Observation of Gapped Topological Surface States and Isolated Surface Resonances in PdTe2 Ultrathin Films.

The superconductor PdTe2 is known to host bulk Dirac bands and topological surface states. The coexistence of superconductivity and topological surface states makes PdTe2 a promising platform for exploring topological superconductivity and Majorana bound states. In this work, we report the spectroscopic characterization of ultrathin PdTe2 films with thickness down to three monolayers (ML). In the 3 ML PdTe2 film, we observed spin-polarized surface resonance states, which are isolated from the bulk bands due to the quantum size effects. In addition, the hybridization of surface states on opposite faces leads to a thickness-dependent gap in the topological surface Dirac bands. Our photoemission results show clearly that the size of the hybridization gap increases as the film thickness is reduced. The observation of isolated surface resonances and gapped topological surface states sheds light on the applications of PdTe2 quantum films in spintronics and topological quantum computation.

A systems framework for national assessment of climate risks to infrastructure.

Extreme weather causes substantial adverse socio-economic impacts by damaging and disrupting the infrastructure services that underpin modern society. Globally, $2.5tn a year is spent on infrastructure which is typically designed to last decades, over which period projected changes in the climate will modify infrastructure performance. A systems approach has been developed to assess risks across all infrastructure sectors to guide national policy making and adaptation investment. The method analyses diverse evidence of climate risks and adaptation actions, to assess the urgency and extent of adaptation required. Application to the UK shows that despite recent adaptation efforts, risks to infrastructure outweigh opportunities. Flooding is the greatest risk to all infrastructure sectors: even if the Paris Agreement to limit global warming to 2°C is achieved, the number of users reliant on electricity infrastructure at risk of flooding would double, while a 4°C rise could triple UK flood damage. Other risks are significant, for example 5% and 20% of river catchments would be unable to meet water demand with 2°C and 4°C global warming respectively. Increased interdependence between infrastructure systems, especially from energy and information and communication technology (ICT), are amplifying risks, but adaptation action is limited by lack of clear responsibilities. A programme to build national capability is urgently required to improve infrastructure risk assessment.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'.

Economic impact of 21-gene recurrence score testing on early-stage breast cancer in Ireland.

The 21-gene test is a validated multi-gene diagnostic test that predicts chemotherapy (CT) benefit in oestrogen receptor positive (ER+), lymph node-negative (N0) breast cancer (BC) patients (pts). Ireland was the first public health care system to reimburse this test in Europe. Study objectives were to assess the impact of this test on decision-making and to analyse the economic impact of testing. Between October 2011 and February 2013, a national, retrospective, cross-sectional observational study of ER+, N0 BC pts tested with the 21-gene test was conducted. Surveyed breast medical oncologists, provided the assumption for the decision impact analysis that grade (G) 1 pts would not have received CT before testing and G2/3 pts would have received CT before testing. Descriptive statistical analyses were performed. 592 pts were identified; Low, intermediate and high recurrence score were identified in 53, 36 and 10 % pts, respectively. 384 (70 %) pts had G2, 129 (22 %) G3 and 76 (13 %) G1 tumours. Post testing, 345 pts (59 %) experienced a change in CT decision; 339 changed to hormone therapy alone and 6 advised to receive CT. 172 (30 %) pts received CT, 12 (3.9 %) of pts with low scores, 108 (50.9 %) of intermediate risk and 50 (90.9 %) of pts with high risk scores. Net reduction in CT use was 58 % and net savings achieved were €793,565. Since public reimbursement, the introduction of the 21-gene test has resulted in a significant reduction in chemotherapy administration and cost savings for the Irish public healthcare system.

Ipilimumab-induced toxicities and the gastroenterologist.

Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors.

Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome: a meta-analysis of 34 studies.

AIMS Guidelines suggest that patients should discontinue clopidogrel for 5 days prior to coronary artery bypass grafting (CABG) where possible. Those with acute coronary syndrome (ACS) are at elevated risk of further myocardial infarction (MI) and death without clopidogrel. This meta-analysis aims to determine the risk of CABG in ACS patients while continuing clopidogrel. METHOD AND RESULTS Thirty-four studies with 22 584 patients undergoing CABG were assessed. Patients with recent clopidogrel exposure (CL) were compared with those without recent clopidogrel (NC). Although mortality is increased in CL vs. NC [odds ratio (OR) 1.6, 95% CI 1.30-1.96, P < 0.00001], it is influenced by the ACS status and case urgency in these mainly non-randomized studies. In ACS patients, there is no significant difference in mortality (OR 1.44, 95% CI 0.97-2.1, P= 0.07) or in postoperative MI (OR 0.57, 95% CI 0.31-1.07, P = 0.08) and stroke rates (OR 1.23, 95% CI 0.66-2.29, P = 0.52). Combined major adverse cardiovascular event (stroke, MI, and death) was not different in the two groups (OR 1.10, 95% CI 0.87-1.41, P= 0.43). Reoperation rates are elevated on clopidogrel but have reduced over time, and were specifically not different in ACS patients (OR 1.5, 95% CI 0.88-2.54, P= 0.13). CONCLUSION Previous studies focused on surrogate endpoints and compared higher risk ACS patients with elective cases. However, many patients have safely undergone CABG on clopidogrel and surgical expertise is growing. Multinational trials are required to fully determine the balance of ischaemia and bleeding. While results are awaited we suggest ACS patients requiring urgent CABG proceed with surgery without delay for a clopidogrel-free period.

