Miracle-dz/UniFAR-FTUs huggingface dataset:
Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma

Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1–5 and 8–12 of each 21-day cycle. Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307–15. ©2017 AACR.
Environmental Regulations and Agricultural Competitiveness

The cost of meeting environmental regulations can be a critical factor in determining the competitiveness of a product, since the cost advantages of producers in one country are often very slim. The existence of negative externalities means that prices are lower than would prevail if all costs where included in the prices of the products. Additional costs associated with new regulations have an effect on the continued importance of a country's agricultural exports. Governments often assist their agricultural sectors in overcoming the disadvantages through subsidies, tax breaks, technical assistance or other means. This assistance increasingly takes the form of green payments, which are currently exempt from the WTO limits imposed on domestic subsidies. Competitiveness can be either enhanced or diminished by the environmental regimes of competing nations.
Severe Neonatal Cholestasis in Cerebrotendinous Xanthomatosis: Genetics, Immunostaining, Mass Spectrometry

Objectives: Cerebrotendinous xanthomatosis (CTX) is caused by defects in sterol 27-hydroxylase (CYP27A1, encoded by CYP27A1), a key enzyme in the bile acid synthesis pathway. CTX usually presents as neurologic disease in adults or older children. The rare reports of CTX manifest as neonatal cholestasis assess the cholestasis as transient, with patient survival. Our experience differs. Methods: Homozygous or compound heterozygous CYP27A1 mutations were detected in 8 neonatal cholestasis patients by whole exome sequencing, panel sequencing, or Sanger sequencing. Their clinical and biochemical data were retrospectively reviewed. Immunostaining for CYP27A1 was conducted in liver of 4 patients. Mass spectrometry was used to analyze patients’ urine samples. Results: All 8 infants had severe cholestasis. Five died from, or were transplanted for, liver failure; 3 cleared their jaundice eventually. Marking for CYP27A1 was weak or absent in 3 of the 4 patient specimens. Mass spectrometry of urine revealed a predominance of sulfated and doubly conjugated (sulfated-glucuronidated) bile alcohols. No patient harbored a putatively pathogenic mutation in genes other than CYP27A1 that have been implicated in cholestatic liver disease. Conclusions: CTX manifest as neonatal cholestasis has a bile acid profile different from CTX manifest in later life, and thus may be overlooked. Immunostaining, mass spectrometry of urine, and genetic studies can support one another in making the diagnosis. A substantial proportion of CTX patients with severe neonatal cholestasis may die or need liver transplantation. CTX manifest in infancy as severe cholestasis warrants further investigation of biochemical diagnostic criteria and best management.
Nonequilibrium critical dynamics of the two-dimensional XY model

The nonequilibrium critical dynamics of the two-dimensional XY model is investigated numerically through Monte Carlo simulations and analytically in the spin-wave approximation. We focus in particular on the behaviour of the two-time response and correlation functions and show that the ageing dynamics depends on the initial conditions. The presence of critical fluctuations leads to nontrivial violations of the fluctuation-dissipation theorem apparently reminiscent of the three-dimensional Edwards-Anderson spin glass model. We compute for this reason the finite-size overlap probability distribution function and find that it is related to the finite-time fluctuation-dissipation ratio obtained in the out-of-equilibrium dynamics, provided that the temperature is not very low.
Understanding and Managing Interest Rate Risks

The book is a systematic summary of modern term structure theories and how interest rate contingent claims are priced under such theories. This is the first book on such an attempt. The book reviews important term structure models and chooses one model to consistantly demonstrate contingent claim pricing. Well-known models are included and their relationships are thoroughly discussed. The book also provides a complete process of model implementation from parameter estimation to hedging. Examples are provided throughout.
Symptoms and rehabilitation needs of patients with early stage breast cancer during primary therapy

The treatment for women diagnosed with early breast cancer is complex, dynamic, and controversial. More choices are available for local control and indications for systemic adjuvant therapy have changed dramatically. Knowledge of predictable physical and psychological responses through the various phases of primary treatment is the first critical element for the rehabilitation of these oncology patients. The health care provider can then anticipate problems, prepare the patient with accurate information, and institute interventions early to minimize symptoms. Information and psychological needs dominate the diagnostic phase, during which communication and emotional support are of paramount importance for decision making. Psychological distress persists through the treatment phase regardless of the choice of mastectomy or breast conservation surgery with radiation. The physical symptoms of these choices are similar, primarily related to the axillary lymph node dissection. Fatigue, breast soreness, sensation, and skin changes are common symptoms with breast irradiation that resolve over time. Nausea, vomiting, fatigue, hair loss, menopausal symptoms, and weight gain are predictable chemotherapy‐related side effects and are reported as mild to moderately distressful by the majority of patients. Consistency of information, support, collaboration, coordination of care, and communication among patients and health care providers are essential to meet the challenge of successful treatment and rehabilitation. Cancer 66:1392‐1401, 1990.
Exploring Agency Dynamics of Crowdfunding in Start-Up Capital Financing

