gebhart/patrepeval huggingface dataset:
Learning under Differing Training and Test Distributions (2009)

One of the main problems in machine learning is to train a predictive model from training data and to make predictions on test data. Most predictive models are constructed under the assumption that the training data is governed by the exact same distribution which the model will later be exposed to. In practice, control over the data collection process is often imperfect. A typical scenario is when labels are collected by questionnaires and one does not have access to the test population. For example, parts of the test population are underrepresented in the survey, out of reach, or do not return the questionnaire. In many applications training data from the test distribution are scarce because they are difficult to obtain or very expensive. Data from auxiliary sources drawn from similar distributions are often cheaply available. This thesis centers around learning under differing training and test distributions and covers several problem settings with different assumptions on the relationship between training and test distributions-including multi-task learning and learning under covariate shift and sample selection bias. Several new models are derived that directly characterize the divergence between training and test distributions, without the intermediate step of estimating training and test distributions separately. The integral part of these models are rescaling weights that match the rescaled or resampled training distribution to the test distribution. Integrated models are studied where only one optimization problem needs to be solved for learning under differing distributions. With a two-step approximation to the integrated models almost any supervised learning algorithm can be adopted to biased training data. In case studies on spam filtering, HIV therapy screening, targeted advertising, and other applications the performance of the new models is compared to state-of-the-art reference methods.
Identification and analysis of alternative splicing events conserved in human and mouse (2005)

Alternative pre-mRNA splicing affects a majority of human genes and plays important roles in development and disease. Alternative splicing (AS) events conserved since the divergence of human and mouse are likely of primary biological importance, but relatively few of such events are known. Here we describe sequence features that distinguish exons subject to evolutionarily conserved AS, which we call alternative conserved exons (ACEs), from other orthologous human/mouse exons and integrate these features into an exon classification algorithm, acescan. Genome-wide analysis of annotated orthologous human-mouse exon pairs identified approximately 2,000 predicted ACEs. Alternative splicing was verified in both human and mouse tissues by using an RT-PCR-sequencing protocol for 21 of 30 (70%) predicted ACEs tested, supporting the validity of a majority of acescan predictions. By contrast, AS was observed in mouse tissues for only 2 of 15 (13%) tested exons that had EST or cDNA evidence of AS in human but were not predicted ACEs, and AS was never observed for 11 negative control exons in human or mouse tissues. Predicted ACEs were much more likely to preserve the reading frame and less likely to disrupt protein domains than other AS events and were enriched in genes expressed in the brain and in genes involved in transcriptional regulation, RNA processing, and development. Our results also imply that the vast majority of AS events represented in the human EST database are not conserved in mouse.
The natural history and treatment outcome of blast phase BCR-ABL− myeloproliferative neoplasms (2008)

We analyzed the outcomes of 74 patients diagnosed with BCR-ABL(-) myeloproliferative neoplasms in blast phase receiving induction chemotherapy (55%), low-intensity therapy (16%), stem cell transplantation (SCT; 3%), or supportive care (26%). Median survival from the date of blastic transformation was 5 months. Patients receiving supportive therapy had a median survival of 6 weeks. Complete remission with or without blood recovery was achieved in 46% of patients receiving induction chemotherapy, but remissions were not durable with a median progression-free survival of only 5 months. Eight patients received SCT either as first therapy or after responding to antileukemia therapy. These patients had a markedly superior survival, with 73% alive at a median follow-up of 31 months. JAK2V617F kinetics were assessed in 16 patients: 0 of 4 negative patients became positive at transformation, and among 12 positive patients, 1 had an increase in JAK2V617F% at transformation, 7 had a substantial decrease, and 4 had stable levels. Myeloproliferative neoplasm blast phase is associated with a dismal prognosis. Responses to chemotherapy can be achieved but are not durable. Long-term survivors had all received SCT either as first therapy or in first remission.
Direct plant gene delivery with a poly(amidoamine) dendrimer (2008)

Plant gene delivery is challenging due to the presence of plant cell walls. Conventional means such as Agrobacterium infection, biolistic particle bombardment, electroporation, or polyethylene glycol attachment are often characterized by high cost, labor extensiveness, and a significant perturbation to the growth of cells. We have succeeded in delivering GFP-encoding plasmid DNA to turfgrass cells using poly(amidoamine) dendrimers. Our new scheme utilizes the physiochemical properties as well as the nanosize of the poly(amidoamine) dendrimer for direct and noninvasive gene delivery. The GFP gene was expressed in the plant cells as observed by confocal fluorescence microscopy. The transfection efficiency may be further improved by optimizing the pH of the cell culture medium and the molar ratio of the dendrimer to DNA. The use of the current delivery system can be extended to virtually all plant species having successful regeneration systems in place.
Randomized controlled study of chemoimmunotherapy of acute myelogenous leukemia (AML) in adults withNocardia Rubra cell-wall skeleton and irradiated allogeneic AML cells (1986)

