To examine differences in growth patterns in preterm infants developing major morbidities including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC) and intraventricular haemorrhage (IVH).
Cohort study of 2521 infants born at a gestational age (GA) of 23–30 weeks from 11 level III neonatal intensive care units in USA and Canada, and 3 Swedish population-based cohorts.
Birth weight and postnatal weight gain were examined relative to birth GA and ROP, BPD, NEC and IVH development.
Among infants with a birth GA of 25–30 weeks, birth weight SD score and postnatal weight were lower in those developing ROP and BPD. Infants developing ROP showed lower growth rates during postnatal weeks 7–9 in the 23–24 weeks GA group, during weeks 4–6 in the 25–26 weeks GA group and during weeks 1–5 in the 27–30 weeks GA group. Infants with BPD born at 27–30 weeks GA showed lower growth rates during postnatal weeks 3–5. Infants with NEC had lower growth rates after postnatal week 6 in all GA groups, with no significant differences in birth weight SD score. IVH was not associated with prenatal or postnatal growth.
In this cohort study of extremely preterm infants, we found that the postnatal growth pattern was associated with morbidities such as ROP, BPD and NEC as well as with gestational age at birth.
Genomic regions with repetitive sequences are considered unstable and prone to swift DNA diversification processes. A highly diverse immune gene family of the sea urchin (Strongylocentrotus purpuratus), called Sp185/333, is composed of clustered genes with similar sequence as well as several types of repeats ranging in size from short tandem repeats (STRs) to large segmental duplications. This repetitive structure may have been the basis for the incorrect assembly of this gene family in the sea urchin genome sequence. Consequently, we have resolved the structure of the family and profiled the members by sequencing selected BAC clones using Illumina and PacBio approaches.
BAC insert assemblies identified 15 predicted genes that are organized into three clusters. Two of the gene clusters have almost identical flanking regions, suggesting that they may be non-matching allelic clusters residing at the same genomic locus. GA STRs surround all genes and appear in large stretches at locations of putatively deleted genes. GAT STRs are positioned at the edges of segmental duplications that include a subset of the genes. The unique locations of the STRs suggest their involvement in gene deletions and segmental duplications. Genomic profiling of the Sp185/333 gene diversity in 10 sea urchins shows that no gene repertoires are shared among individuals indicating a very high gene diversification rate for this family.
The repetitive genomic structure of the Sp185/333 family that includes STRs in strategic locations may serve as platform for a controlled mechanism which regulates the processes of gene recombination, gene conversion, duplication and deletion. The outcome is genomic instability and allelic mismatches, which may further drive the swift diversification of the Sp185/333 gene family that may improve the immune fitness of the species.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3241-x) contains supplementary material, which is available to authorized users.
Strongylocentrotus purpuratus; Gene diversification; Allelic mispairing; Genomic instability Sp185/333; Illumina vs. PacBio
Kisspeptin neuropeptides are encoded by the Kiss1 gene and play a critical role in the regulation of the mammalian reproductive axis. Kiss1 neurones are found in two locations in the rodent hypothalamus: one in the arcuate nucleus (ARC) and another in the RP3V region, which includes the anteroventral periventricular nucleus (AVPV). Detailed mapping of the fibre distribution of Kiss1 neurones will help with our understanding of the action of these neurones in other regions of the brain. We have generated a transgenic mouse in which the Kiss1 coding region is disrupted by a CRE‐GFP transgene so that expression of the CRE recombinase protein is driven from the Kiss1 promoter. As expected, mutant mice of both sexes are sterile with hypogonadotrophic hypogonadism and do not show the normal rise in luteinising hormone after gonadectomy. Mutant female mice do not develop mature Graafian follicles or form corpora lutea consistent with ovulatory failure. Mutant male mice have low blood testosterone levels and impaired spermatogenesis beyond the meiosis stage. Breeding Kiss‐CRE heterozygous mice with CRE‐activated tdTomato reporter mice allows fluorescence visualisation of Kiss1 neurones in brain slices. Approximately 80‐90% of tdTomato positive neurones in the ARC were co‐labelled with kisspeptin and expression of tdTomato in the AVPV region was sexually dimorphic, with higher expression in females than males. A small number of tdTomato‐labelled neurones was also found in other locations, including the lateral septum, the anterodorsal preoptic nucleus, the amygdala, the dorsomedial and ventromedial hypothalamic nuclei, the periaquaductal grey, and the mammillary nucleus. Three dimensional visualisation of Kiss1 neurones and fibres by CLARITY processing of whole brains showed an increase in ARC expression during puberty and higher numbers of Kiss1 neurones in the caudal region of the ARC compared to the rostral region. ARC
Kiss1 neurones sent fibre projections to several hypothalamic regions, including rostrally to the periventricular and pre‐optic areas and to the lateral hypothalamus.
