tbuckley/cabot-search huggingface dataset:
Provision of Palliative Care in Low- and Middle-Income Countries: Overcoming Obstacles for Effective Treatment Delivery
Authors: Breffni Hannon, Camilla Zimmermann, Felicia M. Knaul, Richard A. Powell, Faith N. Mwangi-Powell, Gary Rodin
Journal: Journal of Clinical Oncology (2015)

Despite being declared a basic human right, access to adult and pediatric palliative care for millions of individuals in need in low- and middle-income countries (LMICs) continues to be limited or absent. The requirement to make palliative care available to patients with cancer is increasingly urgent because global cancer case prevalence is anticipated to double over the next two decades. Fifty percent of these cancers are expected to occur in LMICs, where mortality figures are disproportionately greater as a result of late detection of disease and insufficient access to appropriate treatment options. Notable initiatives in many LMICs have greatly improved access to palliative care. These can serve as development models for service scale-up in these regions, based on rigorous evaluation in the context of specific health systems. However, a multipronged public health approach is needed to fulfill the humane and ethical obligation to make palliative care universally available. This includes health policy that supports the integration of palliative care and investment in systems of health care delivery; changes in legislation and regulation that inappropriately restrict access to opioid medications for individuals with life-limiting illnesses; education and training of health professionals; development of a methodologically rigorous data and research base specific to LMICs that encompasses health systems and clinical care; and shifts in societal and health professional attitudes to palliative and end-of-life care. International partnerships are valuable to achieve these goals, particularly in education and research, but leadership and health systems stewardship within LMICs are critical factors that will drive and implement change.
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation
Authors: Sazia Sharmin, Atsuhiro Taguchi, Yusuke Kaku, Yasuhiro Yoshimura, Tomoko Ohmori, Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara, Ryuichi Nishinakamura
Journal: Journal of the American Society of Nephrology (2015)

Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in vitro . These induced human podocytes exhibited apicobasal polarity, with nephrin proteins accumulated close to the basal domain, and possessed primary processes that were connected with slit diaphragm–like structures. Microarray analysis of sorted iPS cell–derived podocytes identified well conserved marker gene expression previously shown in mouse and human podocytes in vivo . Furthermore, we developed a novel transplantation method using spacers that release the tension of host kidney capsules, thereby allowing the effective formation of glomeruli from human iPS cell–derived nephron progenitors. The human glomeruli were vascularized with the host mouse endothelial cells, and iPS cell–derived podocytes with numerous cell processes accumulated around the fenestrated endothelial cells. Therefore, the podocytes generated from iPS cells retain the podocyte-specific molecular and structural features, which will be useful for dissecting human glomerular development and diseases.
Ovarian function after autologous bone marrow transplantation.
Authors: A D Schimmer, M Quatermain, K Imrie, V Ali, J McCrae, A K Stewart, M Crump, C Derzko, A Keating
Journal: Journal of Clinical Oncology (1998)

To determine the frequency of return of ovarian function after autologous bone marrow transplantation (ABMT), and the major factors that predict recovery.Records of 200 consecutive women who underwent ABMT at the University of Toronto Autologous Blood and Marrow Program (Toronto, Canada) were reviewed. Seventeen patients met the inclusion criteria, which were (1) alive at the time of evaluation, (2) disease-free at least 18 months after transplantation, (3) age younger than 50 years at transplantation, and (4) premenopausal before transplantation. Recovery of ovarian function was determined by pregnancy or regular menses, with no menopausal symptoms and an estradiol level greater than 20 pmol/L off hormonal therapy.All 17 patients became menopausal immediately after ABMT. Five patients (29%) recovered ovarian function a median of 24 months post-ABMT (range, 6 to 48 months). The median age at transplantation of women with restored ovarian function was 19 years (range, 19 to 28 years) versus 30 years (range, 22 to 48 years) for those who did not regain function. Younger age at transplantation predicted ovarian recovery (P = .03) by means of a log-rank test. Only one of five women who regained ovarian function received total-body irradiation (TBI) compared with five of 12 women who did not. Univariate analysis suggested a trend for TBI to predict a sustained loss of ovarian function (P = .067). The number of regimens of induction or salvage chemotherapy that contained an alkylating agent ranged from none to five and was not predictive (P = .45).All women became menopausal after ABMT but 29% recovered ovarian function. Younger age at transplantation predicted return of ovarian function, whereas TBI may have had a negative effect.
The Role of Glutamate Neurotoxicity in Hypoxic-Ischemic Neuronal Death
Authors: D W Choi, S M Rothman
Journal: Annual Review of Neuroscience (1990)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Molecular evolution of the human and simian immunodeficiency viruses.
Authors: S Yokoyama
Journal: Molecular Biology and Evolution (1988)