In the last decade venture capital markets around the world have experienced growth both in terms of capital under management and the number of venture capital firms providing finance. Despite this there is growing evidence that a 'funding gap' exists at the earliest stages of new firm development. This paper provides an initial investigation into crowdfunding, identifying how it may be appropriately adopted within the start-up equity-financing context so as to contribute to the aggregated pool of capital available to new (pre-commercial) ventures. An agency theoretical perspective is adopted to investigate the necessary agency-cost control mechanisms unique to emerging crowdfunding models. Given the relational character of the investment process, the venture capitalist's perceptions of agency dynamics in the investorinvestee relationship provide an appropriate lens for analysing the likely acceptance of crowdfunding in start-up financing. Data are drawn using a qualitative methodology (convergent interviews) with Australian venture capitalists that provide early stage financing. A total of 11 venture capitalists were interviewed before convergence of common themes was reached. Results suggest that agency dynamics in crowdfunding models in start-up financing comprise a combination of investor specific factors, and ex-ante and ex-post investment factors.
Provincial and Local Governments in China: Fiscal Institutions and Government Behavior

What are the incentives faced by local officials in China? Without democratic institutions, there is no mechanism for local residents to exercise "voice". Given the hukou registration system, local residents have little opportunity to threaten "exit" if they are unhappy with local taxes and spending. This paper explores an alternative source of incentives, starting from the premise that local officials aim to maximize the jurisdiction's fiscal residual (profits), equal to local tax revenue minus expenditures on public services. In a Tiebout setting with mobile households, this objective should lead to efficient provision. What happens, though, if firms and economic activity but not people are mobile? The paper examines the incentives faced by local Chinese officials in this context, and argues that the forecasted behavior helps to explain both the successes and the problems arising from local government activity in China.
The role of assessment in competency-based medical education

Competency-based medical education (CBME), by definition, necessitates a robust and multifaceted assessment system. Assessment and the judgments or evaluations that arise from it are important at the level of the trainee, the program, and the public. When designing an assessment system for CBME, medical education leaders must attend to the context of the multiple settings where clinical training occurs. CBME further requires assessment processes that are more continuous and frequent, criterion-based, developmental, work-based where possible, use assessment methods and tools that meet minimum requirements for quality, use both quantitative and qualitative measures and methods, and involve the wisdom of group process in making judgments about trainee progress. Like all changes in medical education, CBME is a work in progress. Given the importance of assessment and evaluation for CBME, the medical education community will need more collaborative research to address several major challenges in assessment, including “best practices” in the context of systems and institutional culture and how to best to train faculty to be better evaluators. Finally, we must remember that expertise, not competence, is the ultimate goal. CBME does not end with graduation from a training program, but should represent a career that includes ongoing assessment.
Sexual dysfunction: Overview of prevalence, etiological factors, and treatments

Sexual dysfunctions and sexual problems are reviewed from the perspective of prevalence, broad etiological factors, and available treatments. Although a large percentage of individuals experience sexual problems, with estimates between 10% and 52% of men and 25% and 63% of women, the prevalence of sexual dysfunctions that meet diagnostic criteria is lower and less well established by large scale population‐based studies. Sexual problems and dysfunctions are correlated with other health conditions, including cardiovascular disorders, common diseases such as diabetes, health habits, and mental health. Adequate sexual functioning also appears to be associated with personal well‐being and relationship stability, although this may be more accurate for men than women. Efficacious and effective treatments exist for some of the sexual disorders, and there is an increasing focus on medical (particularly pharmacological) treatments being tested by the pharmaceutical industry. Sexual problems and dysfunctions have been notably under‐researched, particularly from the perspective on consequences to individual mental health, relationships, and family functioning.
[Leather corset for the treatment of camptocormia: 31 cases].