Kiss‐CRE; transgenic; mouse; tdTomato; CLARITY; neuronal distribution
Knee Osteoarthritis (KOA) is a heterogeneous pathology characterized by a complex and multifactorial nature. It has been hypothesised that these differences are due to the existence of underlying phenotypes representing different mechanisms of the disease.
The aim of this study is to identify the current evidence for the existence of groups of variables which point towards the existence of distinct clinical phenotypes in the KOA population. A systematic literature search in PubMed was conducted. Only original articles were selected if they aimed to identify phenotypes of patients aged 18 years or older with KOA. The methodological quality of the studies was independently assessed by two reviewers and qualitative synthesis of the evidence was performed. Strong evidence for existence of specific phenotypes was considered present if the phenotype was supported by at least two high-quality studies.
A total of 24 studies were included. Through qualitative synthesis of evidence, six main sets of variables proposing the existence of six phenotypes were identified: 1) chronic pain in which central mechanisms (e.g. central sensitisation) are prominent; 2) inflammatory (high levels of inflammatory biomarkers); 3) metabolic syndrome (high prevalence of obesity, diabetes and other metabolic disturbances); 4) Bone and cartilage metabolism (alteration in local tissue metabolism); 5) mechanical overload characterised primarily by varus malalignment and medial compartment disease; and 6) minimal joint disease characterised as minor clinical symptoms with slow progression over time.
This study identified six distinct groups of variables which should be explored in attempts to better define clinical phenotypes in the KOA population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-016-1286-2) contains supplementary material, which is available to authorized users.
Knee; Osteoarthritis; Phenotype; Sub-group; Clinical
DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice.
Testicular development and function is the culmination of a complex process of autocrine, paracrine and endocrine interactions between multiple cell types. Dissecting this has classically involved the use of systemic treatments to perturb endocrine function, or more recently, transgenic models to knockout individual genes. However, targeting genes one at a time does not capture the more wide‐ranging role of each cell type in its entirety. An often overlooked, but extremely powerful approach to elucidate cellular function is the use of cell ablation strategies, specifically removing one cellular population and examining the resultant impacts on development and function. Cell ablation studies reveal a more holistic overview of cell–cell interactions. This not only identifies important roles for the ablated cell type, which warrant further downstream study, but also, and importantly, reveals functions within the tissue that occur completely independently of the ablated cell type. To date, cell ablation studies in the testis have specifically removed germ cells, Leydig cells, macrophages and recently Sertoli cells. These studies have provided great leaps in understanding not possible via other approaches; as such, cell ablation represents an essential component in the researchers’ tool‐kit, and should be viewed as a complement to the more mainstream approaches to advancing our understanding of testis biology. In this review, we summarise the cell ablation models used in the testis, and discuss what each of these have taught us about testis development and function.