Molecular evolution and phylogeny of different human immunodeficiency virus type 1 (HIV1) strains, of a type 2 (HIV2) strain, and of two simian immunodeficiency viruses (SIVAGM and SIVMAC) have been studied by comparing the nucleotide sequences of the two regions of their pol genes which encode the reverse transcriptase (RT) and endonuclease/integrase (EN). The analyses show that the different HIV 1s form one cluster (HIV1 group) and that the SIVs and HIV2 form another (HIV2 group). When the entire genomes of a HIV1, a HIV2, and the two SIVs were compared, the SIVAGM showed a unique pattern of mutation accumulations; that is, the SIVAGM has accumulated more nonsynonymous changes than synonymous changes in the RT and EN regions after its recent divergence from SIVMAC-142, and, furthermore, it has a deletion of approximately 350 bp in the region between the pol and env genes. The SIVAGM was apparently derived from cell cultures infected with a macaque isolate, SIVMAC-251. The contamination provides an opportunity to measure the maximum rate of evolution in the SIVAGM by comparing its DNA sequence to those of SIVMAC-251 and SIVMAC-142. The analysis shows that the rates are given approximately by (1.95 +/- 1.37) x 10(-3)/site/year for one SIVAGM sequence and (5.18 +/- 2.25) x 10(-3)/site/year for another.
Efficacy and safety of crizotinib in patients with advanced <i>ROS1</i>-rearranged non-small cell lung cancer (NSCLC).
Authors: Sai-Hong Ignatius Ou, Yung-Jue Bang, D. Ross Camidge, Gregory J. Riely, Ravi Salgia, Geoffrey Shapiro, Benjamin J. Solomon, Jeffrey A. Engelman, Eunice Lee Kwak, Jeffrey W. Clark, Lesley Tye, Keith D. Wilner, Patricia Stephenson, Marileila Varella-Garcia, Kristin Bergethon, Anthony John Iafrate, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2013)

8032 Background: ROS1 receptor tyrosine kinase rearrangements define a subset of NSCLC sensitive to the small-molecule tyrosine kinase inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Updated efficacy and safety data are presented for crizotinib in patients with advanced ROS1-rearranged NSCLC. Methods: ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase 1 crizotinib study (NCT00585195). Patients received crizotinib 250 mg BID. Responses were assessed using RECIST v1.0. The disease control rate (DCR; % stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at weeks 8 and 16. Results: At the data cut-off, 33 patients with ROS1-positive NSCLC had enrolled, and 31 had received crizotinib, with 25 evaluable for response. Median age was 51 years (range 31–72), 79% of patients were never-smokers and 97% had adenocarcinoma histology. The median number of prior treatments for advanced disease was 1 (range 0–7). The objective response rate (ORR) was 56% (95% CI: 24.4–65.1), with 2 CRs, 12 PRs and 8 SDs. 8-week and 16-week DCRs were 76% and 60%, respectively. Median PFS has not been reached, with ~60% of patients still in follow-up for PFS; 6-month PFS probability was 71% (95% CI: 45.6–86.0). Median treatment duration was 24 weeks (range 2.3–112), and 24 patients were on treatment at the data cut-off; 5 patients died (all disease-related). 91% of patients had treatment-related adverse events (AEs): most commonly visual impairment (82%), nausea (36%) and diarrhea (33%). Most AEs were grade 1 in severity. Peripheral edema and elevated transaminases were also reported, similar to the previous experience of crizotinib. There were no treatment-related serious AEs or treatment-related permanent discontinuations. Accrual of patients with ROS1-positive NSCLC is ongoing. Conclusions: As observed in ALK-positive NSCLC, crizotinib had dramatic antitumor activity with a high ORR (56%) in patients with ROS1-positive NSCLC and a generally tolerable and manageable AE profile. These findings indicate that crizotinib is an effective therapy for advanced ROS1-positive NSCLC. Clinical trial information: NCT00585195.
Regulatory mutations in transforming growth factor- 3 gene involved in arrhythmogenic right ventricular cardiomyopathy: AUTHOR'S RETROSPECTIVE
Authors: A. Rampazzo
Journal: Cardiovascular Research (2012)

