tbuckley/cabot-search huggingface dataset:
Targeting PI3K in Human Glioblastoma with PX-866, a small molecule PI3K inhibitor.
Authors: Dimpy Koul, Ruijun Shen, jennifer Edge, Eiji Ivado, Yasuko Kondo, Garth Powis, Lynn Kirkpatric, WK Yung
Journal: Cancer Research (2007)

278   Glioblastoma, the most malignant form of primary brain tumor, is refractory to conventional therapies, making the development of new, rational, targeted therapies an urgent necessity. The phosphatidylinositol-3-kinase (PI-3-kinase)/PTEN/Akt pathway is a survival signaling pathway that is activated in many types of advanced cancers including glioblastomas due to alterations in the PTEN tumor suppressor gene. This leads to increased proliferation, angiogenesis, and inhibition of apoptosis rendering the PI3K/PTEN pathway an attractive target for therapeutic development. Small molecules targeting various signaling nodes along the PTEN-PI3K-Akt pathway have been developed and are currently in different stages of testing. We demonstrate, herein, that a newly developed PI3K inhibitor PX866, a wortmannin analog with selectivity for p110 α, β and γ (ProlX Pharmaceuticals), effectively inhibits signaling through the PI3K/Akt cascade in U87, U251, LN229 glioma cells. PX866 blocked both basal and EGF-induced phosphorylation of Akt and downstream targets, including p70S6K1, TSC-2, and pS6. Treatment of all three glioma cell lines with PX866 showed 50% growth inhibition at 4-8uM concentrations at 48 h. The decrease in cell growth was correlated with G1 arrest characterized by decrease on cyclin D1 and decreased p-RB expression. In addition, PX866 induced autophagy- programmed cell death type-2 in U87 glioma cells in a dose dependent manner as shown by development of acidic vesicular organelles and the autophagosome membrane association of the microtubule-associated protein light chain 3 (LC-3), which are characteristic hallmarks of autophagy, while apoptotic cell death was not observed. PX866 also inhibited invasive and angiogenic capabilities of glioma cells in vitro. In vivo experiment with U87 SC xenograft demonstrated an 84% growth inhibition after 4 weeks treatment at an oral dose of 2.5mg/kg in a qod schedule. PX-866 increased the median survival of animals with i.c. U87 tumors from 31 to 38 days with inhibition of p-AKT and p-S6 as shown by IHC and reverse phase lysate array. Taken together, these data demonstrate PI3K inhibitor PX866 has significant activity in signal inhibition, cell cycle arrest, growth inhibition and autophagy in human glioblastoma in vitro and in vivo affirming that PI3K/Akt pathway is a highly promising molecular target for molecular therapeutics development for glioblastoma and other cancers with aberrant PTEN/PI3K expression.
Diagnostic performance of dedicated breast PET scanner with a ring detector
Authors: R. Hashimoto, S. Akashi-Tanaka, C. Watanabe, H. Masuda, K. Taruno, T. Takamaru, Y. Ide, T. Kuwayama, Y. Hirota, Y. Kobayashi, T. Sawada, M. Hirose, S. Nakamura
Journal: Annals of Oncology (2017)
Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses’ Health Study cohorts
Authors: Medha Barbhaiya, Sara K Tedeschi, Bing Lu, Susan Malspeis, David Kreps, Jeffrey A Sparks, Elizabeth W Karlson, Karen H Costenbader
Journal: Annals of the Rheumatic Diseases (2017)

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, subtyped according to clinical manifestations and autoantibodies. Evidence concerning cigarette smoking and SLE risk has been conflicting. We investigated smoking and SLE risk, overall and by anti-double stranded DNA (dsDNA) presence, in two prospective cohort studies.
GW28-e0603 The characteristics of patients with idiopathic ventricular fibrillation and evaluation of the efficacy with radiofrequency ablation versus ICD: a meta-analysis of individual participant data
Authors: Wenjia Guo, Jing Yang, Kun Li, Yajun Xue, Tingting Lv, Ping Zhang
Journal: Journal of the American College of Cardiology (2017)
Visualization of Peripheral Neuron Sensitization in a Surgical Mouse Model of Osteoarthritis by In Vivo Calcium Imaging
Authors: Rachel E. Miller, Yu Shin Kim, Phuong B. Tran, Shingo Ishihara, Xinzhong Dong, Richard J. Miller, Anne‐Marie Malfait
Journal: Arthritis & Rheumatology (2017)