The effect of immunotherapy with Nocardia rubra cell-wall skeleton (N-CWS) on remission duration and survival of adults with acute myelogenous leukemia (AML) was studied in a prospective randomized controlled study. After having been induced into complete remission and having been consolidated, 73 patients were randomized either to maintenance chemotherapy or maintenance chemotherapy plus immunotherapy with N-CWS and irradiated allogeneic AML cells. Thirty-four patients in the chemotherapy group and 32 in the chemoimmunotherapy group were evaluable. Six months after the closure of the study, the immunotherapy showed a borderline beneficial effect on remission duration (P = 0.080) and on survival length (P = 0.098). When the data were analyzed at 30 months after the entry, there was a borderline significant difference in remission duration (P = 0.080) between the two groups, prolonging the 50% remission period by 110 days; but no significant difference in survival length (P = 0.314), although the 50% survival was 168 days longer in the chemoimmunotherapy group. However, there were 4 (18.2%) 5-year relapse-free survivors among 22 patients (11 in each group) who had been diagnosed more than 5 years before the time of the present analysis, and all of them belonged to the chemoimmunotherapy group (P = 0.090). Thus, immunotherapy with N-CWS and irradiated allogeneic AML cells seems to be active in the treatment of adult AML when used for maintenance therapy in combination with chemotherapy.
Buspirone, Parkinsonʼs Disease, and the Locus Ceruleus (1986)

Buspirone is a novel anxiolytic whose pharmacological profile differs from that of the benzodiazepines and includes dopaminergic agonist effects. Because of these properties, buspirone's usefulness in the management of idiopathic Parkinson's disease was evaluated in a controlled study of 16 outpatients with stage I-IV disease. At doses of 10 to 60 mg/day, no significant group or individual effects could be discerned on standardized disability, dyskinesia, anxiety, or depression scales. At high dose levels (100 mg/day) however, there was a significant worsening of disability ratings and a decrease in dyskinesia scores; anxiety ratings were also significantly increased. The results indicate that buspirone is well tolerated by parkinsonian patients at conventional antianxiety doses of 10 to 40 mg. Clinical effects of high dose treatment, on the other hand, resemble those associated with a reduction in central dopamine mediated synaptic function. Since buspirone reportedly produces dose-dependent stimulation of norepinephrine containing neurons in the locus ceruleus and behavioral symptoms of such activation were observed, these clinical observations support the concept that central noradrenergic stimulation can adversely affect parkinsonian symptoms.
Relaxation‐expansion model for self‐driven retinal morphogenesis (2011)

Abstract The generation of complex organ structures such as the eye requires the intricate orchestration of multiple cellular interactions. In this paper, early retinal development is discussed with respect to the structure formation of the optic cup. Although recent studies have elucidated molecular mechanisms of retinal differentiation, little is known about how the unique shape of the optic cup is determined. A recent report has demonstrated that optic‐cup morphogenesis spontaneously occurs in three‐dimensional stem‐cell culture without external forces, indicating a latent intrinsic order to generate the structure. Based on this self‐organizing phenomenon, we introduce the “relaxation‐expansion” model to mechanically interpret the tissue dynamics that enable the spontaneous invagination of the neural retina. This model involves three consecutive local rules (relaxation, apical constriction, and expansion), and its computer simulation recapitulates the optic‐cup morphogenesis in silico.
Influence of Doxorubicin Dose Intensity on Response and Outcome for Patients With Osteogenic Sarcoma and Ewing's Sarcoma (1991)