This editorial refers to an article by G. Beffagna et al . [13][1] published in Cardiovascular Research in 2005 (see [Box 1][2]). It is accompanied by an editorial by J. Tamargo, pp. 188–190, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden death in young adults and athletes. This heart muscle disease is characterized by myocardial dystrophy, mostly of the right ventricle, with massive fibro-fatty infiltration accounting for ventricular electrical instability at a risk of severe arrhythmias and even cardiac arrest.1,2 The left ventricular myocardium seems to be involved in more than half of the cases.3 The disease is clinically heterogeneous, with inter- and intra-familial variability, ranging from benign to malignant forms with a high risk of sudden cardiac death.3 The prevalence of the disease in the general population has been estimated to vary from 1 in 1000 to 1 in 5000 individuals,4,5 and men are more frequently affected than women, with an approximate ratio of 3:1.6 The disease is familial, and typically autosomal dominant with reduced penetrance in about half the cases, although autosomal recessive forms have been reported as well.3

Most of the pathogenic mutations have been identified in genes encoding the desmosomal proteins plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2).3 Although rare, mutations in some non-desmosomal proteins, such as cardiac ryanodine receptor type-2, transforming growth factor-β3 (TGFβ3), transmembrane protein 43, desmin, titin, and lamin A/C have also been associated with ARVC. Mutations in desmosomal genes have been identified in half of the patients, and a significant proportion of them were found to carry multiple mutations.7,8

Therefore, ARVC is actually defined as a disease of desmosomes. …

 [1]: #ref-13
 [2]: #F2
Stressful life events, genetic liability, and onset of an episode of major depression in women
Authors: K S Kendler, R C Kessler, E E Walters, C MacLean, M C Neale, A C Heath, L J Eaves
Journal: American Journal of Psychiatry (1995)

This study was undertaken to clarify how genetic liability and stressful life events interact in the etiology of major depression.Information about stressful life events and onset of major depressive episodes in the past year was collected in a population-based sample of female-female twin pairs including 2,164 individuals, 53,215 person-months of observation, and 492 onsets of depression.Nine "personal" and three aggregate "network" stressful events significantly predicted onset of major depression in the month of occurrence, four of which predicted onset with an odds ratio of > 10 and were termed "severe": death of a close relative, assault, serious marital problems, and divorce/breakup. Genetic liability also had a significant impact on risk of onset of depression. For severe stressful events, as well as for 10 of the 12 individual stressful events, the best-fitting model for the joint effect of stressful events and genetic liability on onset of major depression suggested genetic control of sensitivity to the depression-inducing effects of stressful life events. In individuals at lowest genetic risk (monozygotic twin, co-twin unaffected), the probability of onset of major depression per month was predicted to be 0.5% and 6.2%, respectively, for those unexposed and exposed to a severe event. In those at highest genetic risk (monozygotic twin, co-twin affected), these probabilities were 1.1% and 14.6%, respectively. Linear regression analysis indicated significant Genotype by Environment interaction in the prediction of onset of major depression.Genetic factors influence the risk of onset of major depression in part by altering the sensitivity of individuals to the depression-inducing effect of stressful life events.
Barrier function of the nasal mucosa in health and type‐2 biased airway diseases
Authors: N. Zhang, K. Van Crombruggen, E. Gevaert, C. Bachert
Journal: Allergy (2015)