To develop a method for analyzing sensory neuron responses to mechanical stimuli in vivo, and to evaluate whether these neuronal responses change after destabilization of the medial meniscus (DMM).DMM or sham surgery was performed in 10-week-old male C57BL/6 wild-type or Pirt-GCaMP3+/- mice. All experiments were performed 8 weeks after surgery. Knee and hind paw hyperalgesia were assessed in wild-type mice. The retrograde label DiI was injected into the ipsilateral knee to quantify the number of knee-innervating neurons in the L4 dorsal root ganglion (DRG) in wild-type mice. In vivo calcium imaging was performed on the ipsilateral L4 DRG of Pirt-GCaMP3+/- mice as mechanical stimuli (paw pinch, knee pinch, or knee twist) were applied to the ipsilateral hind limb.Eight weeks after surgery, mice subjected to DMM had more hyperalgesia in the knee and hind paw compared to mice subjected to sham surgery. Intraarticular injection of DiI labeled similar numbers of neurons in the L4 DRG of mice subjected to sham surgery and mice subjected to DMM. Increased numbers of sensory neurons responded to all 3 mechanical stimuli in mice subjected to DMM, as assessed by in vivo calcium imaging. The majority of responses in mice subjected to sham surgery and mice subjected to DMM were in small to medium-sized neurons, consistent with the size of nociceptors. The magnitude of responses was similar between mice subjected to sham surgery and mice subjected to DMM.Our findings indicate that increased numbers of small to medium-sized DRG neurons respond to mechanical stimuli 8 weeks after DMM surgery, suggesting that nociceptors have become sensitized by lowering the response threshold.
Case 31-2017
Authors: Marjorie A. Curran, Vandana L. Madhavan, Paul A. Caruso, David H. Ebb, Erik A. Williams
Journal: New England Journal of Medicine (2017)

A 19-month-old girl presented with failure to thrive. Growth had been normal until she was 9 months of age, when she weighed 7.0 kg. Over the next 10 months, she did not gain weight despite growing normally in length. She appeared happy and playful. A diagnosis was made.
Hepatitis C virus–induced tumor‐initiating cancer stem–like cells activate stromal fibroblasts in a xenograft tumor model
Authors: Reina Sasaki, Pradip Devhare, Ratna B. Ray, Ranjit Ray
Journal: Hepatology (2017)

Hepatitis C virus (HCV) often causes persistent infection and is an increasingly important factor in the etiology of fibrosis/cirrhosis and hepatocellular carcinoma, although the mechanisms for the disease processes remain unclear. We have shown previously that HCV infection generates an epithelial–mesenchymal transition state and tumor‐initiating cancer stem–like cells in human hepatocytes. In this study, we investigated whether HCV‐induced tumor‐initiating cancer stem–like cells when implanted into mice activate stromal fibroblasts. A number of fibroblast activation markers, including matrix metalloproteinase 2, were significantly increased at the mRNA or protein level in the xenograft tumors, suggesting the presence of tumor‐associated fibroblasts. Fibroblast activation markers of murine origin were specifically increased in tumor, suggesting that fibroblasts migrate to form stroma. Next, we demonstrated that conditioned medium from HCV‐infected human hepatocytes activates fibrosis‐related markers in hepatic stellate cells. We further observed that these HCV‐infected hepatocytes express transforming growth factor beta, which activates stromal fibroblast markers. Subsequent analysis suggested that anti–transforming growth factor beta neutralizing antibody, when incubated with conditioned medium from HCV‐infected hepatocytes, inhibits fibrosis marker activation in primary human hepatic stellate cells. Conclusion: HCV‐infected hepatocytes induce local fibroblast activation by secretion of transforming growth factor beta, and a preneoplastic or tumor state of the hepatocytes influences the network for the tumor‐associated fibroblast environment. (H epatology 2017;66:1766–1778)
Lack of evidence of isoniazid efficacy for the treatment of MDR/XDR-TB in the presence of the<i>katG</i>315T mutation
Authors: Dumitru Chesov, Nelly Ciobanu, Christoph Lange, Thomas Schön, Jan Heyckendorf, Valeriu Crudu
Journal: European Respiratory Journal (2017)

