Miracle-dz/UniFAR-FTUs huggingface dataset:
Exploring Differential Connexin Expression across Melanocytic Tumor Progression Involving the Tumor Microenvironment

The incidence of malignant melanoma, one of the deadliest cancers, continues to increase. Here we tested connexin (Cx) expression in primary melanocytes, melanoma cell lines and in a common nevus, dysplastic nevus, and thin, thick, and metastatic melanoma tumor progression series involving the tumor microenvironment by utilizing in silico analysis, qRT-PCR, immunocyto-/histochemistry and dye transfer tests. Primary melanocytes expressed GJA1/Cx43, GJA3/Cx46 and low levels of GJB2/Cx26 and GJC3/Cx30.2 transcripts. In silico data revealed downregulation of GJA1/Cx43 and GJB2/Cx26 mRNA, in addition to upregulated GJB1/Cx32, during melanoma progression. In three melanoma cell lines, we also showed the loss of GJA1/Cx43 and the differential expression of GJB1/Cx32, GJB2/Cx26, GJA3/Cx46 and GJC3/Cx30.2. The dominantly paranuclear localization of connexin proteins explained the ~10–90 times less melanoma cell coupling compared to melanocytes. In melanocytic tumor tissues, we confirmed the loss of Cx43 protein, fall of cell membrane and elevated paranuclear Cx32 with moderately increased cytoplasmic Cx26 and paranuclear Cx30.2 positivity during tumor progression. Furthermore, we found Cx43, Cx26 and Cx30 proteins upregulated in the melanoma adjacent epidermis, and Cx43 in the tumor flanking vessels. Therefore, differential connexin expression is involved in melanocytic tumor progression where varying connexin isotypes and levels reflect tumor heterogeneity-related bidirectional adaptive interactions with the microenvironment.
The role of physical activity in the context of pulmonary rehabilitation

Abstract Pulmonary rehabilitation is an important treatment for patients with chronic obstructive pulmonary disease (COPD). Although this intervention leads to large and clinically meaningful improvements in exercise capacity and quality of life, the effect of pulmonary rehabilitation on physical activity is controversial. Physical activity is lower in patients with COPD as compared to healthy age-matched controls and it is related to important health outcomes (e.g. increased risk of mortality and hospitalization). It is an important goal for rehabilitation programs to enhance physical activity to more normal levels in order to achieve the ultimate goal of rehabilitation ‘to improve adherence to health enhancing behaviors’. This review discusses the role of physical activity in the context of pulmonary rehabilitation and possible ways to embed interventions geared to behavior change (i.e. to enhance physical activity) and exercise training (i.e. to enhance physical fitness) into comprehensive rehabilitation programs for patients with COPD.
Enhanced lithium storage performance of graphene nanoribbons doped with high content of nitrogen atoms

Nitrogen doping can provide a large number of active sites for lithium-ion storage, thus can yield a higher capacity for lithium-ion batteries. However, most of the reported N-doped graphene-based materials have low nitrogen content (<10 wt%) as the introduction of nitrogen atoms prefer to be produced at edges and defects in the graphene lattices. Owing to the formation of edges and defects, the doped states or active sites can easily be located and nitrogen contents can be determined precisely. Here we present the preparation of N-doped graphene nanoribbons with high nitrogen contents (11.8 wt%) and a facile tunable configuration of doped states. The material can be used as an anode for lithium-ion batteries and shows a higher capacity (the electrode has a reversible capacity of 1100.34 mA h g−1 at a charge/discharge rate of 100 mA g−1, corresponds to a discharge time of about 9 h), better rate performance (the electrode has a reversible capacity of 471 mA h g−1 at the current density of 2 A g−1, corresponds to a discharge time of about 11.6 min) and improved cycling stability (87.37% of the initial capacity after 200 cycles). The experimental results and first-principle calculations suggest that the residual oxygen-containing functional groups of N-doped graphene nanoribbons promote the formation of pyrrolic nitrogen at edges and substantially increase the room for nitrogen doping. This work opens new strategies for designing and developing N-doped graphene anodes for high performance lithium-ion batteries.
Methods in Genetics and Clinical Interpretation Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts

Background—The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods—The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. Conclusions—The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events. (Circ Cardiovasc Genet. 2009;2:73-80.)
Exome sequencing in families with chronic central serous chorioretinopathy

Central serous chorioretinopathy (CSC) is a chorioretinal disease characterized by fluid accumulation between the neuroretina and retinal pigment epithelium with unknown etiology. Family studies have suggested a heritable component for CSC with an autosomal dominant inheritance pattern. Therefore, exome sequencing was performed on familial cCSC to indentify the genetic components contributing to familial cCSC.
Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated.

