tbuckley/cabot-search huggingface dataset:
Clarity is needed on plans for digital NHS, says think tank
Authors: Jacqui Thornton
Journal: BMJ (2016)

The government and NHS leaders must set out a clear and compelling plan for expanding the use of digital technology to avoid losing the commitment of clinicians, the King’s Fund has said.

Digital technology can transform how patients engage with services, drive improvements in efficiency and care coordination, and help people manage their health and wellbeing, the think tank said in its report, A Digital NHS? 1

However, it said that expectations might have been set too high amid financial and operational pressures and that there was a lack of clarity about the funding available to support the work.

The …
Spleen Dimensions Evaluated by Ultrasound are Inversely Associated with Lysosomal Acid Lipase Activity in Patients with Non-Alcoholic Fatty Liver Disease
Authors: L. Polimeni, F. Baratta, D. Pastori, G. Tozzi, G. Labbadia, F. Violi, M. Del Ben, F. Angelico
Journal: Journal of Hepatology (2016)
Risk of Recurrence in Hepatitis B Virus-Related Hepatocellular Carcinoma Patients Failed in Nucleos(T) Ide Analogues (NUCS) Secondary Prevention – A Nationwide Cohort Study
Authors: I.-C. Lee, T.-H. Wang, Y.-W. Hu, H.-C. Lin, Y. Chao, Y.-H. Huang
Journal: Journal of Hepatology (2016)
Reduction of Liver Steatosis and Fibrosis with an Ask1 Inhibitor in a Murine Model of Nash is Accompanied by Improvements in Cholesterol, Bile Acid and Lipid Metabolism
Authors: G. Budas, S. Karnik, T. Jonnson, T. Shafizadeh, S. Watkins, D. Breckenridge, D. Tumas
Journal: Journal of Hepatology (2016)
FDA Enlists Physicians’ Aid
Authors: Rebecca Voelker
Journal: JAMA (2016)

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Idelalisib Monotherapy and Durable Responses in Patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL)
Authors: Peter Martin, Armando Armas, Ajay K Gopal, Emmanuel Gyan, Nina D. Wagner-Johnston, Jan Walewski, Steve Abella, Wei Ye, Betsy Philip, Bess Sorenson, Sven de Vos
Journal: Blood (2015)
Evaluation of EN2 as a urine-based biomarker for prostate cancer.
Authors: A. Michael, L. Plowright, A. Boxall, A. Bhatt, S. Di Palma, C. Parker, H. Pandha, R. Morgan
Journal: Journal of Clinical Oncology (2010)

e15129 Background: Prostate cancer is a leading cause of cancer related death in men but its diagnosis is still complicated by the lack of a highly predictive biochemical marker. Here we show that the transcription factor Engrailed-2 is secreted from prostate tumours in a highly specific manner and is present in the urine of men with prostate cancer. Methods: Urine was collected under standardised conditions from men with prostate cancer, or with non-cancerous conditions of the prostate such as benign prostatic hypertrophy, or men who were found to have no prostate abnormalities after saturation biopsy. Results: Engrailed-2 protein was detected in the untreated, unconcentrated urine of 62% of men with prostate cancer, but only 3% of men with no prostatic abnormalities (n=258, p<0.001). Conclusions: Thus Engrailed-2 is a potential diagnostic marker for prostate cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University of Surrey University of Surrey
Phase II study of weekly paclitaxel carboplatin in the treatment of progressive ovarian cancer
Authors: M. E. Van der Burg, I. Vergote, C. W. Burger, A. van der Gaast
Journal: Journal of Clinical Oncology (2004)