We are grateful for the response by E. Heldal to our correspondence. Similar to other reports [1] from the World Health Organization (WHO) Euro-Region we found that a high proportion (88%) of Mycobacterium tuberculosis strains from patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB) in the Republic of Moldova had a katG 315T mutation, which is strongly suggestive that high-dose isoniazid should not be part of a standardised treatment regimen for patients with MDR/XDR-TB in this country. Further studies are needed to address the possible benefits of high-dose isoniazid therapy adequately <http://ow.ly/XDcd30fiFeR>
Tick-borne encephalitis increasing in Sweden, 2011
Authors: Å Lundkvist, A Wallensten, S Vene, M Hjertqvist
Journal: Eurosurveillance (2011)

Until August, 161 cases of tick-borne encephalitis (TBE) were recorded in Sweden for 2011, leading to an incidence of 1.7 per 100,000 population. Fifty to 59 year-olds (24%) were most affected, 55% of the cases were males. An increase in TBE in Sweden has occurred in the last decade and might be explained by enlarged tick populations, more contact between TBE virus infected ticks and man, and also by growing awareness of the disease. Climatic conditions may have contributed to the increase.
Blood pressure response to CPAP treatment in subjects with obstructive sleep apnoea: the predictive value of 24-h ambulatory blood pressure monitoring
Authors: Anabel L. Castro-Grattoni, Gerard Torres, Montserrat Martínez-Alonso, Ferran Barbé, Cecilia Turino, Alicia Sánchez-de-la-Torre, Anunciacion Cortijo, Joaquin Duran-Cantolla, Carlos Egea, Gonzalo Cao, Manuel Sánchez-de-la-Torre
Journal: European Respiratory Journal (2017)

The reduction in blood pressure (BP) with continuous positive airway pressure (CPAP) is modest and highly variable. In this study, we identified the variables that predict BP response to CPAP. 24-h ambulatory BP monitoring (ABPM), C-reactive protein (CRP), leptin, adiponectin and 24-h urinary catecholamine were measured before and after 6 months of CPAP in obstructive sleep apnoea (OSA) patients. Overall, 88 middle-aged, obese male patients with severe OSA (median apnoea–hypopnoea index 42 events·h −1 ) were included; 28.4% had hypertension. 62 patients finished the study, and 60 were analysed. The daytime diastolic BP (−2 mmHg) and norepinephrine (−109.5 nmol·day -1 ) were reduced after CPAP, but no changes in the 24-h BP, night-time BP, dopamine, epinephrine, CRP, leptin or adiponectin were detected. The nocturnal normotension was associated with an increased night-time-BP (+4 mmHg) after CPAP, whereas nocturnal hypertension was associated with a reduction of 24-h BP (−3 mmHg). A multivariate linear regression model showed differential night-time BP changes after CPAP. Specifically, low night-time heart rate (&lt;68 bpm) and BP dipper profile were associated with increased night-time BP and new diagnosis of nocturnal hypertension. Our results suggest that nocturnal hypertension, circadian BP pattern and night-time heart rate could be clinical predictors of BP response to CPAP and support the usefulness of 24-h ABPM for OSA patients before treatment initiation. These results need to be confirmed in further studies.
GW28-e1121 Six Versus 12 Months of Dual Antiplatelet Therapy After Implantation of Biodegradable Polymer Sirolimus-Eluting Stent In Elder Patients: A subgroup analysis of the I-LOVE-IT 2 Trial
Authors: Jing Yang, Yi Li, Heyang Wang, Jing Li, Yushan Chen, Yaling Han, Wang Shuang
Journal: Journal of the American College of Cardiology (2017)
Emergenza di un nuovo ceppo di MRSA acquisito nella comunità in Germania
Authors: W Witte, C Cuny, B Strommenger, C Braulke, D Heuck
Journal: Eurosurveillance (2004)

