Miracle-dz/UniFAR-FTUs huggingface dataset:
MEK1 and Erk1/2 kinases as targets for the modulation of radiation responses.

BACKGROUND The activation of mitogenic cascades via Ras, c-Raf-1, MEK-1, Erk1/2 is a hall- mark of oncogenic transformation. The cascade is also anti-apoptotic by modulation of Bcl-2, Bcl-xL and BAD function. The impact of MEK-1 on radiation resistance and the role of drugs targeting MEK-1 for the modulation of resistance is unclear. MATERIALS AND METHODS Activation of MEK-1 in four carcinoma cell lines was analyzed using Erk1/2 phosphospecific antibodies. MEK-1 was blocked by PD98059 (2-amino-3methoxyflavin) and influence on radiation responses was determined by apoptotic morphology, caspase-3 activation and colony formation assays. RESULTS MEK-1 kinase was constitutively active and inhibitable by PD98059. The low radiation induced apoptosis rate was not increased by MEK inhibition. PD98059 did not influence cell growth and radiation induced clonogenic cell death. CONCLUSION Since PD98059 did not alter radiation responses despite blocking MEK-1 kinase, MEK-1 and Erk1/2 are not involved in radiation resistance. Thus PD98059 has no potential in the modulation of radiation responses.
Type I interferons are essential mediators of apoptotic death in virally infected cells

The interferons (IFNs) have been extensively studied in the context of host defence against viral infection. In the established model of IFN action, virally infected cells secrete type I IFNs (IFN‐α/β) which induce an antiviral state in uninfected cells. However, it is not clear how IFNs function on the infected cells. It has been reported that cells infected by some viruses die by apoptosis.
Host-Gut Microbiota Metabolic Interactions

The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.
Ciprofloxacin enhances T cell function by modulating interleukin activities

Ciprofloxacin (CIP) is a quinolone carboxylic acid derivative with a broad spectrum of antibacterial activity. CIP (0.1–30 μg/ml) enhanced DNA synthesis of mouse spleen cells and human peripheral blood lymphocytes (PBL) that had been activated with T cell mitogens or with alloantigens. In addition, CIP increased the amount of IL‐2 found in the supernatants of phytohaemagglutinin (PHA)‐stimulated human PBL. The presence of CIP in the medium (0.3–10 μg/ml) increased the levels of IL‐1 found in the culture supernatants of adherence‐enriched mouse macrophages, human monocyte/macrophages and a human monocytic cell line stimulated with lipopolysaccharide. In contrast there was no effect of CIP on the release of IL‐1 by freshly isolated human monocytes or by cells of the keratinocyte line, A431. CIP alone had no influence on the basal release of IL‐2 by NOB‐1 cells, a Tcell line that responds to IL‐1 with an increase in IL‐2 synthesis, but, in combination with recombinant IL‐1, CIP significantly enhanced the release of IL‐2 by these cells. The results of this study suggest that CIP modulates the immune response at two levels—the production of IL‐2 by activated T cells and the production of IL‐1 by activated monocyte/macrophages. However. CIP did not affect the primary antibody response in vitro or in vivo against sheep erythrocytes and ovalbumin respectively. Thus the enhancing action of ciprofloxacin on the immune system appears to be restricted to T cell function and macrophage/T cell interactions.
The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis

Purpose: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. Experimental Design: Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. Results: We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41–0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19–2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43–2.60; P = 2.38e-5). Conclusions: Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268–80. ©2016 AACR.
Understanding the emergence and development of medical collaboration across organizational boundaries: A longitudinal case study

Our goal in this investigation was to help shed light on the very difficult process of collaboration between family physicians and specialists working at different levels of healthcare delivery. More precisely, and grounded on Giddens’ structuration theory, our investigation aims to understand how medical collaboration emerges and develops around chronic patients. This was a longitudinal interpretive case study, the “case” being a continuum-of-care for patients suffering from diabetes, put in place in an urban health center in the Canadian province of Quebec. The study shows how the application of rules of signification and of legitimation, combined with domination resources, have supported the emergence of new forms of collaborative practices. Our analysis reveals, however, that new collaborative practices at the administrative level do not necessarily entail greater shared decision-making in patient management and the mobilization of knowledge across boundaries. The study also corroborates the mutual recursive influence of practices and structures. Our study’s most important contribution concerns the impact of knowledge dynamics, that is, individual and collective learning, on the development of medical collaboration across levels of care.
Cadmium Levels in the Lung, Liver, Kidney Cortex, and Urine Samples from Australians without Occupational Exposure to Metals

