tbuckley/cabot-search huggingface dataset:
Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry
Authors: Jo-David Fine
Journal: JAMA Dermatology (2016)

Accurate estimation of the incidence and prevalence of each subtype of epidermolysis bullosa (EB) is essential before clinical trials can be designed and sufficient funding allocated by government agencies and third-party insurers for the care of these individuals.To determine the incidence and prevalence of inherited EB stratified by subtype in the United States during a 16-year period.Prospective cross-sectional and longitudinal study. Data were obtained from 3271 patients consecutively enrolled in the National Epidermolysis Bullosa Registry from January 1, 1986, through December 31, 2002, using a detailed instrument created with the assistance of the National Institutes of Health. Analyses were performed in January 1999 and April 2015. Participants were patients of all ages with EB.Extensive clinical and laboratory data were collected on patients who were subclassified and serially revalidated based on published diagnostic recommendations by an international panel of experts. Pertinent to this report, estimates were made of the incidence and prevalence during 2 time frames.During the first 5 years of funding of the registry, the overall incidence and prevalence of inherited EB were 19.60 and 8.22 per 1 million live births, respectively. When reassessed over the entire 16 years of the study, the prevalence rose to 11.07, whereas the overall incidence remained unchanged at 19.57 cases. Changes were also observed within some disease subsets as increased numbers of patients were identified, recruited, followed up longitudinally, and resubclassified as needed over time. For example, in 2002, the prevalence of EBS overall and localized EBS had increased considerably by 30.4% and 25.5%, respectively, whereas the prevalence of generalized intermediate EBS declined by 76.7% as a result of later subclassification of some of those patients into other subtypes. In contrast, no significant change was noted in the overall prevalence of JEB or generalized severe JEB, although there was a 73.0% decline in the prevalence of generalized intermediate JEB.Precise estimates of the incidence and prevalence of each major subtype of inherited EB in the United States are now available that should assist investigators in choosing which subtypes are amenable to properly designed, large-scale, clinical trials.
Sustained response to salvage therapy for dabrafenib-resistant metastatic Langerhans cell sarcoma
Authors: G. Lorillon, S. Mourah, L. Vercellino, C. de Margerie-Mellon, C. Pagès, L. Goldwirt, C. Lebbe, J. Tost, A. Tazi
Journal: Annals of Oncology (2016)
Abstract 2183: Baicalein and meformin decrease small cell lung cancer growth by inhibiting the mTOR pathway in itro
Authors: Emily F. Marcinkowski, Dan Raz, Bing Shen, Quanhua Xing, Jin Yan, Wei Wen, Ernest Han, John Yim
Journal: Cancer Research (2016)

Abstract Background: Metformin use has been associated with decreased lung cancer risk in several observational studies and is currently in clinical trial in conjunction with standard chemotherapeutics. One possible antitumor mechanism is the negative regulation of the mTOR pathway. We previously reported that the natural product Baicalein has antitumor effects through targeting mTOR pathway. We hypothesized that Baicalein to have antitumor effects in small cell lung cancer. Methods: H1417 small cell lung cancer cells were cultured and treated with increasing doses of Baicalein or Metformin. The cells were harvested at 24 hours and subjected to Western blotting staining for the downstream products of the mTOR pathway. Cell proliferation was determined by MTT assay at 24, 48, and 72 hours. MTT conversion to formazan dye correlates with the number of living cells. Results: We found a dose dependent decrease in the downstream mTOR1 targets pS6K1 and pS6 using both Baicalein and Metformin. There was also an increase in the expression of the mTOR inhibitors DDIT4 and IRF-1. Using the MTT assay, we were able to demonstrate a marked dose dependent decrease in cell proliferation that was sustained over 72 hours from treatment. Interestingly, Baicalein has a markedly higher potency working at micromolar doses verses Metformin which required millimolar doses. Conclusions: Both Baicalein and Metformin effectively decrease cell proliferation in small cell lung cancer cells in vitro. We have shown these drugs to target the mTOR pathway. Cell proliferation is inhibited at a markedly smaller dose by Baicalein compared with Metformin. Baicalein may be useful in cancer chemotherapy and chemoprevention. Citation Format: Emily F. Marcinkowski, Dan Raz, Bing Shen, Quanhua Xing, Jin Yan, Wei Wen, Ernest Han, John Yim. Baicalein and meformin decrease small cell lung cancer growth by inhibiting the mTOR pathway in itro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2183.
Abstract 659: Novel refinements for the autochthonous mouse model of cancer
Authors: Peter K. Cabeceiras, Nikhil S. Joshi, Tyler Jacks
Journal: Cancer Research (2016)