L'analisi di uno Staphylococcus aureus meticillino-resistente acquisito nella comunita (c-MRSA) produttore di leucocidina Panton-Valentine (PVL) ha rivelato un unico pattern di macrorestrizione- SmaI, diverso da quello dei ceppi epidemici nosocomiali. Questo pattern molecolare corrisponde a quelli mostrati dai ceppi c-MRSA di altri paesi dell'Unione Europea. Tutti gli isolati hanno mostrato resistenza all'acido fusidico, che e codificato dal gene far-1. Dai dati sulla diffusione geografica e data di apparizione, sembra che questi ceppi siano emersi in Germania nella seconda meta del 2002, per cui e probabile che si siano piu ampiamente diffusi gia prima. L'emergenza di MRSA con resistenza all'acido fusidico e un primo segno di emergenza di un clone MRSA PVL-positivo.
Micro-RNA 33b inhibits breast cancer migration and invasion through regulating epithelial-mesenchymal transition in HER2 positive breast cancer cell lines
Authors: B. Pattanayak, A. Adam-Artigues, E. Tormo, I. Garrido, B. Pineda, A. Rovira, J. Albanell, F. Rojo, A. Lluch, P. Eroles
Journal: Annals of Oncology (2017)
DNA repair gene panel mutations in young onset and aggressive vs non aggressive prostate cancer cases in the UK
Authors: R. Eeles, E. Saunders, S. Wakerell, I. Whitmore, C. Cieza-Borrella, K. Govindasami, T. Dadaev, Z. Kote-Jarai, D. Leongamornlert
Journal: Annals of Oncology (2017)
Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer’s disease
Authors: Yue Wang, Zheng Wu, Yu-Ting Bai, Gang-Yi Wu, Gong Chen
Journal: Molecular Neurodegeneration (2017)

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is the major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia. However, whether Gad67 is involved in AD pathology has not been well studied. Here, we investigate the functional role of GAD67 in an AD mouse model with Gad67 haploinsufficiency that is caused by replacing one allele of Gad67 with green fluorescent protein (GFP) gene during generation of GAD67-GFP mice.To genetically reduce GAD67 in AD mouse brains, we crossed the Gad67 haploinsufficient mice (GAD67-GFP+/-) with 5xFAD mice (harboring 5 human familial AD mutations in APP and PS1 genes) to generate a new line of bigenic mice. Immunostaining, ELISA, electrophysiology and behavior test were applied to compare the difference between groups.We found that reduction of GAD67 resulted in a significant decrease of amyloid β production in 5xFAD mice. Concurrently, the abnormal astrocytic GABA and tonic GABA currents, as well as the microglial reactivity were significantly reduced in the 5xFAD mice with Gad67 haploinsufficiency. Importantly, the olfactory memory deficit of 5xFAD mice was rescued by Gad67 haploinsufficiency.Our results demonstrate that GAD67 plays an important role in AD pathology, suggesting that GAD67 may be a potential drug target for modulating the progress of AD.
Sirt1 and Parp1 as epigenome safeguards and microRNAs as SASP-associated signals, in cellular senescence and aging
Authors: Seyedhossein Hekmatimoghaddam, Ali Dehghani Firoozabadi, Mohamad Reza Zare-Khormizi, Fatemeh Pourrajab
Journal: Ageing Research Reviews (2017)
CASP9 c.-1339A&gt;G and CASP3 c.-1191A&gt;G polymorphisms in susceptibility and outcome of head and neck squamous cell carcinoma
Authors: E.F.D. Costa, L. Lopes-Aguiar, G.A.S. Nogueira, T.R.P. Lima, V.T. Liutti, F. Leal, V.C.A. Santos, J.A. Rinck-Junior, G.J. Lourenço, C.S.P. Lima
Journal: Annals of Oncology (2017)
The diagnosis is in the rings
Authors: Saskia Ingen-Housz-Oro, Nicolas Ortonne, Olivier Chosidow
Journal: BMJ (2017)