Abstract The mucosal lining of the upper airways represents the outer surface of the body to the ambient air and its contents and is prepared for it as the first line of defense. Apart from the well‐described physical barrier and the mucociliary clearance, a variety of systems, including the airway microbiome, antimicrobial proteins, damage‐associated molecular patterns, innate lymphoid cells, epithelial‐derived cytokines and chemokines, and finally the adaptive immune system, as well as eosinophils as newly appreciated defense cells form different levels of protection against and response to any possible intruder. Of interest especially for allergic airway disease, mucosal germs might not just elicit a classical Th1/Th17‐biased inflammatory response, but may directly induce a type‐2 mucosal inflammation. Innovative therapeutic interventions may be possible at different levels also; however, whether modulations of the innate or adaptive immune responses will finally be more successful, and how the correction of the adaptive immune response might impact on the innate side, will be determined in the near future.
Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer
Authors: Christina S. Baik, Marc C. Chamberlain, Laura Q. Chow
Journal: Journal of Thoracic Oncology (2015)

Approximately half of all patients with non-small-cell lung cancer (NSCLC) develop brain metastases (BM) during the course of their disease, leading to significant challenges in treatment. Molecular targeted tyrosine kinase inhibitors have proven effective for patients with activating mutations in the epidermal growth factor receptor gene and chromosomal rearrangements involving the anaplastic lymphoma kinase gene. Despite their efficacy in systemic disease control, their effectiveness in patients with BM is not well established. In this article, we review recent data on the use of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for treatment of patients with NSCLC and BM. These data highlight the potential for meaningful disease control within the central nervous system and the inherent challenges in treating patients with NSCLC and BM.
Detection of pathological biomarkers in human clinical samples via amplifying genetic switches and logic gates
Authors: Alexis Courbet, Drew Endy, Eric Renard, Franck Molina, Jérôme Bonnet
Journal: Science Translational Medicine (2015)

With the use of digital genetic amplifiers and logic gates, prototype whole-cell biosensors can be engineered to detect diagnostic biomarkers in complex human clinical samples.
Detection Accuracy of Collective Intelligence Assessments for Skin Cancer Diagnosis
Authors: Ralf H. J. M. Kurvers, Jens Krause, Giuseppe Argenziano, Iris Zalaudek, Max Wolf
Journal: JAMA Dermatology (2015)

<h3>Importance</h3> Incidence rates of skin cancer are increasing globally, and the correct classification of skin lesions (SLs) into benign and malignant tissue remains a continuous challenge. A collective intelligence approach to skin cancer detection may improve accuracy. <h3>Objective</h3> To evaluate the performance of 2 well-known collective intelligence rules (majority rule and quorum rule) that combine the independent conclusions of multiple decision makers into a single decision. <h3>Design, Setting, and Participants</h3> Evaluations were obtained from 2 large and independent data sets. The first data set consisted of 40 experienced dermoscopists, each of whom independently evaluated 108 images of SLs during the Consensus Net Meeting of 2000. The second data set consisted of 82 medical professionals with varying degrees of dermatology experience, each of whom evaluated a minimum of 110 SLs. All SLs were evaluated via the Internet. Image selection of SLs was based on high image quality and the presence of histopathologic information. Data were collected from July through October 2000 for study 1 and from February 2003 through January 2004 for study 2 and evaluated from January 5 through August 7, 2015. <h3>Main Outcomes and Measures</h3> For both collective intelligence rules, we determined the true-positive rate (ie, the hit rate or specificity) and the false-positive rate (ie, the false-alarm rate or 1 − sensitivity) and compared these rates with the performance of single decision makers. Furthermore, we evaluated the effect of group size on true- and false-positive rates. <h3>Results</h3> One hundred twenty-two medical professionals performed 16 029 evaluations. Use of either collective intelligence rule consistently outperformed single decision makers. The groups achieved an increased true-positive rate and a decreased false-positive rate. For example, individual decision makers in study 1, using the pattern analysis as diagnostic algorithm, achieved a true-positive rate of 0.83 and a false-positive rate of 0.17. Groups of 3 individuals achieved a true-positive rate of 0.91 and a false-positive rate of 0.14. These improvements increased with increasing group size. <h3>Conclusions and Relevance</h3> Collective intelligence might be a viable approach to increase diagnostic accuracy in skin cancer and reduce skin cancer–related mortality.
Multiple Genetic Mechanisms Contribute to Visual Sensitivity Variation in the Labridae
Authors: Genevieve A.C. Phillips, Karen L. Carleton, N. Justin Marshall
Journal: Molecular Biology and Evolution (2015)

