Improvements in Survival and Clinical Benefit With Gemcitabine as First-Line Therapy for Patients With Advanced Pancreas Cancer: A Randomized Trial.

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Water Pollution Increases the Risk of Chytridiomycosis in Mexican Amphibians.

Chytridiomycosis is affecting amphibians worldwide, causing the decline and extinction of several amphibian populations. The disease is caused by the fungus Batrachochytrium dendrobatidis (Bd), a multihost pathogen living in freshwater habitats. While several environmental factors have been associated with the prevalence of Bd and its virulence, the effects of water quality on the pathogen are not clear yet. Some evidence suggests that water pollution may reduce amphibians' immune response and increase prevalence of Bd. To explore this hypothesis, we analyzed the relationship between water quality and the presence of Bd by using spatial data mining of 150 geolocations of Bd in amphibians from 9 families where Bd positive specimens have been previously reported, and water quality in 4,202 lentic and lotic water bodies in Mexico from 2010 to 2021. Our model showed that in the 3 main families where Bd was recorded, its presence is high in locations with low water quality, i.e., water polluted likely contaminated with urban and industrial waste. Using this model, we inferred areas suitable for Bd in Mexico; mainly in poorly studied areas along the gulf and on the pacific slope. We further argue that actions to reduce water pollution should become an integral part of public policies to prevent the spread of Bd and protect amphibians from this deadly pathogen.

Patient satisfaction and impact of salivary flow rate on effectiveness of xerostomia products.

OBJECTIVES: To determine the types of products used to treat dry mouth and their perceived effectiveness, the relationship between salivary function and xerostomia symptoms, and whether salivary function predicts response to management strategies. STUDY DESIGN: Cross-sectional study of 87 patients with dry mouth and documented unstimulated whole salivary (UWS) and stimulated whole salivary (SWS) flow rates. Participants completed a questionnaire assessing dry mouth complaints and symptoms and effectiveness of specific dry mouth products. RESULTS: Mean (SD) age was 61.7 (12.9) years including 78 (90%) females. 47 (54%) participants had Sjögren's disease. Oral dryness symptoms (0-10 scale) rated highest with a mean (SD) of 7.2 (2.17); other symptoms scored from 3.4 to 5.1. Lower levels of UWS and SWS were associated with worse dry mouth and difficulty speaking, while lower levels of SWS flow alone were associated with greater difficulty swallowing and a decline in taste. More than half of the participants (55%, n = 48) reported using ≥4 dry mouth products. Participants with normal SWS flow had significantly better responses to lozenges and prescription products. CONCLUSIONS: Patients with dry mouth and normal stimulated flow rates (i.e., residual salivary capacity) respond better to stimulatory products (parasympathomimetic and lozenges). Salivary flow rate assessments may help with recommendations of dry mouth products.

Effect of different durations of using a standing frame on the rate of hip migration in children with moderate to severe cerebral palsy: a feasibility study for a randomised controlled trial.

AIM: To assess the feasibility of a randomised controlled trial (RCT) to evaluate the effect of different doses of standing time on hip migration rate in children with cerebral palsy (CP). METHOD: Children aged 1-12 years with CP GMFCS levels III-V were recruited and randomised to either doubling or continuing with their usual time in their standing frame. Caregivers kept a standing time diary. The primary outcome measure was Reimers hip migration percentage, measured at baseline, 12 and 24 months. A blinded assessor measured secondary clinical outcomes at baseline, 6 and 12 months. Feasibility results are reported following CONSORT guidelines. RESULTS: Twenty-five children were recruited. Nineteen were randomised and 10 completed the 12-month intervention. The mean daily standing time in the intervention group was 49minutes (SD 39.1) (Monday-Sunday) and 58.1 (SD 44.1) minutes during weekdays. In children remaining in the trial, primary and secondary clinical outcome measures were available in 54% and 90% of children respectively. There were three serious adverse events, unrelated to standing. CONCLUSIONS: It may be feasible to conduct an RCT to assess the effect of duration of standing on hip migration in children with CP with an altered protocol. The suggested target dose is 60minutes five times per week compared to a control group standing for 30minutes three times per week, over twelve months. Use of botulinum toxin need not be a criterion for exclusion and radiography should be included as a research cost. NHS Health Research Committee, South West ethics approval (ref 13/SW/0228).

Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.

The EBSD spatial resolution of a Timepix-based detector in a tilt-free geometry.

Performing EBSD with a horizontal sample and a parallel EBSD detector sensor, enables safer specimen movements for data collection of large specimen areas and improves the longitudinal spatial resolution. The collection of electron backscattering patterns (EBSPs) at normal incidence to the electron beam has been revisited via the use of a direct electron detection (DED) sensor. In this article we present a fully operational DED EBSD detection system in this geometry, referred to as the tilt-free geometry. A well-defined Σ=3[101]{121} twin boundary in a Molybdenum bicrystal was used to measure the physical spatial resolution of the EBSD detector in this tilt-free geometry. In this study, two separate methods for estimating the spatial resolution of EBSD, one based on a pattern quality metric and the other on a normalised cross correlation coefficient were used. The spatial resolution was determined at accelerating voltages of 8 kV, 10 kV, 12 kV, 15 kV and 20 kV ranging from ~22-38 nm using the pattern quality method and ~31-46 nm using the normalised cross correlation method.

How decision-making about euthanasia for animals is taught to Australasian veterinary students.

This study set out to explore how euthanasia decision-making for animals was taught to students in eight Australasian veterinary schools. A questionnaire-style interview guide was used by a representative at each university to interview educators. Educators were interviewed about their teaching of euthanasia decision-making for four categories of animals: livestock, equine, companion and avian/wildlife. Using thematic analysis, the terms provided by participants to describe how (mode of teaching) and what (specific content) they taught to students were categorised. Information about content was categorised into human-centred factors that influence decision-making, and animal-based indicators used to directly inform decision-making. All eight representatives reported some teaching relevant to euthanasia decision-making at their university for livestock, companion animal and avian/wildlife. One representative reported no such teaching for equid animals at their university. Observation of a euthanasia case was rarely reported as a teaching method. Five universities reported multiple modes of teaching relevant information, while two universities made use of modalities that could be described as opportunistic teaching (e.g., 'Discussion of clinical cases'). Factors taught at most universities included financial considerations, and that it is the owner's decision to make, while animal-based indicators taught included QoL/animal welfare, prognosis and behaviour change. Overall, most universities used a variety of methods to cover relevant material, usually including lectures and several other approaches for all animal types. However, because two universities relied on presentation of clinical cases, not all students at these veterinary schools will be exposed to make, or assist in making, euthanasia decisions.

How management of grief associated with ending the life of an animal is taught to Australasian veterinary students.

OBJECTIVE: Veterinarians have an important role in supporting and understanding their clients' grief. Veterinary schools have a duty to teach students how best to manage grief - both that of the students/future veterinarians and the clients. This study explores how grief management, associated with ending the life of an animal, was taught to students in eight Australasian veterinary schools. METHODS: A questionnaire-style interview guide was used by a representative at each university to conduct structured interviews with educators in a snowball sampling approach. Educators were interviewed about the teaching of grief management for four categories of animals: livestock, equine, companion and avian/wildlife. The terms used by participants to describe what they taught were grouped into common themes. Teaching was defined by individual participants and included structured and unstructured approaches. The stage in the degree (preclinical or clinical years) that grief management was taught in the veterinary curriculum and by whom (e.g. clinicians or psychologists) is also described. RESULTS: Grief management was taught more in preclinical than clinical years. However, due to how grief was characterised, much of this teaching was general 'nonspecific' teaching that included all categories of animals. Client grief was taught more generically, whereas, grief of veterinarians was taught using specific examples given by clinicians. CONCLUSION: A more robust end-of-life (EoL) management curriculum that includes all aspects of grief management is likely to increase job satisfaction, client happiness and professional satisfaction.

Anti-Müllerian hormone type II receptor in avian follicle development.