BACKGROUND Klinefelter syndrome (KS) with the karyotype 47,XXY is one of the commonest types of congenital chromosomal disorder in males, with an incidence of 0.1% to 0.2% of newborn male infants. It causes hypogonadism and infertility. Until now, however, only about one-quarter of all persons with KS received the diagnosis during their lifetimes. METHODS Selective review of the literature. RESULTS KS is caused by aneuploidy of the sex chromosomes. Small, firm testes, the manifestations of androgen deficiency (sparse development of male-pattern body hair, greater than average height, lack of libido, erectile dysfunction) and, in more than 90% of affected men, azoospermia are its main features in adults. Affected boys may have verbalization difficulties and problems with learning and socialization. KS is often accompanied by other disturbances such as gynecomastia, varicose veins, thrombosis, osteoporosis, the metabolic syndrome, type 2 diabetes, and epilepsy. The most important therapeutic measure is testosterone supplementation, which should be initiated if the testosterone concentration drops below 12 nmol/L and should be given as directed in the guidelines for the treatment of hypogonadism. This recommendation is made even though there have not been any randomized controlled trials documenting the efficacy of testosterone therapy in adolescents or young adults. In some cases, viable sperm can be obtained from individual testicular tubules by biopsy, so that these patients are able to become fathers. CONCLUSION The diagnosis of KS would be less frequently missed if doctors were more aware of, and attentive to, its key manifestations, particularly the small, firm testes, erectile dysfunction, and the comorbidities mentioned above. If the diagnosis were made more often, patients would more often be able to receive early treatment, which would improve their quality of life.
Neoadjuvant Management of Early Breast Cancer: A Clinical and Investigational Position Statement.

BACKGROUND Neoadjuvant treatment is increasingly one of the preferred therapeutic options for early breast cancer and may have some unique outcomes, such as identifying predictive and prognostic factors of response or increasing the knowledge of individual tumor biology. DESIGN A panel of experts from different specialties reviewed published clinical studies on the neoadjuvant management of breast cancer. Recommendations were made that emphasized the clinical multidisciplinary management and the investigational leverage in early breast cancer. RESULTS Neoadjuvant therapy has equivalent efficacy to adjuvant therapy, and it has some additional benefits that include increasing breast conservation, assessing tumor response, establishing prognosis based on the pathological response, and providing a "second opportunity" for nonresponding patients. Achieving pathological complete remission because of neoadjuvant therapy has been correlated with long-term clinical benefit, particularly in HER2-positive and triple-negative breast cancer. In addition, the neoadjuvant setting is a powerful model for the development of new drugs and the identification of prognostic markers. Finally, neoadjuvant therapy has proven to be cost-effective by reducing nondrug costs, avoiding radical surgery, and reducing hospital stays when compared with other treatment approaches. CONCLUSION Neoadjuvant therapy has clinical benefits in early breast cancer and provides in vivo information of individual breast cancer biology while allowing the investigation of new treatment approaches. Access to neoadjuvant therapy should be an option available to all patients with breast cancer through multidisciplinary tumor management. IMPLICATIONS FOR PRACTICE Neoadjuvant treatment should be strongly considered as a therapeutic option for localized breast cancer and is a powerful tool for understanding breast cancer biology and investigating new treatment approaches.
MicroRNA-22 functions as a tumor suppressor by targeting SIRT1 in renal cell carcinoma