Coral reefs are one of the most spectrally diverse environments, both in terms of habitat and animal color. Species identity, sex, and camouflage are drivers of the phenotypic diversity seen in coral reef fishes, but how the phenotypic diversity is reflected in the genotype remains to be answered. The labrids are a large, polyphyletic family of coral reef fishes that display a diverse range of colors, including developmental color morphs and extensive behavioral ecologies. Here, we assess the opsin sequence and expression diversity among labrids from the Great Barrier Reef, Australia. We found that labrids express a diverse palette of visual opsins, with gene duplications in both RH2 and LWS genes. The majority of opsins expressed were within the mid-to-long wavelength sensitive classes (RH2 and LWS). Three of the labrid species expressed SWS1 (ultra-violet sensitive) opsins with the majority expressing the violet-sensitive SWS2B gene and none expressing SWS2A. We used knowledge about spectral tuning sites to calculate approximate spectral sensitivities (λmax) for individual species' visual pigments, which corresponded well with previously published λmax values for closely related species (SWS1: 356–370 nm; SWS2B: 421–451 nm; RH2B: 452–492 nm; RH2A: 516–528 nm; LWS1: 554–555 nm; LWS2: 561–562 nm). In contrast to the phenotypic diversity displayed via color patterns and feeding ecology, there was little amino acid diversity within the known opsin sequence tuning sites. However, gene duplications and differential expression provide alternative mechanisms for tuning visual pigments, resulting in variable visual sensitivities among labrid species.
Stem cell-derived hepatocytes: A novel model for hepatitis E virus replication
Authors: Nicky Helsen, Yannick Debing, Jan Paeshuyse, Kai Dallmeier, Ruben Boon, Mar Coll, Pau Sancho-Bru, Christel Claes, Johan Neyts, Catherine M. Verfaillie
Journal: Journal of Hepatology (2015)

Background & AimsYearly, approximately 20million people become infected with the hepatitis E virus (HEV) resulting in over 3million cases of acute hepatitis. Although HEV-mediated hepatitis is usually self-limiting, severe cases of fulminant hepatitis as well as chronic infections have been reported, resulting annually in an estimated 60,000 deaths. We studied whether pluripotent stem cell (PSC)-derived hepatocytes, mesodermal and/or neuroprogenitor cells support HEV replication.MethodsHuman PSC were differentiated towards hepatocyte-like cells, mesodermal cells and neuroprogenitors and subsequently infected with HEV. Infection and replication of HEV was analyzed by qRT-PCR, RNA in situ hybridization, negative strand RT-PCR, production of infectious virions and transfection with a transient HEV reporter replicon.ResultsPSC-derived hepatocytes supported the complete replication cycle of HEV, as demonstrated by the intracellular presence of positive and negative strand HEV RNA and the production of infectious virions. The replication of the virus in these cells was inhibited by the antiviral drugs ribavirin and interferon-α2b. In contrast to PSC-derived hepatocytes, PSC-derived mesodermal cells and neuroprogenitors only supported HEV replication upon transfection with a HEV subgenomic replicon.ConclusionWe demonstrate that PSC can be used to study the hepatotropism of HEV infection. The complete replication cycle of HEV can be recapitulated in infected PSC-derived hepatocytes. By contrast other germ layer cells support intracellular replication but are not infectable with HEV. Thus the early steps in the viral cycle are the main determinant governing HEV tissue tropism. PSC-hepatocytes offer a physiological relevant tool to study the biology of HEV infection and replication and may aid in the design of therapeutic strategies.