5058 Background: The response rate (RR) of standard chemotherapy in recurrent ovarian cancer (OC) patients (pts) with a progression free interval (PFI) of < 6m is only 15 -20%. Dose dense induction therapy with weekly (w) cisplatin (P) combined with either etoposide RR (58%) or paclitaxel (T) (RR 64%) was very effective in these platinum refractory pts (PFI < 6m). In a phase I study we showed that Tw 90 mg/m2 could safely be combined with carboplatin (C) AUC 4 and that it was better tolerated than TPw. Methods: Treatment consisted of induction therapy with 6 cycles T 90 mg/m2 and C AUC 4 on day 1,8,15 and 29,36,43, followed by 6 cycles 3w TC. The endpoints of the study were RR and toxicity. Results: 50 Pts were evaluable; median PFI was 8 months (m); 18 pts had a PFI of < 6m. Prior therapy median 2(1–6) lines, all pts except 1 were pretreated with TP or TC. The treatment was well tolerated. Toxicity of 286 TCw cycles included; CTC grade 3+4 neutropenia 31%, fever 1.7%, thrombocytopenia 9%, treatment delay 14%, hypersensitivity reaction to T 16% to C 16%, CTC grade 2 nausea/vomiting 2%. No neurotoxicity nor ototoxicity grade 2 or 3 was observed. 43 Pts were evaluable for response. The RR was 53% (CR 12%) in the 18 pts with PFI < 6m, the median progression free survival (PFS) was 10m (1–23m), median survival 13m (1–27m). In the 25 pts with PFI > 6m the RR was 80% (CR 24%). After a median follow-up of 8+m (1+-20+m), 39% had progressed, median PFS was 11m (2–14m), 23% patients had died, median survival 15m (3–19m). Conclusions: weekly TC is very well tolerated. This dose dense TCw is highly active in both TP sensitive as TP refractory patients. TCw is now compared to standard 3w TC in a randomized trial. No significant financial relationships to disclose.
Conflicting mechanisms of AT2 cardioprotection revealed
Authors: Raffaele Altara, Sean P. Didion, George W. Booz
Journal: Cardiovascular Research (2016)

This editorial refers to ‘The angiotensin II type 2 receptor activates flow-mediated outward remodelling through T cells-dependent interleukin-17 production’, by A. Caillon et al., pp. 515–525. 

Coronary artery disease is a major cause of mortality in the developed world due to the death of cardiac muscle because of inadequate delivery of oxygen-rich blood. The knowledge gained from basic research on preventing cardiac muscle loss by enhancing the formation of new arteries in the heart (angiogenesis) has not translated to date into clinical benefit. An alternative, perhaps more promising strategy is to foster arteriogenesis, which refers to the remodelling of pre-existing collateral resistance vessels to form arteries that effectively bypass major arterial obstructions.1–4 Indeed, a positive correlation is observed between the number of collateral arteries and extent of their coverage and survival in patients with coronary artery disease,4 although similar remodelling if it occurs in an atherosclerotic artery may increase the propensity for plaque destabilization and rupture.5 Notably, several pro-arteriogenic mechanisms or treatments promote atherosclerotic plaque development and instability, while conversely anti-atherogenic factors may inhibit arteriogenesis.6 

The structural changes in the vessel wall that occur with arteriogenesis reflect outward remodelling, which is an increase in lumen diameter and relative reduction in wall thickness. The primary stimulus that drives arteriogenesis is sheer stress due to increases in blood flow and entails activation of endothelial cells (EC), basal membrane degradation, infiltration of immune cells, proliferation of vascular smooth muscle cells (VSMC), and changes in the extracellular matrix.1 Specific factors involved in the outward remodelling include nitric oxide (NO), vascular endothelial growth factor, chemokine (C-C) motif ligand 2 (CCL2; also known as monocyte chemoattractant protein 1 …
Activity of GDC-0941, an inhibitor of phosphoinositol 3 kinase (PI3K), in gastrointestinal stromal tumor (GIST) xenograft and duration of response after discontinuation of treatment in combination with imatinib.
Authors: G. Floris, R. Sciot, A. Wozniak, C. Deroose, P. Vermaelen, B. Dewaele, M. Debiec-Rychter, P. Schoffski
Journal: Journal of Clinical Oncology (2010)