Accumulating evidence demonstrates that microRNA-22 (miR-22) was deregulated in many types of cancers and was involved in various cellular processes related to carcinogenesis. However, the exact roles and mechanisms of miR-22 remain unknown in human renal cell carcinoma (RCC). Here, the relationship between miR-22 expression pattern and clinicopathological features of patients with EOC were determined by real-time quantitative RT-PCR (qRT-PCR). Furthermore, the role of miR-22 and possible molecular mechanisms in EOC were investigated by several in vitro approaches and in a nude mouse model. Results from qRT-PCR showed that miR-22 was significantly downregulated in RCC samples compared with corresponding non-cancerous tissues, which was significantly associated with tumor stage and lymph node metastasis. Functional study demonstrated that enforced overexpression of miR-22 in renal cancer cells inhibited proliferation, migration and invasion, and induced cell apoptosis in vitro, and suppressed tumor growth in vivo. In addition, SIRT1 was identified as a direct target of miR-22 by a luciferase reporter assay. Overexpression of miR-22 activated p53 and its downstream target p21 and PUMA, and the apoptosis markers cleaved CASP3 and PARP, and inhibited epithelial-mesenchymal transition (EMT). These findings showed that miR-22 functioned as tumor suppressor in RCC and blocked RCC growth and metastasis by directly targeting SIRT1 in RCC, indicating a potential novel therapeutic role in RCC treatment.
Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology

ABSTRACT Introduction: The blood-brain barrier (BBB) is a highly limiting barrier that prevents the brain from contacting with several circulating molecules, including harmful agents. However, certain systemic nutrients and macromolecules are able to cross the BBB and reach the brain parenchyma, involving the interaction with multiple receptors and/or transporters at the BBB surface. Nanotechnology allows the creation of drug vehicles, functionalized with targeting ligands for binding specific BBB receptors and/or transporters, hence triggering the transport through this biobarrier. Areas covered: This review focuses the BBB receptors/transporters to be exploited in regard to their overall structure and biologic function, as well as their role in the development of strategies envisaging drug delivery to the brain. Then, the interplay between the targeting of these BBB receptors/transporters and nanotechnology is explored, as they can increase by several-fold the effectiveness of brain-targeted therapies. Expert opinion: Nanomedicine may be particularly useful in brain drug delivery, mainly due to the possibility of functionalizing nanoparticles to target specific receptors/transporters. Since the BBB is endowed with numerous receptors and transporters responsible for regulating the proper metabolic activity of the brain, their targeting can be a promising bypass strategy to circumvent the hurdle that the BBB represents for brain drug delivery.
Two‐stage design for phase I–II cancer clinical trials using continuous dose combinations of cytotoxic agents

We present a two‐stage phase I–II design of a combination of two drugs in cancer clinical trials. The goal is to estimate safe dose combination regions with a desired level of efficacy. In stage I, conditional escalation with overdose control is used to allocate dose combinations to successive cohorts of patients and the maximum tolerated dose curve is estimated as a function of Bayes estimates of the model parameters. In stage II, we propose a Bayesian adaptive design for conducting the phase II trial to determine dose combination regions along the maximum tolerated dose curve with a desired level of efficacy. The methodology is evaluated by extensive simulations and application to a real trial.
The Way Forward: Potentiating Protective Immunity to Novel and Pandemic Influenza Through Engagement of Memory CD4 T Cells

Abstract Potentially pandemic strains of influenza pose an undeniable threat to human populations. Therefore, it is essential to develop better strategies to enhance vaccine design and predict parameters that identify susceptible humans. CD4 T cells are a central component of protective immunity to influenza, delivering direct effector function and potentiating responses of other lymphoid cells. Humans have highly diverse influenza-specific CD4 T-cell populations that vary in stimulation history, specificity, and functionality. These complexities constitute a formidable obstacle to predicting immune responses to pandemic strains of influenza and derivation of optimal vaccine strategies. We suggest that more precise efforts to identify and enumerate both the positive and negative contributors of immunity in the CD4 T-cell compartment will aid in both predicting susceptible hosts and in development of vaccination strategies that will poise most human subjects to respond to pandemic influenza strains with protective immune responses.
Resource-rationality and dynamic coupling of brains and social environments

Abstract Leider and Griffiths clarify the basis for unification between mechanism-driven and solution-driven disciplines and methodologies in cognitive science. But, two outstanding issues arise for their model of resource-rationality: human brains co-process information with their environments, rather than merely adapt to them; and this is expressed in methodological differences between disciplines that complicate Leider and Griffiths’ proposed structural unification.
[Renal impairment in multiple myeloma].