A 62 year old man reported a history of recurrent oral ulcers, sometimes with laryngitis, and conjunctivitis. He consulted his doctor in 2011 for acute onset fever (39°C), odynophagia, and laryngitis lasting two days, and was prescribed ibuprofen and clarithromycin. Two days later, conjunctivitis, oral mucous membrane erosions, and cutaneous lesions appeared. The patient was hospitalised on suspicion of Stevens-Johnson syndrome.

Dermatological examination showed several target lesions on the trunk, lower limbs, and scrotum (fig 1, 2⇓), conjunctivitis (fig 3⇓), and diffuse erosions of the mucous membranes involving the mouth (palate, tongue, buccal mucosa, and lips) (fig 4⇓), and glans. Examination of ear, nose, and throat showed diffuse nasal erosion, crusts, and epiglottal erosion. The patient had no dysuria, pain with defecation, or pulmonary symptoms. His general condition was poor, with fever, fatigue, and difficulty eating.



Fig 1  Disseminated target lesions 





Fig 2  Eye involvement with conjunctivitis 





Fig 3  Lip and tongue erosions





Fig 4  Lesions with three rings



Blood examination showed normal blood cell counts, increased C reactive protein (160 mg/L), negative herpes simplex virus culture from the mouth and skin, and negative HIV, herpes simplex virus, Mycoplasma pneumoniae , and Chlamydia pneumoniae serologies. Skin biopsy showed a dense lichenoid lymphocytic infiltrate with necrotic keratinocytes in the basal layer. Direct and indirect immunofluorescence tests were both negative.



### 1. What is the diagnosis and what clinical findings suggest this? 

#### Short answer

A diagnosis of erythema multiforme major …
Cobertura de vacunación en la Unión Europea
Authors: N Guérin, C Roure
Journal: Eurosurveillance (1997)

Los 15 paises de la Union Europea han ratificado el quinto objetivo del programa Salud para todos en el ano 2000 de la OMS Europa, que dice: “En el ano 2000, no deberia haber casos de poliomielitis, difteria, tetanos neonatal, sarampion, parotiditis ni de rubeola congenita originados en la Region y deberia haber una reduccion importante en la incidencia y consecuencias negativas de otras enfermedades transmisibles, en particular la infeccion por HIV”.
PIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer
Authors: S.S. Kumar, G. Dougall, A-L. Vallier, L. Jones, W. Qian, E. Provenzano, C. Caldas, P. Pantziarka, J. Carroll, R. Baird
Journal: Annals of Oncology (2017)
Comparison of prognostic models for hepatocellular carcinoma (HCC) in patients treated with the sorafenib: Results from a Canadian multi-center HCC database.
Authors: Haider Samawi, Hao-Wen Sim, Kelvin K. Chan, Mohammed Abdullah Alghamdi, Richard M. Lee-Ying, Jennifer J. Knox, Parneet Gill, Adriana Romagnino, Eugene Batuyong, Yoo-Joung Ko, Winson Y. Cheung, Vincent C. Tam
Journal: Journal of Clinical Oncology (2017)