Abstract There are many levels of genetic regulation at play in autochthonous mouse models of cancer. For instance, mouse models can be programed to knockout tumor suppressor genes and enable transcription of oncogenes in order to cause normal cells to transform into cancer cells that can eventually form tumors and metastasize. Concurrently to this, a gene of interest (GOI) under the control of a tetracycline-response element (TRE) promoter can be studied in a doxycycline-dependent fashion. The GOI under the control of the TRE promoter will be transcribed only in the presence of a transcriptional activator fusion protein, rtTA, and a chemical compound, doxycycline. Unfortunately, it is extremely difficult to limit the doxycycline-dependent expression of the GOI only to cancer cells, so normal cells will invariably express the GOI. This inaccuracy can limit the translation of results from mouse model to human patient. In the interest of engineering models that closely recapitulate the disease in question, we propose to limit the expression of rtTA and the GOI to cancer cells by linking rtTA expression to cell cycle regulation. The cell cycle is leveraged because rapid division and proliferation are characteristics intrinsic to proliferative cancer cells, and some cell cycle proteins are abundantly expressed in cancer cells but not expressed in normal cells. By fusing rtTA to cell cycle proteins that are expressed in cycling cancer cells, we hope to improve the accuracy and capabilities of the autochthonous mouse model of cancer. Citation Format: Peter K. Cabeceiras, Nikhil S. Joshi, Tyler Jacks. Novel refinements for the autochthonous mouse model of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 659.
Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: Analysis of safety, clinical activity, and PD-L1 expression.
Authors: Andrea B. Apolo, Jeffrey R. Infante, Omid Hamid, Manish R. Patel, Ding Wang, Karen Kelly, Anthony E. Mega, Carolyn D. Britten, Alain Ravaud, Alain C. Mita, Howard Safran, Tom Stinchcombe, Hans Juergen Grote, Anja von Heydebreck, Jean-Marie Cuillerot, James L. Gulley
Journal: Journal of Clinical Oncology (2016)

4514 Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report updated safety and efficacy associated with avelumab as a 2nd-line therapy in patients (pts) with metastatic urothelial carcinoma (mUC; NCT01772004). Methods: Pts with mUC unselected for PD-L1 expression received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by IHC. Results: As of Oct 7, 2015, 44 pts (27 [61.4%] with visceral metastasis) were treated with avelumab (median 14 wks [range 2-56]) and followed for a median of 11 mos (range 10-13). Median age was 68 y (range 30-84), ECOG PS was 0 (43.2%) or 1 (56.8%), and median number of prior therapies was 2 (range 1-6). Treatment-related (TR) AEs occurred in 30 pts (68.2%); the most common (≥10%) were infusion-related reaction (20.5%), fatigue (20.5%), asthenia (11.4%), and nausea (11.4%). Grade ≥3 TRAEs were asthenia, myositis, decreased appetite, and elevated CPK or AST (each 1 event) and no treatment-related deaths occurred. ORR was 18.2% (8 pts; 95% CI: 8.2, 32.7) with 2 CRs and 6 PRs; 4 were ongoing. SD was observed in 17 pts (38.6%); disease-control rate was 56.8%. PD-L1 expression was evaluable in 35 pts. Using a ≥5% cutoff for tumor cell staining, 12/35 [34.3%] were PD-L1+; ORR was 50.0% in PD-L1+ pts (6/12; 95% CI: 21.1, 78.9) vs 4.3% in PD-L1- pts (1/23; 95% CI: 0.1, 21.9). PFS rate at 24 wks was 58.3% (95% CI: 27.0, 80.1) in PD-L1+ pts vs 16.6% (95% CI: 4.2, 36.0) in PD-L1-. ORR in pts +/- baseline visceral metastasis was 18.5% (5/27) and 17.6% (3/17), respectively. OS at 12 mos was 50.9% (95% CI: 32.6, 66.6) for the overall population. Conclusions: Avelumab showed an acceptable safety profile and promising clinical activity in pts with mUC. Greater activity in pts with PD-L1+ tumors was observed. A randomized phase 3 trial of avelumab in pts with mUC is underway. *Proposed INN. Clinical trial information: NCT01772004.
Terlipressin given by continuous intravenous infusion or by intravenous boluses: Is there already an answer?
Authors: Ângelo Zambam de Mattos, Angelo Alves de Mattos
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. To the Editor: This letter regards the recently published article by Cavallin et al.1 The authors compared terlipressin given by continuous intravenous infusion (TERLI‐INF) and by intravenous boluses for hepatorenal syndrome and concluded that TERLI‐INF is the most suitable approach because it was safer and required lower doses.1 Nevertheless, we understand that some issues about the study need further discussion. The authors defined drug‐related adverse effects as their primary endpoint and calculated the sample size accordingly.1 We believe that evaluating the effectiveness of treatments was as important as their safety and that it would probably require a larger sample. Therefore, we understand that the study could have been underpowered regarding response to treatment and transplant‐free survival. Actually, patients randomized to the intravenous bolus had better transplant‐free survival than those randomized to TERLI‐INF (69% and 53%, respectively), and the lack of statistical difference between groups might be related to a type II error. Regarding adverse events, the authors decided to use lower initial doses of terlipressin for the TERLI‐INF group (2 mg/day) than for the intravenous bolus group (3 mg/day).1 In a study by some of the same authors, though, the initial dose of terlipressin given by continuous infusion was 3 mg/day.2 Considering that the TERLI‐INF group used lower doses of the drug, it is reasonable to expect fewer side effects. Concerning the dose of terlipressin used by each group, the authors stated that lower doses were required when the drug was administered by continuous infusion.1 This could suggest that using terlipressin by continuous infusion would lead to lower treatment costs. Nevertheless, the study showed data related only to responders from each group,1 while it would be interesting to know the mean dose of terlipressin used by all patients randomized for each group in order to make economical inferences. Moreover, starting treatment with lower doses of terlipressin in the TERLI‐INF group would also have influence on a cost analysis. Finally, despite the fact that performing an economic evaluation was not the aim of this study, it is important to remember that more than just the mean dose of a drug should be considered when evaluating the economic aspects of a treatment strategy. We have recently demonstrated this in an economic evaluation that compared all direct medical costs involved in the treatment of hepatorenal syndrome using terlipressin and noradrenaline and proved that the terlipressin strategy was actually more economical, different from what is commonly expected.3
Which approach should be used for endoscopic ultrasound-guided biliary drainage?
Authors: Carlo Fabbri, Lorenzo Fuccio, Rastislav Kunda, Alberto Larghi
Journal: Endoscopy (2016)