INTRODUCTION Camptocormia is an acquired postural disease leading to wide-ranging emerging rachidian kyphosis. Kyphosis can be observed when the patient stands up, walks or sits. The functional impact can be significant. When the etiology is better known, personalized treatments are often deceitful. Physical therapy and orthesis may be proposed. Classical antikyphotic orthesis for the trunk are usually not well tolerated and are quickly abandoned. We proposed the use of traditional leather orthesis for such cases. MATERIALS AND METHOD This retrospective study undertaken between April 2001 and April 2003 included 31 patients with camptocormia for whom orthesis was indicated. Eight patients benefited from use of a classical lumbar belt. All assessed the ortheses as not satisfactory. In 27 patients, leather orthesis was prescribed, and 20 used it, 19 of whom answered a questionnaire assessing functional benefits as follows: the patient is well or very well straightened, suffers less from trunk pain, suffers less or no longer when standing up without assistance during a long period, has less or no difficulty to walk, feels less or no longer tired because of the effort to stay straight without the orthesis, does not resent the alteration of social life because of the orthesis, and assesses active life as satisfactory. RESULTS The average time to wear the othesis was 33 months. Sixty-eight percent of patients wore it at least 9 hours a day; 84% were able to put it on by themselves. The respiratory and cutaneous consequences were judged good and digestive and urinary tolerance adequate. With the orthesis, 74% of the patients responded positively to 5 of the 7 functional areas assessed. Why patients do not wear ortheses is often explained by the failure to obtain a satisfactory straight position and/or an ankle flexion, associated significant pathology, lack of motivation and difficulty in putting the orthesis on alone.
Mechanosensing of shear by Pseudomonas aeruginosa leads to increased levels of the cyclic-di-GMP signal initiating biofilm development

Significance It is well established that mechanical inputs, such as strain and elasticity, can be sensed by eukaryotic cells and can impact phenotype and behavior. In contrast, very little is known about how prokaryotes may respond to mechanical inputs. Here, we show that bacteria can sense shear and can respond by initiating biofilms. This is an important advance in fundamental microbiology and mechanobiology. Biofilms are difficult to prevent using extant approaches. Our knowledge points the way to a hitherto-undeveloped type of antibiofilm surface that thwarts mechanosensing by not sustaining sufficiently high shear. This would prevent bacteria from sensing surface attachment, activating cyclic-di-GMP signaling, and forming a biofilm. Biofilms are communities of sessile microbes that are phenotypically distinct from their genetically identical, free-swimming counterparts. Biofilms initiate when bacteria attach to a solid surface. Attachment triggers intracellular signaling to change gene expression from the planktonic to the biofilm phenotype. For Pseudomonas aeruginosa, it has long been known that intracellular levels of the signal cyclic-di-GMP increase upon surface adhesion and that this is required to begin biofilm development. However, what cue is sensed to notify bacteria that they are attached to the surface has not been known. Here, we show that mechanical shear acts as a cue for surface adhesion and activates cyclic-di-GMP signaling. The magnitude of the shear force, and thereby the corresponding activation of cyclic-di-GMP signaling, can be adjusted both by varying the strength of the adhesion that binds bacteria to the surface and by varying the rate of fluid flow over surface-bound bacteria. We show that the envelope protein PilY1 and functional type IV pili are required mechanosensory elements. An analytic model that accounts for the feedback between mechanosensors, cyclic-di-GMP signaling, and production of adhesive polysaccharides describes our data well.
Hepatitis C Virus Testing and Linkage to Care in North Carolina and South Carolina Jails, 2012–2014

Objective. We evaluated a hepatitis C virus (HCV) testing and linkage-to-care post-release program among detainees of small- to medium-sized jails in North Carolina and South Carolina as part of the Hepatitis Testing and Linkage to Care initiative. Methods. An HCV testing and linkage-to-care program was implemented in selected jails in North Carolina and South Carolina from December 2012 to March 2014. Health-care workers not affiliated with the jails conducted HCV antibody (anti-HCV) and HCV ribonucleic acid (RNA) testing and linkage-to-care activities. The North Carolina jail provided universal opt-out testing for HCV; South Carolina jails initially targeted high-risk individuals before expanding to routine testing. Results. Of 669 detainees tested for HCV in North Carolina, 88 (13.2%) tested anti-HCV positive, of whom 81 (92.0%) received an HCV RNA test, 66 (81.5%) of whom tested HCV RNA positive (i.e., currently infected). Of the 66 detainees with current HCV infection, 18 were referred to HCV medical care post-release and 10 attended their first appointment. Of 224 detainees tested for HCV in South Carolina, 18 (8.0%) tested anti-HCV positive, of whom 13 received an HCV RNA test. Nine of 13 detainees tested HCV RNA positive, seven detainees were referred to post-release medical care, and two detainees attended their first appointment. Overall, 106 of 893 (11.9%) detainees were anti-HCV positive. Conclusion. This study demonstrated that HCV testing, identification of infection, and linkage to care are feasible among jail populations. The rate of anti-HCV positivity was lower than that found in national studies of incarcerated populations, suggesting that HCV infection prevalence in jails may vary across U.S. states or regions.
Rtt109 Acetylates Histone H3 Lysine 56 and Functions in DNA Replication