e15653 Background: Several staging systems and models (TNM, BCLC, Okuda, CLIP and ALBI) have been developed to estimate the prognosis of patients with HCC. Most of these were developed prior to the prevalent use of sorafenib. The purpose of this study was to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib. Methods: Patients who received sorafenib for the treatment of HCC between January 1, 2008 and June 30, 2015 in the provinces of British Columbia and Alberta, as well as Princess Margaret Cancer Centre and Sunnybrook Odette Cancer Centre in Toronto, Ontario were included. Survival outcomes for each model were assessed with Kaplan-Meier (KM) curves and compared with the log-rank test. Time dependent area under the curve (t-AUC) was used to test the discriminatory power of each model (higher t-AUC = more discriminatory power). Akaike information criterion (AIC), a measure of goodness-of fit of models while penalizing overly complex models, was used to compare the models (lower AIC = better model). Results: A total of 681 patients were included in this analysis. Median age was 64 years (range 8-91). Majority were males (80%), had a Child-Pugh score A (86%), ECOG performance status 0 (30%) and 1 (60%). 37% of patients were of East Asian ethnicity. Most common etiology for liver disease was hepatitis B (33%) and C (29%). At start of sorafenib, most patients were BCLC stage C (92%) and TNM stage IV (61%). The median overall survival for the entire cohort was 9.2 months (95% CI 8-10.4). See table below for t-AUC and AIC results. Conclusions: According to ourlarge multi-center study, CLIP appears to be the most informative in predicting survival in HCC patients treated with sorafenib. Prospective studies are needed to determine its role in patient selection for clinical trials and in guiding treatment decisions. The TNM and BCLC staging systems were the least useful in predicting survival in this population. [Table: see text]
PRO-002, a phase Ib dose-escalation study of NUC-1031 with carboplatin for recurrent ovarian cancer
Authors: S.P. Blagden, A. Sukumaran, L. Spiers, V.K. Woodcock, A. Lipplaa, S. Nicum, C. Gnanaranjan, D.J. Harrison, E. Ghazaly
Journal: Annals of Oncology (2017)
One to two hours of exercise each week nearly halves long term risk of depression, finds study
Authors: Susan Mayor
Journal: BMJ (2017)

Exercising for one to two hours every week reduces the risk of developing depression by 44% compared with no regular leisure time physical activity, a large follow-up study has found.1

Several surveys have previously shown a cross sectional association between exercise and lower rates of depression and anxiety. But the possibility of reverse causality, in which low mood could lead to reduced levels of exercise, has limited the interpretation of these findings.

The new study prospectively analysed levels of exercise and rates of newly diagnosed depression and anxiety …
Epidemia di tossinfezione alimentare da Salmonella enteritidis causata da un formaggio fresco commerciale
Authors: M. G. Panico, F Primiano, F Nappi, F Attena
Journal: Eurosurveillance (1999)

Tra il 30 Giugno e il 2 Luglio 1998, nove casi di sospetta tossinfezione alimentare sono stati segnalati da tre ospedali al Servizio di Epidemiologia e Prevenzione (SEP) della ASL NA 4. Il SEP ha immediatamente avviato le indagini sul focolaio epidemico.
Synchronous vs metachronous metastatic disease: Impact of time to metastasis on outcome in metastatic renal cell carcinoma patients treated with targeted therapy
Authors: F. Donskov, W. Xie, J.C. Wells, A.P. Fraccon, F. Pasini, C. Porta, I. Stukalin, J.L. Lee, A. Bamias, T. Yuasa, I.D. Davis, C. Pezaro, R. Kanesvaran, G.A. Bjarnason, H-W. Sim, N. Agarwal, C.K. Kollmannsberger, C.M. Canil, T.K. Choueiri, D.Y.C. Heng
Journal: Annals of Oncology (2017)
Unilateral Plantar Erythema Nodosum in Sarcoidosis
Authors: Axel J. Hueber, Georg Schett, Bernhard Manger
Journal: Arthritis & Rheumatology (2017)

A 32-year old male Caucasian patient presented with mild exertional dyspnea, pain and swelling of both ankles, and general malaise. On examination symmetrical arthritis of both ankles and a vivid nodular erythema with slight pain on pressure was detected on the sole of the right foot (A). A therapy with ibuprofen had not led to any improvement of symptoms.

This article is protected by copyright. All rights reserved.