animal models; germ cell transplantation; germ cells; gonadal development; Leydig cells; macrophages; paracrine factors; Sertoli cell; spermatogenesis; testis
We assessed evidence of exposure to viruses and bacteria in an unmanaged and long-isolated population of Soay sheep (Ovis aries) inhabiting Hirta, in the St Kilda archipelago, 65 km west of Benbecula in the Outer Hebrides of Scotland. The sheep harbour many metazoan and protozoan parasites but their exposure to viral and bacterial pathogens is unknown. We tested for herpes viral DNA in leucocytes and found that 21 of 42 tested sheep were infected with ovine herpesvirus 2 (OHV-2). We also tested 750 plasma samples collected between 1997 and 2010 for evidence of exposure to seven other viral and bacterial agents common in domestic Scottish sheep. We found evidence of exposure to Leptospira spp., with overall seroprevalence of 6·5%. However, serological evidence indicated that the population had not been exposed to border disease, parainfluenza, maedi-visna, or orf viruses, nor to Chlamydia abortus. Some sheep tested positive for antibodies against Mycobacterium avium subsp. paratuberculosis (MAP) but, in the absence of retrospective faecal samples, the presence of this infection could not be confirmed. The roles of importation, the pathogen–host interaction, nematode co-infection and local transmission warrant future investigation, to elucidate the transmission ecology and fitness effects of the few viral and bacterial pathogens on Hirta.
In a number of papers dating back to the 1970s, Parker has hypothesized that, in a perfectly ideal environment, complex photospheric motions acting on a continuous magnetic field will result in the formation of tangential discontinuities corresponding to singular currents. I review direct numerical simulations of the problem and find that the evidence points to a tendency for thin but finite-thickness current layers to form, with thickness exponentially decreasing in time. Given a finite resistivity, these layers will eventually become important and cause the dynamical process of energy release. Accordingly, a body of work focuses on evolution under continual boundary driving. The coronal volume evolves into a highly dynamic but statistically steady state where quantities have a temporally and spatially intermittent nature and where the Poynting flux and dissipation are decoupled on short time scales. Although magnetic braiding is found to be a promising coronal heating mechanism, much work remains to determine its true viability. Some suggestions for future study are offered.
the Sun; corona; magnetic fields; magnetic reconnection
The majority of breast conserving surgery (BCS) is performed in younger women. There is little published information about the views of women aged over 70 regarding BCS. The aim of this study was to investigate the attitudes of this age group towards BCS, and factors which may influence their treatment decision-making.
A questionnaire was sent to all patients who were aged 70 or over at the time they had breast cancer surgery in NHS Lanarkshire between 1999 and 2013. This detailed surgical options and recommendations, timing of decision making, treatment expectations, psychological and cosmetic concerns and other factors which may have influenced any decision made e.g. travel for radiotherapy and potential side effects.
Responses were received from 339 patients, 192 of whom had a mastectomy with the remaining undergoing BCS. In the mastectomy group 18 % (35) would have preferred to have BCS had it been an option, with 40 % (76) of group being happy to take neoadjuvant endocrine therapy to try and facilitate this. However, only 14 % (26) of patients would have considered neoadjuvant chemotherapy with the same aim. Almost half (82) of the mastectomy patients said that the risk of local recurrence following BCS was a factor which influenced their decision.
BCS is something that patients aged over 70 are interested in considering in the same way as younger patients. More than a third of patients requiring mastectomy would be willing to take neoadjuvant endocrine therapy to attempt to downstage their tumour to facilitate BCS.
Breast cancer; Breast conserving surgery; Elderly
Herbaspirillum spp. are Gram-negative bacteria that inhabit soil and water. Infections caused by these organisms have been reported in immunocompromised hosts. We describe severe community-acquired pneumonia and bacteremia caused by Herbaspirillum aquaticum or H. huttiense in an immunocompetent adult male.
The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.