Anti-Müllerian hormone (AMH) helps maintain the ovarian reserve by regulating primordial follicle activation and follicular selection in mammals, although its role within the avian ovary is unknown. In mammals, AMH is primarily produced in granulosa cells of preantral and early antral follicles. Similarly, in the hen, the granulosa cells of smaller follicles are the predominant source of AMH. The importance of AMH in mammalian ovarian dynamics suggests the protein and its specific Type II receptor, AMHRII, may have conserved functions in the hen. AMHRII mRNA expression is highest (P < 0.01) in small follicles of the hen and decreases as follicle size increases. Similarly, expression of AMHRII and AMH is highest in granulosa cells from small follicles as compared to larger follicles. Dissection of 3-5 mm follicles into ooplasm and granulosa components shows that AMHRII mRNA levels are greater in ooplasm than granulosa cells. Furthermore, immunohistochemistry also revealed AMHRII staining in the oocyte and granulosa cells. AMH expression in mammals is elevated during periods of reproductive dormancy, possibly protecting the ovarian reserve. AMHRII and AMH mRNA were significantly higher (P < 0.05) in nonlaying ovaries of broiler hens. In molting layer hens, AMHRII mRNA was significantly greater (P < 0.05) compared to nonmolting hen ovaries. These results suggest that AMH may have a direct effect on the oocyte and, thereby, contribute to bidirectional communication between oocyte and granulosa cells. Enhanced expression of AMHRII and AMH during reproductive quiescence supports a potential role of AMH in protecting the ovarian reserve in hens.

Occludin expression and regulation in small follicles of the layer and broiler breeder hen.

Synchronized yolk accumulation and follicle development are essential for egg production in oviparous species. In birds, yolk is incorporated into the oocyte by an avian specific yolk receptor (LR8), and it has been suggested that occludin (OCLN), a tight junction protein, mediates transfer of yolk material to the oocyte surface. OCLN may be a key regulator of yolk accumulation and follicle growth, however, the expression and regulation of OCLN in granulosa cells during various stages of follicle development is unknown. In the first experiment, we found that LR8 and OCLN mRNA were highest in small follicles within the ovary. In addition, OCLN decreased with increasing follicle size. OCLN mRNA was more abundant in the germinal disc region of the granulosa cell layer than the non-germinal disc region. In addition, we found epidermal growth factor (EGF) and activin B, decreased OCLN mRNA, while activin A increased OCLN. In the second experiment, restricted fed (RF) broiler breeder hens were randomly divided into two groups and one group remained on RF and the other was fed ad libitum (FF). OCLN expression in granulosa cells of 3-5mm follicles of FF hens was lower compared to RF hens and yolk weights were higher in the FF group, however, LR8 mRNA in small whole follicles (<3mm) did not differ between groups. In conclusion, the level of feed intake is related to or may directly regulate OCLN mRNA expression or may have an indirect effect through paracrine or autocrine factors in the ovary.

Bone morphogenetic protein 15 may promote follicle selection in the hen.

In the hen, optimal ovulation rate depends on selection of a single follicle into the pre-ovulatory hierarchy. Follicle selection is associated with increased oocyte growth and changes in gene expression in granulosa cells surrounding the oocyte, in preparation for ovulation. This study investigated the expression, function and regulation of bone morphogenetic protein-15 (BMP15) during follicle development in the hen. BMP15 mRNA expression was analyzed in the ooplasm and granulosa cells of 3mm follicles and was confirmed to be primarily in the ooplasm. BMP15 was detected by immunoblotting in 6 and 8mm follicles near the time of follicle selection. Expression of mRNA for BMP15 receptors (BMPR1B and BMPR2) in granulosa cells increased with follicle size, indicating that BMP15 may play an important role around follicle selection. The function of BMP15 was examined by culturing granulosa cells from 3-5mm and 6-8mm follicles with recombinant human BMP15 (rhBMP15). BMP15 increased expression of follicle stimulating hormone receptor (FSHR) mRNA and decreased anti-Müllerian hormone (AMH) mRNA and occludin (OCLN), factors associated with follicle maturation and growth in the hen. Hormonal regulation of BMP15 was assessed by whole follicle culture with estradiol (E2) which increased BMP15 mRNA expression. The distinct expression pattern of BMP15 and its receptors, coupled with the effects of BMP15 to increase FSHR mRNA and decrease AMH mRNA and OCLN mRNA and protein expression suggest that the oocyte may have a role in follicle selection in the chicken.

Intrafamilial phenotypic heterogeneity of epidermolytic ichthyosis associated with a new missense mutation in keratin 10.

