippoglossoides, a deep-water marine flatfish.

Large aggregations of rodlet cells in the gonads of male and female Greenland halibut Reinhardtius hippoglossoides are reported for the first time. These rodlet cells were not arranged epithelially but rather were found throughout the connective tissue between oocytes (females) or within lymphatic spaces between testicular lobules (males). The reason for large aggregations of rodlet cells in the gonads and not other tissues of this species is uncertain.

Gross, histological and ultrastructural morphology of the aglomerular kidney in the lined seahorse Hippocampus erectus.

Histologic evaluation of the renal system in the lined seahorse Hippocampus erectus reveals a cranial kidney with low to moderate cellularity, composed of a central dorsal aorta, endothelial lined capillary sinusoids, haematopoietic tissue, fine fibrovascular stroma, ganglia and no nephrons. In comparison, the caudal kidney is moderately to highly cellular with numerous highly convoluted epithelial lined tubules separated by interlacing haematopoietic tissue, no glomeruli, fine fibrovascular stroma, numerous capillary sinusoids, corpuscles of Stannius and clusters of endocrine cells adjacent to large calibre vessels. Ultrastructural evaluation of the renal tubules reveals minimal variability of the tubule epithelium throughout the length of the nephron and the majority of tubules are characterized by epithelial cells with few apical microvilli, elaborate basal membrane infolding, rare electron dense granules and abundant supporting collagenous matrix.

Pancreatic cancer risk after treatment of Hodgkin lymphoma.

BACKGROUND: Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents. PATIENTS AND METHODS: We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls. RESULTS: Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide. CONCLUSION: Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Transitional B cell subsets in human bone marrow.

B cells originate from precursors in the bone marrow, and the first cells which migrate to the peripheral blood have been classified as 'transitional B cells'. Transitional B cells have been characterized in human blood with stage 1 (T1) and stage 2 (T2) subsets being proposed. In the present study, 27 normal human bone marrow samples were analysed for transitional B cell markers by eight-colour flow cytometry. T1 transitional B cells (CD45(+)CD19(+)CD10(+)IgM(+)IgD(lo)) and T2 transitional B cells (CD45(+)CD19(+)CD10(+)IgM(+)IgD(+)) were identified in normal bone marrow samples at a mean frequency of 3·2 and 3·1% of total B lineage cells, respectively. A majority of the bone marrow transitional B cells were CD24(hi)CD38(hi) , the phenotype of blood transitional B cells. Consistent with recent peripheral blood data, T2 B cells had a significantly higher CD21 expression compared with T1 B cells (72·4 versus 40·9%) in the bone marrow. These data raise the possibility that transitional B cells are capable of differentiating from T1 to T2 B cells within the bone marrow. Furthermore, transitional cells at either stages 1 or 2 might be capable of migrating out of the bone marrow.

RAxML-Light: a tool for computing terabyte phylogenies.

MOTIVATION: Due to advances in molecular sequencing and the increasingly rapid collection of molecular data, the field of phyloinformatics is transforming into a computational science. Therefore, new tools are required that can be deployed in supercomputing environments and that scale to hundreds or thousands of cores. RESULTS: We describe RAxML-Light, a tool for large-scale phylogenetic inference on supercomputers under maximum likelihood. It implements a light-weight checkpointing mechanism, deploys 128-bit (SSE3) and 256-bit (AVX) vector intrinsics, offers two orthogonal memory saving techniques and provides a fine-grain production-level message passing interface parallelization of the likelihood function. To demonstrate scalability and robustness of the code, we inferred a phylogeny on a simulated DNA alignment (1481 taxa, 20 000 000 bp) using 672 cores. This dataset requires one terabyte of RAM to compute the likelihood score on a single tree. CODE AVAILABILITY: https://github.com/stamatak/RAxML-Light-1.0.5 DATA AVAILABILITY: http://www.exelixis-lab.org/onLineMaterial.tar.bz2 CONTACT: alexandros.stamatakis@h-its.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome.