10020 Background: Oncogenic signaling in GISTs is sustained mainly via PI3K/AKT rather than RAS/MAPK pathway. We tested the efficacy of GDC-0941 (GDC) alone and in combination with imatinib (IM) in IM-sensitive GIST xenograft. Methods: Nude mice were grafted bilaterally with human GIST bearing KIT exon 11 mutation. They were orally dosed over 19 days in 4 groups: A (control); B (GDC-0941 75mg/kg/d); C (IM 50mg/kg/bid); D (GDC+IM, doses/schedule=B+C). In addition, xenografts re-growth after treatment withdrawal was evaluated. Micro-FDG-PET assessed standardized uptake values (SUV) and tumor/lesion glycolysis (TLG) over 8 weeks. Histopathology included H&E, KIT and Ki-67 staining. KIT signaling status was assessed by Western blot. Results: IM and GDC+IM reduced tumor volume by 86% and 95%, respectively, while GDC had no significant effect. IM and GDC treatments showed only grade 1 or grade 1&2 histologic response (HR), while grade 3 HR was observed in 75% of tumors under GDC+IM. Compared to control, mitotic activity decreased 2-fold under GDC, while it was not detectable in the other arms. Apoptotic activity was respectively 3- and 15-fold higher than control under IM and GDC+IM, being almost unaffected under GDC alone. After 24 hrs, SUV decreased in all treated groups, and remained low particularly under IM. The highest reduction in TLG was observed under GDC+IM. In GDC and IM groups, inhibition of AKT was visible but incomplete. Only GDC+IM induced complete PI3K/AKT pathway knockdown. After treatment discontinuation, immediate tumor re-growth was observed in IM group, whereas GDC+IM treatment yielded long-lasting volumetric effect (98% and 15% of baseline, respectively, after 4 weeks of treatment end). SUV and TLG increased constantly under IM, whereas same parameters remained low in GDC+IM. Mitotic index in GDC+IM was still 2-fold lower than in controls. Conclusions: The combination of GDC-0941 and imatinib has extensive antitumor efficacy in GIST xenograft, inducing more substantial apoptosis and durable effects than imatinib alone. This effect was sustained even after treatment withdrawal. No significant financial relationships to disclose.
A Pair of Brothers with Aceruloplasminemia Due to a Novel Nonsense Mutation: Unusual Phenotype and Effectiveness of Iron-Chelation Therapy by Deferasirox
Authors: M. Fiorini, F. Ferrara, S. Scarlini, D. Bocchi, F. Cavallieri, F. Valzania, A. Caleffi, A. Pietrangelo, E. Corradini
Journal: Journal of Hepatology (2016)
Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (≥60 years) who benefit from intensive post‐induction consolidation therapy
Authors: Wolfgang R. Sperr, Otto Zach, Iris Pöll, Susanne Herndlhofer, Paul Knoebl, Ansgar Weltermann, Berthold Streubel, Ulrich Jaeger, Michael Kundi, Peter Valent
Journal: American Journal of Hematology (2016)

Although it is generally appreciated that a subset of elderly patients with acute myeloid leukemia (AML) may benefit from intensive consolidation, little is known about variables predicting such benefit. We analyzed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. About 115 patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR (P < 0.05). About 92% (105/115) of the CR-patients received up to four consolidation cycles of intermediate dose ARA-C. Median continuous CR (CCR) and disease-free survival (DFS) were 1.3 and 1.1 years, respectively. CCR, DFS, and survival at 5 years were 23%, 18%, and 15%, respectively. Only karyotype and mutated NPM1 (NPM1mut) were independent predictors of survival. NPM1mut showed a particular prognostic impact in patients with normal (CN) or non-monosomal (Mkneg) karyotype by Haemato-Oncology Foundation for Adults in the Netherlands (HOVON)-criteria, or intermediate karyotype by Southwest Oncology Group (SWOG)-criteria. The median CCR was 0.94, 1.6, 0.9, and 0.5 years for core-binding-factor, CN/Mkneg-NPM1mut, CN/Mkneg-NPM1-wild-type AML, and AML with monosomal karyotype, respectively, and the 5-year survival was 25%, 39%, 2%, and 0%, respectively (P < 0.05). Similar results (0.9, 1.5, 0.9, and 0.5 years) were obtained using modified SWOG criteria and NPM1 mutation status (P < 0.05). In summary, elderly patients with CN/Mkneg-NPM1mut or CBF AML can achieve long term CCR when treated with intensive induction and consolidation therapy whereas most elderly patients with CN/Mkneg-NPM1wt or Mkpos AML may not benefit from intensive chemotherapy. For these patients either hematopoietic-stem-cell-transplantation or alternative treatments have to be considered. Am. J. Hematol. 91:1239-1245, 2016. © 2016 Wiley Periodicals, Inc.
Urinary Micro-Albumin Level and its Modification Status Serve as an Non-Invasive Marker for Outcome Prediction in Acute-On-Chronic Liver Failure (ACLF) Patients
Authors: S. Hussain, S. Das, J.S. Maras, S.M. Shasthry, S.K. Sharma, S.K. Sarin
Journal: Journal of Hepatology (2016)
Cardiac t-tubules: where structural plasticity meets functional adaptation
Authors: Samuel A. Watson, Filippo Perbellini, Cesare M. Terracciano
Journal: Cardiovascular Research (2016)

This editorial refers to ‘Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis’, by M. Frisk et al. , pp. 443–451. 