Abstract The authors undertook this study to assess levels of cadmium exposure in the general population. Samples of lung, liver, and kidney were obtained from 61 cadavers (43 males, 18 females; 2–89 yr of age, mean age = 38.5 yr) who died from accidental causes and who were subject to postmortem examinations at the John Tonge Centre for Forensic Sciences, Queensland Health Scientific Services, Brisbane, Australia, in 1997 and 1998. Samples of bladder urine were also obtained from 22 cadavers. Tissue and urine samples were analyzed for cadmium, zinc, and copper with inductively coupled plasm (ICP) mass spectrometry. The overall mean values for cadmium in the lung, liver, and kidney cortex samples were 0.13, 0.95, and 15.45 μg/gm wet tissue weight. The average renal cadmium level in subjects with high lung-cadmium levels (n = 13) was 6 μg/gm wet tissue weight higher than that of similarly aged subjects who had medium lung-cadmium levels (n = 30). In females, the average level of cadmium in the liver was 74% greater than in males, and the average liver cadmium in females with high lung-cadmium levels was 100% higher than in males in the same age range who had the same high lung-cadmium levels. Renal cadmium accumulation tended to be greater in females than in males who were in the same age range and who had similar lung-cadmium levels, a result that suggested that there was a higher absorption rate of cadmium in females. The mean value for a urinary cadmium excretion of 2.30 μg/gm creatinine was found in a subset of samples that had a mean age of 39 yr and a renal cortex cadmium concentration of 18.6 μg/gm wet tissue weight. Urinary cadmium excretion rates were correlated more strongly with lung and kidney cadmium content than with age or liver cadmium levels. The results suggest that urinary cadmium excretion may be increased in smokers and could provide some estimate of body cadmium burdens in future Australian epidemiological studies.
Y-box-binding protein YB-1 identifies high-risk patients with primary breast cancer benefiting from rapidly cycled tandem high-dose adjuvant chemotherapy.

PURPOSE To investigate the potential of Y-box-binding protein YB-1, a multifunctional protein linked to tumor aggressiveness and multidrug resistance, to identify patients with breast cancer likely to benefit from dose-intensified chemotherapy regimens. PATIENTS AND METHODS YB-1 was immunohistochemically determined in 211 primary tumors from the prospective, randomized West German Study Group WSG-AM-01 trial in high-risk (> or = 10 involved lymph-nodes) breast cancer (HRBC). Predictive impact of YB-1 was assessed by multivariate survival analysis, including time-varying factor-therapy interactions. RESULTS At median follow-up of 61.7 months, patients receiving rapidly cycled tandem high-dose therapy (HD; two cycles [2x] epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) every 14 days, followed by 2x epirubicin 90 mg/m(2), cyclophosphamide 3,000 mg/m(2), and thiotepa 400 mg/m(2) every 21 days) had better disease-free survival (DFS; hazard ratio [HR] = 0.62; 95% CI, 0.44 to 0.89) and overall survival (OS; HR = 0.59; 95% CI, 0.4 to 0.89) than those receiving conventional dose-dense chemotherapy (DD; 4x epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), followed by 3x cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) every 14 days). High YB-1 was associated with aggressive tumor phenotype (negative steroid hormone receptor status, positive human epidermal growth factor receptor 2 and p53 status, high MIB-1, unfavorable tumor grade) and poor OS (median 78 v 97 months; P = .01). In patients with high YB-1, HD yielded a 63-month median DFS (P = .001) and a 46-month median OS advantage (P = .002) versus DD. In multivariate models, patients with high B-1 receiving HD (v DD) had one third the hazard rate after 20 months for DFS and one sixth after 40 months for OS. CONCLUSION In a randomized prospective cancer therapy trial, for the first time, a strong predictive impact of YB-1 on survival has been demonstrated: enhanced benefit from HD (v DD) therapy occurs in HRBC with high YB-1. Future trials could therefore address optimal chemotherapeutic strategies,taking YB-1 into account.
Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung

The expression of matrix mdalloproteinase‐2 (MMP‐2; 72 kDa type IV collagenase/gelatinase A) and MMP‐9 (92 kDa type IV collagenase/gelatinase B) was Immunohisto chemically Investigated In 79 T1 adenocarcinomas of the lung using non‐commerclal polydonal anti‐MMP‐2 and ‐9 antibodies. Thirty‐two (41%) and 22 (28%) among the 79 cases were positive in the tumor cells for MMP‐2 and ‐9, respectively. The incidences of MMP‐2 and ‐9 Immunoreactivities were higher (64 and 45%, respectively) in poorly differentiated tumors than in well differentiated tumors (36 and 25%, respectively), and lower in bronchloloalveolar carcinoma (22 and 10%, respectively) compared with other subtypes of adenocarcinoma. The prognosis for patients with MMP‐2 andor ‐9 positive Immunoreactivities was significantly poorer than for those with a MMP‐negative tumor (P<0.05). The degree of collagenization was divided into four grades, and tumors with a small to abundant amount of collagen (grade 2 and grade 3 fibrosis) had a higher Incidence of Immunoreactivity to both types of MMP. It is estimated that these expressions might be responsible for tumor Invasion, metastasis, and for grade 2 and grade 3 fibrosis In T1 adenocarcinoma of the lung.
Human Skin Constructs with Spatially Controlled Vasculature Using Primary and iPSC‐Derived Endothelial Cells