Multiple myeloma is a haematological malignancy common in people of African descent. Renal impairment is a common complication in patients newly diagnosed with multiple myeloma which is associated with a poor median survival when present. About 20-50% of patients present with renal impairment and about 5-10% have severe renal impairment requiring haemodialysis. There is an increased risk of mortality in severe renal impairment. The eGFR is a better indicator of renal impairment than the serum creatinine. Renal pathology in myeloma may be immunoglobulin or nonimmunoglobulin based with myeloma cast nephropathy due to the toxic effects of excessive monoclonal free light chains being the most common cause of the renal impairment. In recent years, novel therapy have improved outcome in patients with multiple myeloma who have renal impairment. Bortezomib based regimen are the cornerstone of management as they bring about the fastest renal response with a high overall response rate. Early diagnosis and prompt management is essential to achieve reversal of renal impairment.
Mitochondrial RNA granules are critically dependent on mtDNA replication factors Twinkle and mtSSB

Abstract Newly synthesized mitochondrial RNA is concentrated in structures juxtaposed to nucleoids, called RNA granules, that have been implicated in mitochondrial RNA processing and ribosome biogenesis. Here we show that two classical mtDNA replication factors, the mtDNA helicase Twinkle and single-stranded DNA-binding protein mtSSB, contribute to RNA metabolism in mitochondria and to RNA granule biology. Twinkle colocalizes with both mitochondrial RNA granules and nucleoids, and it can serve as bait to greatly enrich established RNA granule proteins, such as G-rich sequence factor 1, GRSF1. Likewise, mtSSB also is not restricted to the nucleoids, and repression of either mtSSB or Twinkle alters mtRNA metabolism. Short-term Twinkle depletion greatly diminishes RNA granules but does not inhibit RNA synthesis or processing. Either mtSSB or GRSF1 depletion results in RNA processing defects, accumulation of mtRNA breakdown products as well as increased levels of dsRNA and RNA:DNA hybrids. In particular, the processing and degradation defects become more pronounced with both proteins depleted. These findings suggest that Twinkle is essential for RNA organization in granules, and that mtSSB is involved in the recently proposed GRSF1-mtRNA degradosome pathway, a route suggested to be particularly aimed at degradation of G-quadruplex prone long non-coding mtRNAs.
Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease

The lungs are essential for gas exchange and serve as the gateways of our body to the external environment. They are easily accessible for drugs from both sides, the airways and the vasculature. Recent literature provides evidence for a role of Transient Receptor Potential (TRP) channels as chemosensors and essential members of signal transduction cascades in stress-induced cellular responses. This review will focus on TRP channels (TRPA1, TRPC6, TRPV1, and TRPV4), predominantly expressed in non-neuronal lung tissues and their involvement in pathways associated with diseases like asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), lung fibrosis, and edema formation. Recently identified specific modulators of these channels and their potential as new therapeutic options as well as strategies for a causal treatment based on the mechanistic understanding of molecular events will also be evaluated.
Retraction: Gemcitabine Sensitivity Can Be Induced in Pancreatic Cancer Cells through Modulation of miR-200 and miR-21 Expression by Curcumin or Its Analogue CDF.

This article (1) has been retracted at the request of the editors. Following an institutional review by Wayne State University (Detroit, MI), the primary affiliation for several of the authors, it was determined that the article (1) included multiple instances of data falsification and/or fabrication including data reuse, cutting/ pasting, relabeling, inappropriate covering or removal of dots and smudges, overlaying/masking, and data composition. Specifically, the review found multiple instances of inappropriate image manipulation of the PTEN, pAkt, and tropomyosin Western blot bands from the MIAPaCa-E experiments and the PTEN and tropomyosin bands from the MIAPaCa-M experiments in Fig. 3A, and a fabricated composite Western blot of pAKT and PTEN (Fig. 3C) and PTEN (Fig. 3D) constructed from bands taken from multiple sources. As a result of these findings, the institution recommended retraction and, upon internal review, the editors agree with this recommendation.
Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions A Scientific Statement From the American Heart Association

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%. 5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …