In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.

Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21- Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT- 61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer

Pelvic floor muscle behavior during Valsalva leak point pressure measurement in males and females affected by stress urinary incontinence.

PURPOSE: We evaluated pelvic floor muscle (PFM) behavior during Valsalva leak point pressure (VLPP) measurement in males and females affected by stress urinary incontinence and investigated whether VLPP results are influenced by PFM contraction. MATERIALS AND METHODS: A total of 25 females and 14 males underwent surface electromyographic (EMG) recording of PFM activity while performing VLPP. We investigated 2 conditions, VLPP during spontaneous strain (test A), and with simultaneous relaxation of the pelvic floor (test B). We analyzed average EMG activity (microV) at rest and during VLPP in tests A and B, the increasing EMG activity during tests A and B (the difference between average EMG activity during tests A and B and at rest), and the mean duration (seconds) of EMG activity during tests A and B. RESULTS: We detected a significant increase in EMG activity during tests A and B as compared to activity at rest (p <0.0001). Increasing EMG activity during test B was significantly reduced in females (p <0.05) but not in males. During test A patients reporting urinary incontinence showed a significantly lower EMG activity than that of continent patients (p <0.05). A significant reduction in maximum abdominal pressure was detected in test B compared to test A, but there was no difference in VLPP values between tests A and B. CONCLUSIONS: PFM activity significantly increases during VLPP measurement. Eliminating muscular contraction of the pelvic floor does not significantly alter VLPP results

A prospective evaluation of survivorship of asymptomatic degenerative rotator cuff tears

BACKGROUND: The purpose of this prospective study was to report the long-term risks of rotator cuff tear enlargement and symptom progression associated with degenerative asymptomatic tears. METHODS: Subjects with an asymptomatic rotator cuff tear in one shoulder and pain due to rotator cuff disease in the contralateral shoulder enrolled as part of a prospective longitudinal study. Two hundred and twenty-four subjects (118 initial full-thickness tears, fifty-six initial partial-thickness tears, and fifty controls) were followed for a median of 5.1 years. Validated functional shoulder scores were calculated (visual analog pain scale, American Shoulder and Elbow Surgeons [ASES], and simple shoulder test [SST] scores). Subjects were followed annually with shoulder ultrasonography and clinical evaluations. RESULTS: Tear enlargement was seen in 49% of the shoulders, and the median time to enlargement was 2.8 years. The occurrence of tear-enlargement events was influenced by the severity of the final tear type, with enlargement of 61% of the full-thickness tears, 44% of the partial-thickness tears, and 14% of the controls (p < 0.05). Subject age and sex were not related to tear enlargement. One hundred subjects (46%) developed new pain. The final tear type was associated with a greater risk of pain development, with the new pain developing in 28% of the controls, 46% of the shoulders with a partial-thickness tear, and 50% of those with a full-thickness tear (p < 0.05). The presence of tear enlargement was associated with the onset of new pain (p < 0.05). Progressive degenerative changes of the supraspinatus muscle were associated with tear enlargement, with supraspinatus muscle degeneration increasing in 4% of the shoulders with a stable tear compared with 30% of the shoulders with tear enlargement (p < 0.05). Nine percent of the shoulders with a stable tear showed increased infraspinatus muscle degeneration compared with 28% of those in which the tear had enlarged (p = 0.07). CONCLUSIONS: This study demonstrates the progressive nature of degenerative rotator cuff disease. The risk of tear enlargement and progression of muscle degeneration is greater for shoulders with a full-thickness tear, and tear enlargement is associated with a greater risk of pain development across all tear types. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence

Evaporite sinkholes of the Friuli Venezia Giulia region (NE Italy)

Sinkholes are common in the Friuli Venezia Giulia (FVG) Region (NE Italy), where the presence of karstifiable rocks favours their occurrence accelerated by intense rainfalls. Their existence has been reported since the end of the 1800s along the Tagliamento Valley, in correspondence with the mantled evaporites (gypsum). Furthermore, tens of evaporite sinkholes have been documented on the reliefs adjacent to the village of Sauris and along the narrow W\u2013Eoriented valleys, where regional faults have played a major role in their spatial distribution. This paper reports for the first time an inventory of the sinkholes affecting the evaporites of the FVG Region. These phenomena were mapped and categorised using a genetic classification. The main output is an A0-format map, which incorporates a 1:50,000 scale Sinkhole Inventory Map (SIM). The SIM encompasses 552 sinkholes. The cover suffosion sinkholes are the most abundant, followed by bedrock collapses. There is a clear prevalence of the circular shape (65%) over other shapes. Diameters are 1\u2013140 m, with depths ranging 0.1\u201340 m with a mean value of 4.5 m. The SIM can motivate regional planning authorities to perform further investigations aimed to understand the geomorphological evolutions of these phenomena

T.E.A. Study: three-day ertapenem versus three-day Ampicillin-Sulbactam.