Together with neurons and other highly specialized cells, cardiomyocytes are usually described as terminally differentiated (i.e. unable to re-enter the cell cycle and repair damaged myocardium). This feature implies a weak response to injury and contrasts with the observation that cardiomyocytes are remarkably resilient to damage, are able to survive several decades, often the whole life, despite relentless and constantly varying function.1 In recent years, it has been shown that a degree of cardiomyocyte renewal occurs, but this is still insufficient to explain the ability of the heart to perform reliably in the long-term and survive injury.1 A new paradigm, considering cardiomyocytes as highly plastic cells that rapidly respond to changes in their environment to enhance survival, is emerging.2 Among different stimuli, mechanical load is an important physiological and pathological regulator of cardiomyocyte structure and function and is likely to have a direct, primary role.3 Within a normal range of mechanical load, myocyte structural changes allow adaptation and maintenance of optimal cardiac function; in contrast, chronic and worsening overload leads to cardiomyocyte dysfunction and the development of heart failure. Surprisingly, chronic unloading induces similar molecular changes to overload,2 suggesting that the optimal structure–function relationship in the heart occurs in a highly modulated, defined range of mechanical load. The reasons for this behaviour and the cellular and molecular mechanisms remain poorly understood.

In the failing heart, a pleiotropic adaptive response results in vast alterations to cardiomyocyte structure and subsequent function. This includes morphological changes, such as cardiomyocyte hypertrophy and gap junction remodelling, and functional changes, ranging from altered β-adrenoceptor …
What is rheumatoid arthritis? Considering consequences of changed classification criteria
Authors: Annette H M van der Helm-van Mil, Angela Zink
Journal: Annals of the Rheumatic Diseases (2016)

Rheumatoid arthritis (RA) was recognised as a separate disease entity in the middle of the 20th century. Since then several sets of classification criteria were developed for use in clinical studies. The 1987 American College of Rheumatology (ACR) criteria1 have been criticised as they are fulfilled rather late in the disease. Consequently, trials that included patients with RA based on the 1987 criteria studied patients with relatively long-standing arthritis. The aim of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) expert panel was therefore to develop novel criteria without the features of long-standing disease such as erosions or nodules. Indeed the hitherto developed 2010 ACR/EULAR classification criteria for RA2 are fulfilled earlier in the disease course than the 1987 criteria.3 ,4 Thus, the major objective of the new criteria was achieved.

The study of Nordberg et al 5 makes us think about the consequences of the novel criteria for the phenotype of RA. According to the 1987 criteria, the characteristic phenotype of RA consists of symmetric polyarthritis of small joints with morning stiffness (ignoring the features of long-standing disease nodules and erosions). Symmetry and morning stiffness are no longer included in the 2010 criteria. There is less emphasis on clinical elements in the 2010 criteria, and this is paralleled by an emphasis on the results of additional investigations: anti-citrullinated peptide antibodies (ACPA) and acute phase responses were introduced (table 1). The majority of the six points required to fulfil the 2010 criteria can be achieved either by the presence of autoantibodies or on the number of swollen joints. Nordberg et al showed that patients with ACPA-positive RA fulfilling the 2010 criteria have less inflamed joints (measured with either physical examination or with ultrasound) than patients with ACPA-negative RA. This finding is not surprising if we …
A Phase II Trial of CHOP Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) for Previously Untreated Elderly Diffuse Large B-Cell Lymphoma (DLBCL) Patients.
Authors: Pier Luigi Zinzani, Monica Tani, Stefano Fanti, Vittorio Stefoni, Gerardo Musuraca, Paolo Castellucci, Enrica Marchi, Mariapaola Fina, Michele Baccarani
Journal: Blood (2006)
Hematological Characteristics of Infants and Young Children Presenting with Different Levels of Malarial Anemia at a Rural District Hospital in Western Kenya.
Authors: Enrico M. Novelli, John Michael Ong’echa, Greg Davenport, Christopher C. Keller, Tom Were, Collins Ouma, Richard Otieno, Caterina Rosano, Sandra Kaplan, Douglas J. Perkins
Journal: Blood (2006)
Peri-Transplant Treatment with Direct-Acting Antivirals of HIV-HCV Coinfected Patients
Authors: V. Aguilera, C. Vinaixa, A. Rubín, M. García-Eliz, M. Blanes, S. Benlloch, E. Pareja, M. Berenguer, M. Prieto
Journal: Journal of Hepatology (2016)
Possible utility of actinin-4 as a predictive biomarker of the efficacy of postoperative adjuvant chemotherapy for completely resected early stage lung adenocarcinoma.
Authors: Hideaki Shiraishi, Yutaka Fujiwara, Takanori Kakuya, Nami Miura, Yukio Watabe, Rintaro Noro, Koji Tsuta, Fumihiko Kakizaki, Masahiro Kamita, Hirokazu Shoji, Wilber Huang, Shun-ichi Watanabe, Tesshi Yamada, Yuichiro Ohe, Kazufumi Honda
Journal: Journal of Clinical Oncology (2016)