We read with great interest the study by Ogura et al. [1] that retrospectively compared the clinical outcome of endoscopic ultrasound (EUS)-guided choledochoduodenostomy (EUS-CD) versus hepaticogastrostomy (EUS-HG) for distal bile duct drainage in 39 patients with concomitant duodenal obstruction. Overall, they found that EUS-HG was associated with significantly longer stent patency and fewer adverse events than EUS-CD. Therefore, the authors concluded that EUS-HG should be preferred over EUS-CD.
Abstract 2864: Role of ribosomal protein, Rpl22 in regulation of acute lymphoblastic leukemia
Authors: Nehal R. Solanki-Patel, Noa Greenberg, Shu Rao, Suraj Peri, Michael Slifker, Charles Mullighan, David Wiest
Journal: Cancer Research (2016)

Abstract Inactivation of ribosomal proteins (RP) is known to cause diseases called ribosomopathies, which are often associated with abnormal hematopoiesis and an increased risk for development of leukemia. Our laboratory has recently reported an important link between inactivation of one such ribosomal protein, Rpl22, and poor survival in T cell acute lymphoblastic leukemia (T-ALL) patients. Preliminary bioinformatic analysis shows that RPL22 is lost in ∼10% of pediatric T-ALL patients, who exhibit a more aggressive disease course. Deletion of the RPL22 locus is also enriched in the early T-cell precursor (ETP-ALL) subset of T-ALL patients, which exhibit a more aggressive disease course. Thus, RPL22 loss appears to be a marker for poor outcome in pediatric T-ALL patients. While RP inactivation has previously been linked to increased cancer risk, the mechanistic basis for this linkage remained unclear. We have recently demonstrated that inactivation of Rpl22 promotes leukemic transformation by activating NF-κB and inducing the stem cell gene, LIN28B. Nevertheless, the molecular link between Rpl22 inactivation and the induction of NF-κB activity remained unclear. We have now determined that inactivation of Rpl22 activates NF-κB signaling by exacerbating ER stress responses. Indeed, Rpl22 loss results in hyperactivation of the PERK-EIF2α-ATF4 stress pathway, which is known to activate NF-κB. We have demonstrated that knockdown of PERK using shRNA abrogates the activation of NF-κB in Rpl22 mutant cells and returns Lin28B expression levels to baseline. This reduction in Lin28B eliminates the predisposition to transformation exhibited by Rpl22 mutant cells, as evidenced by decreased formation of colonies in soft agar. Taken together, these data suggest that RPL22 inactivation may serve as a negative prognostic indicator in T-ALL and that pharmacologic targeting of ER stress pathways may represent a novel therapeutic alternative in this molecularly-defined subclass of T-ALL. Citation Format: Nehal R. Solanki-Patel, Noa Greenberg, Shu Rao, Suraj Peri, Michael Slifker, Charles Mullighan, David Wiest. Role of ribosomal protein, Rpl22 in regulation of acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2864.
How valuable is physical examination of the cardiovascular system?
Authors: Andrew Elder, Alan Japp, Abraham Verghese
Journal: BMJ (2016)