Vascularization of engineered human skin constructs is crucial for recapitulation of systemic drug delivery and for their long‐term survival, functionality, and viable engraftment. In this study, the latest microfabrication techniques are used and a novel bioengineering approach is established to micropattern spatially controlled and perfusable vascular networks in 3D human skin equivalents using both primary and induced pluripotent stem cell (iPSC)‐derived endothelial cells. Using 3D printing technology makes it possible to control the geometry of the micropatterned vascular networks. It is verified that vascularized human skin equivalents (vHSEs) can form a robust epidermis and establish an endothelial barrier function, which allows for the recapitulation of both topical and systemic delivery of drugs. In addition, the therapeutic potential of vHSEs for cutaneous wounds on immunodeficient mice is examined and it is demonstrated that vHSEs can both promote and guide neovascularization during wound healing. Overall, this innovative bioengineering approach can enable in vitro evaluation of topical and systemic drug delivery as well as improve the potential of engineered skin constructs to be used as a potential therapeutic option for the treatment of cutaneous wounds.
Perceptions and needs of patients with migraine: a focus group study.

OBJECTIVE This study's purpose was to identify the areas that people find most difficult in living with migraines and, in that regard, what kinds of assistance would be most helpful to them and to other people who have migraine headaches. STUDY DESIGN Four focus groups, each consisting of 4 to 8 participants, were held. Discussions, which were recorded and organized according to category and theme, focused on problems in living with migraines and effective treatment of migraines. POPULATION Participants were 24 people who had been experiencing 1 to 2 migraines a month, each lasting 1 to 2 days, for at least 6 months. RESULTS Five themes emerged: (1) impact on family, (2) misunderstanding by others, (3) effect on work, (4) physician care issues, and (5) issues related to medical insurance and drug companies. A majority of participants identified early treatment as the most important consideration for new migraine sufferers. Many participants preferred to have a relationship with their physicians in which they developed a treatment plan together rather than receiving generic educational materials. CONCLUSIONS Results suggest that patients are interested in understanding their migraines and securing relevant information in addition to obtaining pain relief. Patients desired collaborative relationships with their physicians and a team approach to treatment. Suggestions for physicians who treat patients who have migraines are reviewed.
Trends in the psychopharmacological treatment of bipolar disorder: a nationwide register-based study

Objective In bipolar disorder, treatment with antidepressants without concomitant use of mood stabilisers (antidepressant monotherapy) is associated with development of mania and rapid cycling and is therefore not recommended. The present study aimed to investigate the psychopharmacological treatment patterns in bipolar disorder over time, with a focus on antidepressant monotherapy. Methods Cohort study with annual cross-sectional assessment of the use of psychotropic medications between 1995 and 2012 for all Danish residents aged 10 years or older with a diagnosis of bipolar disorder registered in the Danish Psychiatric Central Research Register. Users of a given psychotropic medication were defined as individuals having filled at least one prescription for that particular medication in the year of interest. Results We identified 20 618 individuals with bipolar disorder. The proportion of patients with bipolar disorder using antidepressants, atypical antipsychotics and anticonvulsants increased over the study period, while the proportion of patients using lithium, typical antipsychotics and benzodiazepines/sedatives decreased. The proportion of patients treated with antidepressant monotherapy decreased from 20.5% in 1997 to 12.1% in 2012, and among antidepressant users, the proportion in monotherapy decreased from 47.7% to 23.9%, primarily driven by a decrease in the use of tricyclic antidepressants. Conclusion The results show an increase in the proportion of patients with bipolar disorder being treated with antidepressants in the period from 1997 to 2012. However, in accordance with international treatment guidelines, the extent of antidepressant monotherapy decreased during the same period.
Store depletion induces Gαq-mediated PLCβ1 activity to stimulate TRPC1 channels in vascular smooth muscle cells