e20003 Background: We previously identified gene amplification and protein overexpression of actinin-4 (ACTN4) associated with prognosis in the early stage of lung adenocarcinoma. However, predictive biomarkers of the efficacy of postoperative adjuvant chemotherapy (ADC) remained unknown. Methods: We performed our exploratory research in two steps. In Step 1, we extracted clinical information and mRNA profiles from the public database of a randomized phase-III trial of adjuvant vinorelbine plus cisplatin after complete resection of stage IB or II non-small cell lung cancer (JBR.10). We then reanalyzed the impact of ACTN4 on the efficacy of ADC. In Step 2, we measured ACTN4 protein levels in patients with completely resected stage II or IIIA lung adenocarcinoma at the National Cancer Center Hospital from January 2008 to December 2011 using immunohistochemistry (IHC) according to REMARK guideline. We then retrospectively compared survival between ADC with platinum doublet and observation (OBS) groups. Results: In Step 1, the 133 patients enrolled in JBR.10 were divided into two groups by expression of the ACTN4 transcript; ACTN4 positive (ACTN4 (+)) group (n = 25) and ACTN4 negative (ACTN4 (-)) group (n = 108). In the ACTN4 (+) group, overall survival (OS) was significantly longer in the ADC subjects (n = 15) compared with the OBS (n = 10) (hazard ratio [HR] = 0.27; p = 0.042). However, no differences in OS were noted between the ADC (n = 56) and OBS (n = 52) subejects among the ACTN4 (-) group. These results indicated that only the ACTN4 (+) group derived a significant survival benefit with ADC. In Step 2, a total of 148 eligible patients were also classified into two groups based on IHC findings. In the ACTN4-IHC (+) group (n = 75), patients with ADC (n = 22) survived longer on average than those with OBS (n = 53) (HR = 0.307; p = 0.028). In contrast, in the ACTN4-IHC (-) group (n = 73), no tangible survival benefit was noted with ADC (HR = 0.926; p = 0.876). Conclusions: ACTN4 may be a useful biomarker for predicting survival with ADC in completely resected early-stage lung adenocarcinoma.
Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease
Authors: Marialuisa Alliegro, Rita Ferla, Edoardo Nusco, Chiara De Leonibus, Carmine Settembre, Alberto Auricchio
Journal: Molecular Therapy (2016)

Enzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI). However, systemic administration of high doses of AAV might result in both cell-mediated immune responses and insertional mutagenesis. Here we evaluated whether the combination of low doses of AAV2/8 with a less frequent (monthly) than canonical (weekly) ERT schedule may be as effective as the single treatments at high doses or frequent regimen. A greater reduction of both urinary glycosaminoglycans, considered a sensitive biomarker of therapeutic efficacy, and storage in the myocardium and heart valves was observed in mice receiving the combined than the single therapies. Importantly, these levels of correction were similar to those we obtained in a previous study following either high doses of AAV2/8 or weekly ERT. Our data show that low-dose gene therapy can be used as a means to rarify ERT administration, thus reducing both the risks and costs associated with either therapies.