An approach to evaluating scrotal skin-based lesions: A case report of Basal Cell Carcinoma of the Scrotum in patient with multiple risk factors.

Basal cell carcinoma (BCC) is rare on non-sun exposed skin such as the scrotum and thus diagnosis is often delayed. This case highlights an approach to scrotal skin lesions, risk factors and diagnostic features of BCC. Importantly, scrotal BCCs are more likely to metastasise than non-scrotal BCCs. Management should consist of wide local excision and recommended follow up with thorough clinical history, skin examination and imaging in high-risk patients.

16 T diffusion microimaging of fixed prostate tissue: preliminary findings.

Diffusion tensor microimaging was used to investigate the water diffusion properties of formalin-fixed prostate tissue at spatial resolution approaching the cellular scale. Diffusion tensor microimaging was performed at 16.4 T with 40 µm isotropic voxels. Diffusion tensor microimaging clearly demonstrated distinct microscopic diffusion environments and tissue architecture consistent with that seen on light microscopy of the same tissue. The most restricted diffusion environment is the secretory epithelial cell layer (voxel bulk mean diffusivity, D = 0.4 ± 0.1 × 10(-3) mm(2)/sec). Diffusion in the fibromuscular stromal matrix is relatively less restricted (D = 0.7 ± 0.1 × 10(-3) mm(2)/sec). In tumor tissue (Gleason pattern 4+4) distinct glandular and ductal structures are absent in the diffusion-weighted images and diffusivity is low (D = 0.5 ± 0.1 × 10(-3) mm(2)/sec). Distinct stromal and epithelial diffusion compartments are the most likely origin of biexponential diffusion decay observed in vivo.

Epithelioid sarcoma of the penis: A penile sparing approach, and long-term implications.

A 33-year-old male presented with a one-centimetre lesion at the penoscrotal junction which was excised and revealed to be an epithelioid sarcoma (ES). A wide local excision of the lesion and subsequent neoadjuvant radiotherapy followed, with transposition of the patient's testicles laterally to protect fertility. At 3-year follow-up, the patient has no local or distant recurrence but does have a low sperm count. The patient has also had intermittent haematospermia since his treatment for which a cause has yet to be identified. This case highlights that ES of the penis can be managed successfully with surgical excision and local radiotherapy.

Painful ovulation in a 46,XX SRY -ve adult male with SOX9 duplication.

46,XX disorders of sexual development (DSDs) occur rarely and result from disruptions of the genetic pathways underlying gonadal development and differentiation. We present a case of a young phenotypic male with 46,XX SRY-negative ovotesticular DSD resulting from a duplication upstream of SOX9 presenting with a painful testicular mass resulting from ovulation into an ovotestis. We present a literature review of ovulation in phenotypic men and discuss the role of SRY and SOX9 in testicular development, including the role of SOX9 upstream enhancer region duplication in female-to-male sex reversal. LEARNING POINTS: In mammals, the early gonad is bipotent and can differentiate into either a testis or an ovary. SRY is the master switch in testis determination, responsible for differentiation of the bipotent gonad into testis.SRY activates SOX9 gene, SOX9 as a transcription factor is the second major gene involved in male sex determination. SOX9 drives the proliferation of Sertoli cells and activates AMH/MIS repressing the ovary. SOX9 is sufficient to induce testis formation and can substitute for SRY function.Assessing karyotype and then determination of the presence or absence of Mullerian structures are necessary serial investigations in any case of DSD, except for mixed gonadal dysgenesis identified by karyotype alone.Treatment is ideal in a multidisciplinary setting with considerations to genetic (implications to family and reproductive recurrence risk), psychological aspects (sensitive individualized counseling including patient gender identity and preference), endocrinological (hormone replacement), surgical (cosmetic, prophylactic gonadectomy) fertility preservation and reproductive opportunities and metabolic health (cardiovascular and bones).

Androgen receptor actions modify skin structure and chemical carcinogen-induced skin cancer susceptibility in mice.