Lung ablation can be used to treat both primary and secondary thoracic malignancies. Evidence to support its use, particularly for metastases from colonic primary tumours, is now strong, with survival data in selected cases approaching that seen after surgery. Because of this, the use of ablative techniques (particularly thermal ablation) is growing and the Royal College of Radiologists predict that the number of patients who could benefit from such treatment may reach in excess of 5000 per year in the UK. Treatment is often limited to larger regional centres, and general radiologists often have limited awareness of the current indications and the techniques involved. Furthermore, radiologists without any prior experience are frequently expected to interpret post-treatment imaging, often performed in the context of acute complications, which have occurred after discharge. This review aims to provide an overview of the current indications for pulmonary ablation, together with the techniques involved and the range of post-procedural appearances.
We set out to assess the health care resource utilization and cost of cervical cancer from the perspective of a single-payer health care system.
Retrospective observational data for women diagnosed with cervical cancer in British Columbia between 2004 and 2009 were analyzed to calculate patient-level resource utilization patterns from diagnosis to death or 5-year discharge. Domains of resource use within the scope of this cost analysis were chemotherapy, radiotherapy, and brachytherapy administered by the BC Cancer Agency; resource utilization related to hospitalization and outpatient visits as recorded by the B.C. Ministry of Health; medically required services billed under the B.C. Medical Services Plan; and prescriptions dispensed under British Columbia’s health insurance programs. Unit costs were applied to radiotherapy and brachytherapy, producing per-patient costs.
The mean cost per case of treating cervical cancer in British Columbia was $19,153 (standard error: $3,484). Inpatient hospitalizations, at 35%, represented the largest proportion of the total cost (95% confidence interval: 32.9% to 36.9%). Costs were compared for subgroups of the total cohort.
As health care systems change the way they manage, screen for, and prevent cervical cancer, cost-effectiveness evaluations of the overall approach will require up-to-date data for resource utilization and costs. We provide information suitable for such a purpose and also identify factors that influence costs.
Cost of care; cervical cancer
Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products.
In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m2/day (ch14.18-UTC) and 25 mg/m2/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3–5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM® version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (Cmax). All comparisons were based on a standardized single-dose regimen (17.5 mg/m2 over 10 h).
Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products’ systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88–1.04) and Cmax (1.04; 90 % CI 0.98–1.11) within standard bioequivalence bounds (90 % CI 0.80–1.25). Products’ adverse events were similar and consistent with those previously reported.
Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2955-9) contains supplementary material, which is available to authorized users.
ch14.18; Dinutuximab; Pharmacokinetics; Safety; Tolerability; Unituxin
Examination of a cohort of cats experimentally infected with feline immunodeficiency virus (FIV) for 5.75 years revealed detectable proviral DNA in peripheral blood mononuclear cells (PBMCs) harvested during the asymptomatic phase, undetectable plasma viral RNA (FIV gag), and rarely detectable cell-associated viral RNA. Despite apparent viral latency in peripheral CD4+ T cells, circulating CD4+ T cell numbers progressively declined in progressor animals. The aim of this study was to explore this dichotomy of peripheral blood viral latency in the face of progressive immunopathology. The viral replication status, cellular immunophenotypes, and histopathologic features were compared between popliteal lymph nodes (PLNs) and peripheral blood. Also, we identified and further characterized one of the FIV-infected cats identified as a long-term non-progressor (LTNP).
PLN-derived leukocytes from FIV-infected cats during the chronic asymptomatic phase demonstrated active viral gag transcription and FIV protein translation as determined by real-time RT-PCR, Western blot and in situ immunohistochemistry, whereas viral RNA in blood leukocytes was either undetectable or intermittently detectable and viral protein was not detected. Active transcription of viral RNA was detectable in PLN-derived CD4+ and CD21+ leukocytes. Replication competent provirus was reactivated ex vivo from PLN-derived leukocytes from three of four FIV-infected cats. Progressor cats showed a persistent and dramatically decreased proportion and absolute count of CD4+ T cells in blood, and a decreased proportion of CD4+ T cells in PLNs. A single long-term non-progressor (LTNP) cat persistently demonstrated an absolute peripheral blood CD4+ T cell count indistinguishable from uninfected animals, a lower proviral load in unfractionated blood and PLN leukocytes, and very low amounts of viral RNA in the PLN.
Collectively our data indicates that PLNs harbor important reservoirs of ongoing viral replication during the asymptomatic phase of infection, in spite of undetectable viral activity in peripheral blood. A thorough understanding of tissue-based lentiviral reservoirs is fundamental to medical interventions to eliminate virus or prolong the asymptomatic phase of FIV infection.
The context within which health care and public health systems operate is framed by health policies. There is growing consensus about the need for increased health policy leadership and a health professional workforce prepared to assume these leadership roles. At the same time, there is strong evidence supporting the need for a broader policy lens and the need to intentionally target health disparities. We reviewed the published literature between 1983 and 2013 regarding health policy training. From 5124 articles identified, 33 met inclusion criteria. Articles varied across common themes including target audience, goal(s), health policy definition, and core curricular content. The majority of articles were directed to medical or nursing audiences. Most articles framed health policy as health care policy and only a small number adopted a broader health in all policies definition. Few articles specifically addressed vulnerable populations or health disparities. The need for more rigorous research and evaluation to inform health policy training is compelling. Providing health professionals with the knowledge and skills to engage and take leadership roles in health policy will require training programs to move beyond their limited health care-oriented health policy framework to adopt a broader health and health equity in all policies approach.
health policy; health policy training; training; education; curriculum; health professionals; health disparities; health equity; health in all policies; public health
Supplementing nutrition education with skills-building activities may enhance community awareness of diet-related cancer prevention guidelines. To develop a cookbook with lifestyle tips, recipes were solicited from the National Black Leadership Initiative on Cancer (NBLIC) community coalitions and dietary intake advice from participants in the Educational Program to Increase Colorectal Cancer Screening (EPICS). With guidance from a chef and registered dietitian, recipes were tested, assessed, and transformed; lifestyle advice was obtained from focus groups. The cookbook with lifestyle tips, named “Down Home Healthy Living (DHHL) 2.0,” was distributed in print form to 2,500 EPICS participants and shared electronically through websites and social media.
To investigate the longitudinal association between television viewing time and risk of incident diabetes mellitus in an elderly sample of adults in England.
Analyses of data from the English Longitudinal Study of Ageing. At baseline (2008), participants reported their television viewing time and physical activity level. Diabetes mellitus was recorded from self-reported physician diagnosis at 2-year follow-up. Associations between television viewing time and combined television viewing time and physical activity level with risk of incident diabetes mellitus at follow-up were examined using adjusted logistic regression models.
A total of 5964 participants (mean ± SD age 65 ±9 years at baseline, 44% male) were included in the analyses. There was an association between baseline television viewing time and risk of incident diabetes mellitus at 2-year follow-up (≥ 6h/day compared with <2h/day; odds ratio 4.27, 95% CI 1.69, 10.77), although the association was attenuated to the null in final adjusted models that included BMI. Participants who were inactive/had high television viewing time at baseline were almost twice as likely to have diabetes mellitus at 2-year follow-up than those who were active/had low television viewing time (fully adjusted odds ratio 1.94, 95% CI 1.02, 3.68), although active participants reporting high television viewing were not at risk.
Interventions to reduce the incidence of diabetes in the elderly that focus on both increasing physical activity and reducing television viewing time might prove useful.
A sustainable world is one in which human needs are met equitably and without sacrificing the ability of future generations to meet their needs. Human well-being is described by four primary elements—basic human needs, economic needs, environmental needs, and subjective well-being. These elements can interact in a myriad of ways to influence overall well-being. What makes changes in human well-being sustainable for a population or a nation? Two major interactional concepts can push changes in human well-being toward a sustainable state in space and time—social equity and intergenerational equity. The concept of social equity distributes well-being over space, ensuring the fair treatment of all members of society promoting spatial sustainability of a well-being decision. The concept of intergenerational equity distributes well-being through time, ensuring the well-being of present and future generations of a population or nation, promoting temporal sustainability of a well-being decision. The roles of social and intergenerational equity in terms of their influence on human well-being are examined with a focus on more sustainable decision-making.
Well-being; Sustainability; Social equity; Environmental justice; Intergenerational equity
Effective protection against pathogens requires the host to produce a wide range of immune effector proteins. The Sp185/333 gene family, which is expressed by the California purple sea urchin Strongylocentrotus purpuratus in response to bacterial infection, encodes a highly diverse repertoire of anti-pathogen proteins. A subset of these proteins can be isolated by affinity to metal ions based on multiple histidines, resulting in one to four bands of unique molecular weight on standard Western blots, which vary depending on the individual sea urchin. Two dimensional gel electrophoresis (2DE) of nickel-isolated protein samples followed by Western blot was employed to detect nickel-isolated Sp185/333 (Ni-Sp185/333) proteins and to evaluate protein diversity in animals before and after immune challenge with marine bacteria. Ni-Sp185/333 proteins of the same molecular weight on standard Western blots appear as a broad complex of variants that differ in pI on 2DE Western blots. The Ni-Sp185/333 protein repertoire is variable among animals, and shows a variety of changes among individual sea urchins in response to immune challenges with both the same and different species of bacteria. The extraordinary diversity of the Ni-Sp185/333 proteins may provide significant anti-pathogen capabilities for sea urchins that survive solely on innate immunity.
Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques.
Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model.
Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model.
Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.
pancreatic cancer; radiation resistance; cholesterol; zoledronic acid; radiosensitiser
Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia.
We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008–2010 and 2011–2013). Durability of successful treatment and progression to OAC were also evaluated.
508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51).
Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2–4% at 1 year in these high-risk patients.
Trial registration number
BARRETT'S OESOPHAGUS; OESOPHAGEAL CANCER; ENDOSCOPIC PROCEDURES
Vatalanib (PTK 787/ZK22584) is an oral polytyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy.
Vatalanib treatment consisted of a twice daily oral dosing using a “ramp-up schedule,” beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. the primary objective of this study was to evaluate the 6-month survival rate.
Sixty-seven patients were enrolled. The median age was 64, and 66 %(N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20 %; N = 13), fatigue (17 %; N = 11), abdominal pain (17 %; N = 11), and elevated alkaline phosphatase (15 %; N = 10). among the 65 evaluable patients, the 6-month survival rate was 29 % (95 % CI 18–41 %) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. two patients had objective partial responses, and 28 % of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug.
Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.
Vatalinib; Pancreatic adenocarcinoma; Tyrosine kinase inhibitor; Second-line treatment
Background and Objective
The etiology and exact incidence of infantile hemangiomas (IH) are unknown. Prior studies have noted immunohistochemical and biologic characteristics shared by IH and placental tissue. We investigated the possible association between placental anomalies and the development of IH, as well as the demographic characteristics and other risk factors for IH.
578 pregnant women were prospectively enrolled and their offspring followed for 9 months. Placental evaluations were performed and demographic data collected on all mother-infant pairs.
594 infants were evaluated: 32 hemangiomas (either IH or congenital (CH)) were identified in 27 infants, yielding an incidence of 4.5% for IH and 0.3% for CH. Placental anomalies were noted in almost 35% of hemangioma-related pregnancies, approximately twice the incidence noted in pregnancies with unaffected infants. (p = 0.025). Other risk factors for IH included prematurity (p = 0.016) and low birth weight (p = 0.028). All IH were present by 3 months of age, and cessation of growth had occurred in all by 9 months of age. Most occurred on the trunk. Of note, 20% of identified IH were abortive/telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention.
This is the first prospective American study to document the incidence of IH in infants followed from birth to early infancy. The association with placental anomalies was statistically significant. The overall incidence mirrors prior estimates, but the need for treatment was lower than previously reported.
infantile hemangioma; congenital hemangioma; abortive/telangiectatic hemangioma; placental anomalies