Physical examination of the cardiovascular system is central to contemporary teaching and practice in clinical medicine. Evidence about its value focuses on its diagnostic accuracy and varies widely in methodological quality and statistical power. This makes collation, analysis, and understanding of results difficult and limits their application to daily clinical practice. Specific factors affecting interpretation and clinical application include poor standardisation of observers' technique and training, the study of single signs rather than multiple signs or signs in combination with symptoms, and the tendency to compare physical examination directly with technological aids to diagnosis rather than explore diagnostic strategies that combine both. Other potential aspects of the value of physical examination, such as cost effectiveness or patients' perceptions, are poorly studied. This review summarises the evidence for the clinical value of physical examination of the cardiovascular system. The best was judged to relate to the detection and evaluation of valvular heart disease, the diagnosis and treatment of heart failure, the jugular venous pulse in the assessment of central venous pressure, and the detection of atrial fibrillation, peripheral arterial disease, impaired perfusion, and aortic and carotid disease. Although technological aids to diagnosis are likely to become even more widely available at the point of care, the evidence suggests that further research into the value of physical examination of the cardiovascular system is needed, particularly in low resource settings and as a potential means of limiting inappropriate overuse of technological aids to diagnosis.
NHS’s financial woes undermine quality and safety drive
Authors: Richard Vize
Journal: BMJ (2016)

The announcement by NHS England and NHS Improvement of a “reset” of NHS finances to try to cut deficits,1 2 as well as the accusation that 63 trusts were guilty of excessive growth in their pay bill, can be seen as the end of the policy drive around quality and safety that followed the Mid Staffordshire scandal.

When Jeremy Hunt succeeded Andrew Lansley as health secretary for England, his determination to obliterate discussion of health reforms by attacking Labour’s record on quality meant that clinicians and managers quickly concluded that running up deficits by recruiting staff was preferable to being identified as “the next Mid Staffs.” The safety debate quickly morphed into more staff being equated with higher care standards, while years of poor workforce planning and stagnating pay left trusts in a bidding war to employ unsustainable numbers of nurses and doctors through agencies.

Meanwhile, funding …
Abstract 3808: Novel compound conferring selectivity for cancer cells
Authors: Dilan B. Jaunky, Pat Forgione, Alisa Piekny
Journal: Cancer Research (2016)

Abstract There is a need to develop novel compounds that can effectively treat a broad range of cancers on their own, or in combination with approved therapies. As personalized medicine is developed, combinatorial approaches will become more common making it crucial to increase the repertoire of available drugs. In the past, drugs often were developed to target a biologically-relevant molecule, but structural limitations, stability and solubility issues, or lack of selectivity have hindered the clinical use of many of these drugs. Our approach was to first find a ‘high-quality’ compound that is selective for cancer cells, then characterize its mechanism of action and identify its target. High throughput screening (HTS) helped to rapidly identify a subset of compounds with selective toxicity toward MCF-7 (breast cancer) cells. Some of these compounds were further tested for their efficacy in HeLa (cervical cancer) cells, and we found one that selectively causes mitotic arrest at 250 nM in comparison to non-cancerous HFF-1 (foreskin fibroblast) cells. At 200 nM, this compound synergizes with drugs known to affect microtubule dynamics and cause mitotic arrest including Nocodazole and Paclitaxel (currently in use as an anti-cancer drug), causing them to be more effective at lower concentrations. Excitingly, this compound also provides a shielding effect for HFF-1 cells treated with Paclitaxel. To learn the mechanism of action for this compound, we performed immunofluorescence microscopy on HeLa and HFF-1 cells treated with a range of concentrations. We found that the mitotic spindle is improperly organized in HeLa cells at 250 nM, but not in HFF-1 cells. Interestingly, microtubules are completely gone in mitotic HeLa cells and are reduced in mitotic HFF-1 cells treated with &amp;gt;500 nM. Given that this compound synergizes with drugs that directly bind to tubulin subunits to modify their dynamics of assembly and disassembly, and differently affects cancerous vs. healthy cells, we hypothesize that it has a unique mechanism of action and may affect microtubule nucleation. We are continuing to characterize the compound, and will identify its molecular target. In addition, we are generating further iterations to explore the Structure-Activity Relationship, and optimize its efficacy. Our in vitro data shows that our approach has the potential to identify novel compounds with the potential for therapeutic use. Citation Format: Dilan B. Jaunky, Pat Forgione, Alisa Piekny. Novel compound conferring selectivity for cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3808.