Mutations in the keratin 10 gene (KRT10) have been shown to underlie several forms of epidermolytic ichthyosis (EI), including generalized, annular and naevoid variants. We investigated an autosomal dominant pedigree with ichthyosis in which there was intrafamilial clinical heterogeneity, with the affected individual family members presenting with features of either erythrokeratoderma progressiva, annular EI, localized or superficial EI, or more generalized EI. Sanger sequencing identified a new heterozygous missense mutation (c.457C>A; p.Leu153Met) in KRT10 in all affected individuals. No additional mutations were identified in the genes for keratin 1 (KRT1) keratin 2 (KRT2), connexin 31 (GJB3) or connexin 30.3 (GJB4) that might account for the clinical heterogeneity seen in this family. Our findings illustrate the intrafamilial variability in phenotype and diverse clinical presentations that can occur in EI resulting from a single mutation in KRT10.

Strategies for engaging with future radiation protection professionals: a public outreach case study.

It is evident that there is a nuclear skills shortage within the UK, and logically it can be assumed that the shortfall extends to the radiation protection arena. Plans for nuclear new-build and the decommissioning of existing nuclear sites will require many more people with radiological knowledge and practical competencies. This converts to a nuclear industry requirement in the order of 1000 new recruits per year over at least the next ten years, mainly as new apprentices and graduates. At the same time, the strong demand for persons with radiation protection know-how in the non-nuclear and health care sectors is unlikely to diminish. The task of filling this skills gap is a significant one and it will require a determined effort from many UK stakeholders. The Society for Radiological Protection (SRP) has adopted a strategy in recent years to help address this skills gap. The aim is to engage the interest of secondary school students in the science of radiation and inspire them to follow a career in radiation protection. This paper presents the reasoning behind this strategy and, in an 'outreach case study', describes the establishment of the annual SRP Schools Event. This event is becoming an important addition to the national efforts aimed at increasing the numbers of skilled UK radiation protection professionals over the forthcoming decades.

Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: implications for xenograft models of human prostate cancer.

BACKGROUND: Ephrin-B2 is the sole physiologically-relevant ligand of the receptor tyrosine kinase EphB4, which is over-expressed in many epithelial cancers, including 66% of prostate cancers, and contributes to cancer cell survival, invasion and migration. Crucially, however, the cancer-promoting EphB4 signalling pathways are independent of interaction with its ligand ephrin-B2, as activation of ligand-dependent signalling causes tumour suppression. Ephrin-B2, however, is often found on the surface of endothelial cells of the tumour vasculature, where it can regulate angiogenesis to support tumour growth. Proteolytic cleavage of endothelial cell ephrin-B2 has previously been suggested as one mechanism whereby the interaction between tumour cell-expressed EphB4 and endothelial cell ephrin-B2 is regulated to support both cancer promotion and angiogenesis. METHODS: An in silico approach was used to search accessible surfaces of 3D protein models for cleavage sites for the key prostate cancer serine protease, KLK4, and this identified murine ephrin-B2 as a potential KLK4 substrate. Mouse ephrin-B2 was then confirmed as a KLK4 substrate by in vitro incubation of recombinant mouse ephrin-B2 with active recombinant human KLK4. Cleavage products were visualised by SDS-PAGE, silver staining and Western blot and confirmed by N-terminal sequencing. RESULTS: At low molar ratios, KLK4 cleaved murine ephrin-B2 but other prostate-specific KLK family members (KLK2 and KLK3/PSA) were less efficient, suggesting cleavage was KLK4-selective. The primary KLK4 cleavage site in murine ephrin-B2 was verified and shown to correspond to one of the in silico predicted sites between extracellular domain residues arginine 178 and asparagine 179. Surprisingly, the highly homologous human ephrin-B2 was poorly cleaved by KLK4 at these low molar ratios, likely due to the 3 amino acid differences at this primary cleavage site. CONCLUSION: These data suggest that in in vivo mouse xenograft models, endogenous mouse ephrin-B2, but not human tumour ephrin-B2, may be a downstream target of cancer cell secreted human KLK4. This is a critical consideration when interpreting data from murine explants of human EphB4+/KLK4+ cancer cells, such as prostate cancer cells, where differential effects may be seen in mouse models as opposed to human clinical situations.