Depletion of sarcoplasmic reticulum (SR) Ca2+ stores activates store‐operated channels (SOCs) composed of canonical transient receptor potential (TRPC) 1 proteins in vascular smooth muscle cells (VSMCs), which contribute to important cellular functions. We have previously shown that PKC is obligatory for activation of TRPC1 SOCs in VSMCs, and the present study investigates if the classic phosphoinositol signaling pathway involving Gαq‐mediated PLC activity is responsible for driving PKC‐dependent channel gating. The G‐protein inhibitor GDP‐β‐S, anti‐Gαq antibodies, the PLC inhibitor U73122, and the PKC inhibitor GF109203X all inhibited activation of TRPC 1 SOCs, and U73122 and GF109203X also reduced store‐operated PKC‐dependent phosphorylation of TRPC1 proteins. Three distinct SR Ca2+ store‐depleting agents, 1,2‐bis (2‐aminophenoxy) ethane‐N,N,N',N'‐tetraacetic acid acetoxymethyl ester, cyclopiazonic acid, and N,N,N',N'‐tetrakis(2‐pyridylmethyl)ethane‐1,2‐diamineed, induced trans‐locations of the fluorescent biosensor GFP‐PLCδ1‐PH from the cell membrane to the cytosol, which were inhibited by U73122. Knockdown of PLCβ1 with small hairpin RNA reduced both store‐operated PLC activity and stimulation of TRPC1 SOCs. Immunoprecipitation studies and proximity ligation assays revealed that store depletion induced interactions between TRPC 1 and Gαq, and TRPC 1 andPLCβ1. We propose a novel activation mechanism for TRPC 1 SOCs in VSMCs, in which store depletion induces formation of TRPC1‐Gαq‐PLCβ1 complexes that lead to PKC stimulation and channel gating. —Shi, J., Miralles, F. , Birnbaumer, L. , Large, W. A. , Albert, A. P. Store depletion induces Gαq‐mediated PLCβ1 activity to stimulate TRPC1 channels in vascular smooth muscle cells. FASEB J. 30, 702‐715 (2016). www.fasebj. org
The combined effect of relaxation response and acupuncture on quality of life in patients with HIV: a pilot study.

OBJECTIVES Treatment advances have transformed human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) into a chronic manageable disease; quality of life (QoL) has become an important health outcome. Some studies have shown the individual effects of acupuncture and the relaxation response (RR) in improving QoL of patients with HIV/AIDS. In light of the presumed shared features of acupuncture and the RR, we conducted a pilot study to examine the effects of adding the RR to usual acupuncture treatment on improving the QoL of HIV/AIDS patients. DESIGN Two-arm double-blind randomized controlled trial. SETTINGS/LOCATION AND SUBJECTS: We enrolled 119 patients with HIV/AIDS (mean age 46 years, 85% male) who had at least 1 of the highly prevalent HIV-related symptoms and who were receiving acupuncture treatment in an acupuncture clinic in Boston, MA. INTERVENTION We randomized patients into intervention (N = 58) and control (N = 61) groups. All participants received individualized acupuncture treatments prescribed by their acupuncturists. While receiving acupuncture treatment, the intervention group wore earphones to listen to tapes with instructions to elicit the RR followed by soft music that was routinely played in the clinic; the control group listened only to soft music. OUTCOME MEASURES Three (3) QoL scales: the Medical Outcomes Study HIV health survey, the Functional Assessment of HIV Infection, and the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, measured at baseline, 4-week, 8-week, and 12-week follow-ups. RESULTS At the 12-week follow-up, the intervention group showed significant improvements in emotional (p = 0.0002), spiritual/peace (p = 0.02), physical (p = 0.003) and mental health (p = 0.0003) QoL from baseline. Results of mixed effects regression models indicated linear trends of improvement over time in these dimensions of QoL for the intervention group (p < 0.02). In the control group, the only significant improvement was observed in the emotional QoL (p < 0.01). The intervention group showed trends of greater improvements than the control group (p = 0.07 for 12-week physical health QoL). CONCLUSIONS Data from this pilot trial suggested that adding the RR to acupuncture may enhance improvement in QoL of patients with HIV/AIDS. Further investigation on this putative synergistic effect is warranted.
Comparison of perinatal outcomes in late preterm birth between singleton and twin pregnancies

Objective To determine whether late preterm twin neonates have a more favorable perinatal outcome than singleton late preterm neonates. Methods We studied 401 late preterm births between 34+0 and 36+6 weeks of gestation, from January 2011 to December 2014 in our institution. We compared the maternal and neonatal characteristics and perinatal outcomes between singleton and twin pregnancies. Perinatal outcomes included Apgar score, admission to the neonatal intensive care unit (NICU) or special care nursery, duration of NICU stay, and the rate of composite morbidity (antibiotic use, hypoglycemia, hypocalcemia, hyperbilirubinemia requiring phototherapy, respiratory support, and respiratory distress syndrome). Results A total of 289 neonates were in the singleton group and 112 in the twin group. The twin group showed smaller mean birth weight despite of longer gestational age at delivery. In addition, there were significant differences in the indication of delivery and cesarean section rate between the 2 groups. Overall, the risk of composite morbidity was similar between 2 groups (odds ratio, 1.4; 95% confidence interval, 0.8 to 2.4). Conclusion Our findings suggest that late preterm twins do not show a more favorable outcome than singleton late preterm births.