A predisposing gene for breast and ovarian cancer has recently been mapped to chromosome 17q12-21. If this gene is a tumour suppressor gene, allele losses would be expected in the tumours of affected family members and the losses should affect the wild-type chromosome, reflecting the need for inactivation of the wild-type allele at the predisposing locus. In four multiple case breast-ovarian cancer families, we have found that in each of nine tumours which showed allele losses, the losses were from the wild-type chromosome. This suggests that the putative 'breast-ovarian' cancer gene is indeed a tumour suppressor gene.

A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21.

We have constructed a physical map of a 4 cM region on chromosome 17q12-21 that contains the hereditary breast and ovarian cancer gene BRCA1. The map comprises a contig of 137 overlapping yeast artificial chromosomes and P1 clones, onto which we have placed 112 PCR markers. We have localized more than 20 genes on this map, ten of which had not been mapped to the region previously, and have isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. Two genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients have been sequenced in breast cancer patients without revealing any deleterious mutations. These new reagents should facilitate the identification of BRCA1.

Risk of treatment-related esophageal cancer among breast cancer survivors.

BACKGROUND: Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. DESIGN: Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. RESULTS: The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). CONCLUSIONS: Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

White matter tracts that overlap with the thalamus and the putamen are protected against multiple sclerosis pathology.

BACKGROUND: The thalamus and the putamen are highly connected hubs implicated in multiple sclerosis (MS) pathology. It remains unclear if white matter (WM) tracts, which pass through them, have a different susceptibility to MS pathology, and if so, if their impact on disability predominates over that exerted by disease in other WM tracts. We hypothesized that WM tracts connected to and passing through these hubs (subsequently termed hub+ tracts) would be more susceptible to MS-related pathology than tracts that do not pass through them (hub- tracts) due to retrograde and anterograde distant degeneration. Thus, we compared the lesion load and neurite orientation dispersion and density imaging (NODDI) derived metrics between hub+ and hub- tracts and assessed the relationship between these MRI metrics and those of physical impairment. METHODS: Eighteen patients (mean age of 45.5 years, 12 females) had 3 Tesla MRI consisting of T1-weighted and T2-weighted Fluid Attenuated Inversion Recovery (FLAIR), and NODDI from which the orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (IVF) were derived. Forty-nine WM tracts, i.e., 12 hub+ and 37 hub- tracts, were segmented out. Exploratory analyses of the differences in lesion burden, whole tract and normal appearing WM (NAWM) NODDI metrics were carried out between the two types of tracts using a Mann-Whitney U test. Correlations with physical impairment, quantified using the expanded disability status scale (EDSS) and timed 25-foot walk (T25FW) test were assessed using Spearman correlation analyses. RESULTS: Hub- tracts had larger T1- (p<0.001) and T2-lesion (p<0.001) volumes; lower ODI (p<0.001), NDI (p<0.001) and higher IVF (p = 0.020) in comparison to hub+ tracts. Measures of tissue injury in hub+ tracts correlated with those of clinical disability, though less strongly than in hub- tracts. CONCLUSIONS: Contrary to our hypothesis, our exploratory pilot study results suggest that WM tracts that overlap with the thalamus and the putamen have a lower degree of lesional and non-lesional tissue injury, suggesting a protective role of the hubs against MS pathology or a higher degree of vulnerability of those not passing through hub stations. We also show a weaker association between disability impairment and hub+ pathology, compared to that in hub- tracts. Our findings point to a potential role of disease location in relation to hubs as guidance for treatment personalization in MS.

Community-based service provision for the prevention and management of maternal obesity in the North East of England: a qualitative study.