Background: Intra-abdominal infections are one of the most common infections encountered by a general surgeon. However, despite this prevalence, standardized guidelines outlining the proper use of antibiotic therapy are poorly defined due to a lack of clinical trials investigating the ideal duration of antibiotic treatment. The aim of this study is to compare the efficacy and safety of a three-day treatment regimen of Ampicillin-Sulbactam to that of a three-day regimen of Ertapenem in patients with localized peritonitis ranging from mild to moderate severity. Methods: This study is a prospective, multi-center, randomized investigation performed in the Department of General, Emergency, and Transplant Surgery of St. Orsola-Malpighi University Hospital in Bologna, Italy. Discrete data were analyzed using the Chi-squared and Fisher exact tests. Differences between the two study groups were considered statistically significant for p-values less than 0.05. Results: 71 patients were treated with Ertapenem and 71 patients were treated with Ampicillin-Sulbactam. The two groups were comparable in terms of age and gender as well as the site of abdominal infection. Post-operative infection was identified in 12 patients: 10 with wound infections and 2 with intra-abdominal infections. In the Ertapenem group, 69 of the 71 patients (97%) were treated successfully, while the therapy failed in 2 cases (3%). Therapy failures were more frequent in the Unasyn group, amounting to 10 of 71 cases (p = 0.03). Conclusion: According to these preliminary findings, the authors conclude that a three-day Ertapenem treatment regimen is the most effective antibiotic therapy for patients with localized intra-abdominal infections ranging from mild to moderate severity

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Use of domesticated pigs by Mesolithic hunter-gatherers in northwestern Europe

Acknowledgements We thank the Archaeological State Museum Schleswig-Holstein, the Archaeological State Offices of Brandenburg, Lower Saxony and Saxony and the following individuals who provided sample material: Betty Arndt, Jo¨rg Ewersen, Frederick Feulner, Susanne Hanik, Ru¨diger Krause, Jochen Reinhard, Uwe Reuter, Karl-Heinz Ro¨hrig, Maguerita Scha¨fer, Jo¨rg Schibler, Reinhold Schoon, Regina Smolnik, Thomas Terberger and Ingrid Ulbricht. We are grateful to Ulrich Schmo¨lcke, Michael Forster, Peter Forster and Aikaterini Glykou for their support and comments on the manuscript. We also thank many institutions and individuals that provided sample material and access to collections, especially the curators of the Museum fu¨r Naturkunde, Berlin; Muse´um National d0 Histoire Naturelle, Paris; Smithsonian Institution, National Museum of Natural History, Washington D.C.; Zoologische Staatssammlung, Mu¨nchen; Museum fu¨r Haustierkunde, Halle; the American Museum of Natural History, New-York. This work was funded by the Graduate School ‘Human Development in Landscapes’ at Kiel University (CAU) and supported by NERC project Grant NE/F003382/1. Radiocarbon dating was carried out at the Leibniz Laboratory, CAU. This work is licensed under a Creative Commons AttributionNonCommercial-NoDerivs 3.0 Unported License.Peer reviewedPublisher PD

THE CHANGING PACE OF INSULAR LIFE : 5000 YEARS OF MICROEVOLUTION IN THE ORKNEY VOLE (MICROTUS ARVALIS ORCADENSIS)

Peer reviewe

Catching allergy by a simple questionnaire

Background: Identifying allergic rhinitis requires allergy testing, but the first-line referral for rhinitis are usually primary care physicians (PCP), who are not familiar with such tests. The availability of easy and simple tests to be used by PCP to suggest allergy should be very useful. Methods: The Respiratory Allergy Prediction (RAP) test, based on 9 questions and previously validated by a panel of experts, was evaluated in this study. Results: An overall number of 401 patients (48.6% males, age range 14-62 years) with respiratory symptoms was included. Of them, 89 (22.2%) showed negative results to SPT, while 312 (77.8%) had at least one positive result to SPT. Cohen's kappa coefficient showed that all questions had an almost perfect excellent agreement between pre and post-test. The algorithm of decision-tree growth Chi-squared Automatic Interaction Detector showed that answering yes to the question 4 (Your nasal/ocular complains do usually start or worsen during the spring?), 6 (Did you ever had cough or shortness of breath, even during exercise?) and 8 (Do you use nasal sprays frequently?) gave a probability to have a positive SPT of 85%. Conclusions: These findings show that RAP test can be proposed as an useful tool to be used by physician other than allergists when evaluating patients with rhinitis, suggesting the need of allergy testing