The goal of this study was to use dose-intensity analyses of published Ewing's sarcoma and osteogenic sarcoma trials to determine which agents were most closely associated with a favorable response. The percentage of patients with more than 90% tumor necrosis following neoadjuvant chemotherapy was the end point for analysis of osteogenic sarcoma trials, and disease-free survival and percentage of patients with distant-only relapse were the end points for analysis of Ewing's sarcoma trials. The data were analyzed using logistic regression analysis to circumvent the distortion of univariate analysis resulting from the correlation between doxorubicin dose intensity and the dose intensity of other agents. Our analysis suggests that doxorubicin dose intensity is an important determinant of favorable outcome for both Ewing's sarcoma and osteogenic sarcoma and that the dose intensities of other agents do not contribute as significantly to outcome as does doxorubicin dose intensity. Increasing dactinomycin dose intensity was associated with a poorer outcome in treatment of osteogenic sarcoma and Ewing's sarcoma, most likely resulting from regimens with a higher dactinomycin dose intensity having a lower doxorubicin dose intensity. While our analysis of osteogenic sarcoma trials is consistent with significant activity for cisplatin and high-dose methotrexate (and likely ifosfamide), a rank ordering of the efficacy of these agents when given with doxorubicin in multiagent regimens is not possible. Our analysis illustrates the importance of analyzing the contributions of individual agents to combination chemotherapy regimens. In the design of future clinical trials for osteogenic sarcoma and Ewing's sarcoma, careful attention should be given to optimizing doxorubicin dose intensity in regimens to be tested.
CD133+ Cancer Stem Cell–like Cells Derived from Uterine Carcinosarcoma (Malignant Mixed Müllerian Tumor) (2011)

Cancer stem cells (CSCs) that display tumor-initiating properties have recently been identified. CD133, a surface glycoprotein linked to organ-specific stem cells, has been described as a marker of CSCs in different tumor types. We herein identify and characterize CSCs in human uterine carcinosarcoma (malignant mixed Müllerian tumor), which is one of the most aggressive and therapy-resistant gynecological malignancies and is considered to be of mesodermal origin. The CD133(+) population was increased in uterine carcinosarcoma, and this population showed biphasic properties in the primary tumor. CD133(+) cells predominantly formed spheres in culture and were able to differentiate into mesenchymal lineages. CD133(+) cells were more resistant to cisplatin/paclitaxel-induced cytotoxicity in comparison with CD133(-) cells. A real-time polymerase chain reaction analysis of the genes implicated in stem cell maintenance revealed that CD133(+) cells express significantly higher levels of Oct4, Nanog, Sox2, and Bmi1 than CD133(-) cells. Moreover, CD133(+) cells showed a high expression level of Pax2 and Wnt4, which are genes essential for Müllerian duct formation. These CD133(+) cells form serially transplantable tumors in vivo and the resulting CD133(+) tumors replicated the EpCAM, vimentin, and estrogen and progesterone receptor expression of the parent tumor, indicating that CSCs likely differentiated into cells comprising the uterine carcinosarcoma tissue. Moreover, strong CD133 expression in both epithelial and mesenchymal elements in primary tumor demonstrated significant prognostic value. These findings suggest that CD133(+) cells have the characteristics of CSCs and Müllerian mesenchymal progenitors.
Sterols. XIV. Pyroandrosterone and Derivatives (1937)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSterols. XIV. Pyroandrosterone and DerivativesRussell E. Marker, Oliver Kamm, David M. Jones, and Lawson W. MixonCite this: J. Am. Chem. Soc. 1937, 59, 7, 1363–1366Publication Date (Print):July 1, 1937Publication History Published online1 May 2002Published inissue 1 July 1937https://doi.org/10.1021/ja01286a059RIGHTS & PERMISSIONSArticle Views52Altmetric-Citations9LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (344 KB) Get e-Alerts Get e-Alerts
A Cape Colonial childhood : the recollections of Dr. R.A. St. Leger (2001)

Robert Arthur (Bob) St Leger (1865-1953) was a son of F Y St Leger, first editor and co-founder of the Cape Times. The first fourteen years of his life, the period covered by these reminiscences, were spent in Queenstown where he was born, his father being then Rector of St Michael's, Kimberley, Stellenbosch and Cape Town. He was educated at the Dioscesan College, Rondebosch, and at Tonbridge School, Kent.
Mammalian Transforming Growth Factor β1 Activated after Ingestion byAnopheles stephensiModulates Mosquito Immunity (2003)

During the process of bloodfeeding by Anopheles stephensi, mammalian latent transforming growth factor beta1 (TGF-beta1) is ingested and activated rapidly in the mosquito midgut. Activation may involve heme and nitric oxide (NO), agents released in the midgut during blood digestion and catalysis of L-arginine oxidation by A. stephensi NO synthase (AsNOS). Active TGF-beta1 persists in the mosquito midgut to extended times postingestion and is recognized by mosquito cells as a cytokine. In a manner analogous to the regulation of vertebrate inducible NO synthase and malaria parasite (Plasmodium) infection in mammals by TGF-beta1, TGF-beta1 regulates AsNOS expression and Plasmodium development in A. stephensi. Together, these observations indicate that, through conserved immunological cross talk, mammalian and mosquito immune systems interface with each other to influence the cycle of Plasmodium development.
Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients (2017)

The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.
Lack of DNA homology in a pair of divergent chromosomes greatly sensitizes them to loss by DNA damage. (1989)