Acetylation of histone H3 lysine 56 (H3-K56) occurs in S phase, and cells lacking H3-K56 acetylation are sensitive to DNA-damaging agents. However, the histone acetyltransferase (HAT) that catalyzes global H3-K56 acetylation has not been found. Here we show that regulation of Ty1 transposition gene product 109 (Rtt109) is an H3-K56 HAT. Cells lacking Rtt109 or expressing rtt109 mutants with alterations at a conserved aspartate residue lose H3-K56 acetylation and exhibit increased sensitivity toward genotoxic agents, as well as elevated levels of spontaneous chromosome breaks. Thus, Rtt109, which shares no sequence homology with any other known HATs, is a unique HAT that acetylates H3-K56.
The Gender Revolution in Science and Technology

The confluence between the gender and information technology (IT) revolutions has the potential to create a new development paradigm. The transition from an industrial to a knowledge society opens up new opportunities for women in the emerging technology transfer, innovation and entrepreneurship (TIE)fields that avoid some of the negative consequences of academic science. The spread of information and communication technologies (ICTs) in developing countries empowers women by upgrading skills, enhancing employment opportunities, creating income for reinvestment and political strength. This article addresses the consequences of gender inequalities in depressing the contribution of women and the growing opportunities for them to use technology in order to take economic and social advancement into their own hands. ********** The gender revolution in science and technology (ST * Domestic responsibilities, which fall disproportionately on women; and * Lack of social capital (i.e., the relative exclusion from strong networks and the feeling of being outsiders in the field of science) and over-reliance on human capital. (7) As the gender revolution evolves, new vistas appear in the transition from an industrial to a knowledge-based society, bringing increased opportunities for women in the emerging technology transfer, innovation and entrepreneurship (TIE) fields. TIE provides an alternative path that enables women to avoid some of the negative social and psychological consequences of academic science's gendered structures. In this article we address the consequences of gender inequalities in depressing the contribution of women and the growing opportunities for them to use technology in order to take economic and social advancement into their own hands, mostly exemplified through studies from India. …
Calcineurin Mediates the Protective Effect of Postconditioning on Skeletal Muscle

We aimed to investigate whether ischemic postconditioning (I-postC) protects skeletal muscle against ischemia-reperfusion (I/R) injury through the calcineurin (CaN) pathway. Male Wistar rats underwent 4 h of right-hind-limb ischemia induced by clamping the femoral artery, then reperfusion for 2 h (I/R-2 h), 12 h (I/R-12 h), or 24 h (I/R-24 h) with or without I-postC. Ischemic postconditioning was induced by three cycles of 1-min reperfusion and 1-min ischemia at the onset of reperfusion after prolonged ischemia. The I-postC-24 h group was treated with or without cyclosporine A (a CaN inhibitor) 10 mg/kg per day for 3 days before artery occlusion. Cultured skeletal muscle cells (SMCs) from neonatal rats were exposed to 2-h hypoxia then 24-h reoxygenation (H/R), then postconditioned with two cycles of 10-min reoxygenation and 10-min hypoxia after prolonged hypoxia (hypoxia postconditioning [H-postC]) in the presence or absence of cyclosporine A. We observed the effects of activated CaN overexpression on apoptosis and viability of SMCs under H-postC. Ischemic postconditioning attenuated the increase in the level of malondialdehyde in skeletal muscle induced by I/R-2 h and I/R-24 h (P < 0.05) and lactate dehydrogenase in plasma induced by I/R-12 h and I/R-24 h (P < 0.05). Cyclosporine A abolished the protective role of I-postC in malondialdehyde level and lactate dehydrogenase leakage (P < 0.05, vs. I-postC group). Hypoxia postconditioning suppressed SMC apoptosis induced by H/R (P < 0.05, vs. H/R), which was accompanied by increased CaN expression. Cyclosporine A abolished the antiapoptotic effect of H-postC on SMCs (P < 0.05, vs. H-postC group). Overexpression of activated CaN strengthened the cytoprotection of H-postC (P < 0.05, vs. H-postC group). Ischemic postconditioning may protect skeletal muscle against I/R injury through the CaN pathway.ABBREVIATIONS-I-postC-ischemic postconditioning; I/R-ischemia-reperfusion; CsA-cyclosporine A; H/R-hypoxia-reoxygenation; H-postC-hypoxia postconditioning; CaN-calcineurin; LDH-lactate dehydrogenase; MDA-malondialdehyde; SMC-skeletal muscle cell; pCDB-pcDNA3.1-Myc-His (B); ANOVA-analysis of variance