OBJECTIVES: This study was conducted to develop a better understanding of community-based initiatives relating to maternal obesity, and to gain community service providers' views on maternal obesity services and their perceived role in the management and prevention of maternal obesity. STUDY DESIGN: An interpretive constructionist approach using semi-structured interviews and focus groups. METHODS: Semi-structured interviews and focus groups were carried out with community service providers in the North East of England, UK. Data were analysed using thematic content analysis. RESULTS: Five dominant themes emerged: community-based obesity services, understanding maternal obesity services, participation in maternal obesity services, challenges in the development of community maternal obesity services, and factors contributing to successful maternal obesity services. Community service providers identified their role in tackling maternal obesity alongside maternity services. Participants identified a lack of community maternal obesity services, distinct training requirements, and felt that a multi-agency approach was likely to be required. CONCLUSIONS: Increasing rates of maternal obesity and the relationship between maternal obesity and childhood obesity mean that the preconception, pregnancy and postnatal periods are important and timely stages in the life course for public health intervention. However, current public health and community service provision lacks structured maternal obesity objectives.

Stem cell deficiencies and thymic abnormalities in fetal mouse trisomy 16.

Mouse fetuses with trisomy 16 have severe abnormalities of several hematopoietic stem cell and precursor populations. The thymus is extremely hypoplastic, with a greater than or equal to 80% reduction in the number of thymocytes. This cellular deficiency appears to be the result of a deficiency in the number of precursor cells in the early thymus, since the rate of proliferation of thymocytes in explanted day-14 thymuses was normal. However, the functional maturation of thymocytes was delayed in vitro in day-17 organ explants, although the maximal response to the mitogenic and interleukin 2-stimulating effects of concanavalin A are quantitatively normal. B cells and pre-B cells in the fetal liver were moderately decreased, but the ability of fetal liver cells to be transformed by Abelson murine leukemia virus was nearly totally lost. There were also significant relative and absolute decreases in the number of spleen, culture, and erythroid colony-forming units (CFU-S, CFU-C, CFU-E) and of erythroid burst-forming units (BFU-E) in the trisomic liver, and the trisomic animals were anemic with small spleens and livers. However, unlike other genetically caused anemias, there was no reduction in the number of germ cells. The hematopoietic abnormalities in the trisomy 16 mouse, involving the lymphoid, myeloid, and erythroid cell lineages, are much more generalized than the abnormalities in any of the other described genetically caused immunodeficiencies or anemias in the mouse. They are also more severe than those in human trisomy 21 (Down syndrome), for which mouse trisomy 16 is a genetic model, but there does exist an interesting parallel between the thymic abnormalities in the two species.

Second solid cancers after radiotherapy for breast cancer in SEER cancer registries.

BACKGROUND: Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. METHODS: We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. RESULTS: By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33-1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer ( approximately 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR=0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1+year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total. CONCLUSIONS: Most second solid cancers in breast cancer survivors are not related to radiotherapy.

MRI of the corpus callosum in multiple sclerosis: association with disability.

Inflammatory demyelination and axon damage in the corpus callosum are prominent features of multiple sclerosis (MS) and may partially account for impaired performance on complex tasks. The objective of this article was to characterize quantitative callosal MRI abnormalities and their association with disability. In 69 participants with MS and 29 healthy volunteers, lesional and extralesional callosal MRI indices were estimated via diffusion tensor tractography. expanded disability status scale (EDSS) and MS functional composite (MSFC) scores were recorded in 53 of the participants with MS. All tested callosal MRI indices were diffusely abnormal in MS. EDSS score was correlated only with age (r = 0.51). Scores on the overall MSFC and its paced serial auditory addition test (PASAT) and 9-hole peg test components were correlated with callosal fractional anisotropy (r = 0.27, 0.35, and 0.31, respectively) and perpendicular diffusivity (r = -0.29, -0.30, and -0.31) but not with overall callosal volume or callosal lesion volume; the PASAT score was more weakly correlated with callosal magnetization-transfer ratio (r = 0.21). Anterior callosal abnormalities were associated with impaired PASAT performance and posterior abnormalities with slow performance on the 9-hole peg test. In conclusion, abnormalities in the corpus callosum can be assessed with quantitative MRI and are associated with cognitive and complex upper-extremity dysfunction in MS.