Men are significantly more susceptible to non-melanoma skin cancers than women, and the androgen receptor (AR) is widely distributed in the skin, suggesting a ro\le for androgens acting via AR. Therefore, we explored the role of androgen action via AR in susceptibility to experimental 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis and in skin structural development of male and female mice. We demonstrate that both the male gender and androgen action via AR modify the susceptibility to carcinogen-induced skin cancer, but the effect depends on the carcinogenesis model used. Following systemic DMBA exposure, males were significantly (p < 0.05) more susceptible to DMBA-induced experimental skin cancer than females and AR inactivation significantly delayed cancer detection in both male (median time to palpable tumours 19 vs. >35 weeks (wild-type [WT] vs. AR knockout [ARKO], p < 0.001) and female (27 vs. >35 weeks, p = 0.008)) mice. In contrast, following DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multistage local skin carcinogenesis, AR inactivation protected against formation of DMBA-induced skin cancers in both male and female mice. The skin structure was also affected by gender effect as well as the AR inactivation and could at least partly explain the different responses between the carcinogenesis models (systemic vs. topical). In addition, AR inactivation modified Cox-1 and Cox-2 expression in the skin, suggesting possible molecular mechanism for the AR effect on skin. Finally, some gender differences are observed also in ARKO mice insensitive to androgens, suggesting that factors other than androgens also play a role in gender-dependent skin carcinogenesis.

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer.

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas.

BACKGROUND: The prognosis for patients with localized primary cutaneous melanoma is known to depend principally on tumor thickness, and to a lesser extent on ulcerative state and Clark level. We have recently found in an analysis of 3661 patients that tumor mitotic rate (TMR) is also an important prognostic parameter, ranking second only to tumor thickness. However, few studies have assessed the accuracy and reproducibility with which these features of a melanoma are recorded by histopathologists. AIM: To assess interobserver reproducibility of major pathologic prognostic parameters in cutaneous melanoma. METHODS: Single hematoxylin and eosin-stained slides of 69 dermally invasive primary cutaneous melanomas were circulated among six pathologists with differing experience in the assessment of melanocytic tumors. The observers independently determined the tumor thickness, Clark level of invasion, ulcerative state, and TMR for each lesion. Intraclass correlation coefficients and kappa scores for multiple ratings per subject were calculated. RESULTS: The intraclass correlation coefficients were 0.96 for tumor thickness and 0.76 for TMR. The kappa scores were 0.83 for ulcerative state and 0.60 for Clark level. These results indicated excellent agreement among the pathologists for measurements of tumor thickness, ulcerative state, and TMR and fair to good agreement for Clark level. CONCLUSIONS: Appropriately trained and experienced histopathologists can assess prognostically important features of melanomas accurately and reproducibly. Given our recent finding of the significance of TMR in determining prognosis, it is important that this feature be assessed by a standardized method and documented for all primary cutaneous melanomas.

Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors.

Hormones, notably estrogens, are pivotal in the origins of breast cancer but androgenic effects, while supported by persistence of AR expression in breast cancers, remain controversial. This study determined the role of the androgen actions via androgen receptor (AR) in experimental mammary cancer. Androgen-resistant female and male mice (ARKO) were generated using Cre/loxP technique and featured a global AR inactivation. The effect of AR inactivation and influence of genetic background on 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis was confirmed using two separate ARKO models with different genetic backgrounds. The onset of palpable mammary tumors was significantly faster in ARKO females (median time 22 vs 34 weeks, respectively; (p = 0.0024; multivariate Cox regression) compared to WT and independent of the mouse genetic background. The cumulative incidence at 9 months was 81 ± 10% [mean ± SE] for ARKO compared to 50 ± 13% in WT females. The increased DMBA susceptibility of ARKO females was associated with a higher epithelial proliferation index but not with major structural or receptor (estrogen or progesterone) expression differences between the virgin WT or ARKO female mammary glands. AR inactivation allowed substantial ductal extension in ARKO males while WT males displayed only rudimentary epithelial branches or complete regression of epithelial structures. Yet, DMBA did not induce epithelial mammary tumors in WT or ARKO males, demonstrating that AR inactivation alone is insufficient to promote mammary tumors. These results demonstrate that AR inactivation accelerates mammary carcinogenesis in female mice exposed to the chemical carcinogen DMBA regardless of mouse genetic background but require prior exposure to endogenous ovarian hormones.

Transformation and progression of Waldenström's macroglobulinemia following cladribine therapy in two cases: natural evolution or iatrogenic causation?

We report two cases of Waldenström's macroglobulinemia with an unusual aggressive transformation following treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA), a purine analogue. The first patient developed transformation to a diffuse large-cell non-Hodgkin lymphoma, while the second developed extensive extramedullary involvement. Both patients displayed rapid progression following transformation and were refractory to chemotherapy. Both patients were pretreated with multiple courses of prednisone and chlorambucil, and transformation occurred shortly after therapy with cladribine. We propose that immune suppression from alkylating agents and purine analogues may have contributed to the unusual progression, resulting in a dismal outcome.