Chromosomal DNA is considered a priori to be a target for the induction of numerical (whole chromosome) aneuploidy in mitotic cells. If true, DNA repair would be expected to contribute to genome stability. One type of repair that appears to play an important role in the response of many organisms to DNA-damaging agents involves recombination. Using the yeast Saccharomyces cerevisiae containing a pair of DNA divergent (homoeologous) chromosomes, we have been able to determine the importance of recombinational repair of DNA damage in the maintenance of chromosome number. Specifically, the induction of aneuploidy by ionizing radiation has been examined in diploids that had one chromosome III replaced by a divergent chromosome from Saccharomyces carlsbergensis. The chromosomes are functionally equivalent but lack precise DNA homology over one-half their length. The absence of homology, and thus the opportunity for recombinational repair (presumably of DNA double-strand breaks) in the divergent chromosomes, results in high levels (5-10%) of aneuploidy for chromosome III at doses of radiation resulting in almost no killing. For homologous chromosomes, the frequency of loss is 20-50 times lower.
Activated keratinocytes in the epidermis of hypertrophic scars. (1998)

The etiology of hypertrophic scarring, a pathological end point of wound healing, is unknown. The scars most commonly occur when epithelialization has been delayed during, for example, the healing of deep dermal burn wounds. Hypertrophic scars are conventionally described as a dermal pathology in which the epidermis has only a passive role. In this study, the expression of keratin intermediate filament proteins and filaggrin has been investigated in the epidermis of hypertrophic scars and site-matched controls from the same patients. Hypertrophic scar epidermis was found to express the hyperproliferative keratins K6 and K16 in interfollicular epidermis in association with K17 and precocious expression of filaggrin. K16 mRNA was localized by in situ hybridization using a highly specific cRNA probe. In contrast to the immunohistochemical location of K16 protein, the K16 mRNA was found to be expressed in the basal cell layer of normal skin. In hypertrophic scars the mRNA distribution corroborated the abnormal K16 protein distribution. These results suggest the keratinocytes in hypertrophic scar epidermis have entered an alternative differentiation pathway and are expressing an activated phenotype. Activated keratinocytes are a feature of the early stages of wound healing producing growth factors that influence fibroblasts, endothelial cells, and the inflammatory response. We propose that cellular mechanisms in the pathogenesis of hypertrophic scarring are more complex than isolated dermal phenomena. The persistence of activated keratinocytes in hypertrophic scar epidermis implicates abnormal epidermal-mesenchymal interactions.
Ghrelin Uses Gαi2 and Activates Voltage-Dependent K+ Channels to Attenuate Glucose-Induced Ca2+ Signaling and Insulin Release in Islet β-Cells (2007)

Ghrelin reportedly serves as a physiological regulator of insulin release. This study aimed to explore signaling mechanisms for insulinostatic ghrelin action in islet beta-cells, with special attention to heterotrimeric GTP-binding proteins and K(+) channels. Plasma insulin and growth hormone (GH) concentrations in rats were measured by enzyme-linked immunosorbent assay (ELISA). Islets were isolated from rats, ghrelin-knockout (Ghr-KO) mice, and wild-type mice by collagenase digestion, and insulin release was determined by ELISA. In rat single beta-cells, cytosolic Ca(2+) concentration ([Ca(2+)](i)) was measured by fura-2 microfluorometry, and membrane potentials and whole cell currents by patch-clamp technique. In rats, systemic ghrelin administration decreased plasma insulin concentrations, and this effect was blocked by treatment with pertussis toxin (PTX), whereas stimulation of GH release remained unaffected. In rat islets, ghrelin receptor antagonist increased and exogenous ghrelin suppressed glucose-induced insulin release in a PTX-sensitive manner. Glucose-induced insulin release from islets was greater in Ghr-KO than wild-type mice, and this enhanced secretion was blunted with PTX. Ghrelin PTX sensitively increased voltage-dependent K(+) (Kv) currents without affecting ATP-sensitive K(+) channels in rat beta-cells. In the presence of Kv channel blockers, ghrelin failed to suppress insulin release. Ghrelin attenuated glucose-induced action potentials and [Ca(2+)](i) increases in beta-cells. Suppressions of [Ca(2+)](i) increase and insulin release by ghrelin were blunted in beta-cells treated with PTX and with antisense oligonucleotide specific for G-protein Galpha(i2)-subunit. Ghrelin attenuates glucose-induced insulin release via PTX-sensitive Galpha(i2)-mediated activation of Kv channels and suppression of [Ca(2+)](i) in beta-cells, representing the unique signaling of ghrelin distinct from that for GH release.