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Hybrid male sterility is one of the fastest evolving intrinsic reproductive barriers between recently isolated populations. A leading explanation for the evolution of hybrid male sterility involves genomic conflicts with meiotic drivers in the male germline. There are, however, few examples directly linking meiotic drive to hybrid sterility. In this study, we report that the Sex-Ratio chromosome of Drosophila pseudoobscura , which causes X-chromosome drive within the USA subspecies, causes near-complete male sterility when it is moved into the genetic background of the Bogota subspecies. In addition, we show that this new form of sterility is genetically distinct from the sterility of F1 hybrid males in crosses between USA males and Bogota females. Our observations provide a tractable study system where noncryptic drive within species is transformed into strong hybrid sterility between very young subspecies. [ABSTRACT FROM AUTHOR]

The majority of occupational lung diseases have long latency periods, with disease manifesting at an older age. We conducted an extensive literature review and analyzed data for age-related mortality, the impact of age on the lungs and occupational lung diseases, changes in the workforce, and considerations for surveillance to maintain a healthy workforce. Age is a major factor in occupational lung diseases, which in turn predisposes older adults to other health conditions and reduces their quality of life and life expectancy. More specifically, age-related changes in the lungs increase the susceptibility to environmental exposure-induced lung injuries and are linked to poor prognosis. Data from the Work-Related Lung Disease Surveillance Report published by the National Institute for Occupational Safety and Health (NIOSH, 2008) indicated that death from occupational lung diseases among U.S. residents peaked in the age group 75--84 years. Interestingly, the age group 65--74 years recorded a substantial number of deaths, second to the age group 75--84 years. This trend represents a shift in U.S. mortality for all diseases, which peaks at ≥85 years. Improved surveillance and early detection will be instrumental in reducing the burden of occupational lung injury in older adults, many of whom are staying in the workforce longer. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer can create a shield of suppressive innate immune cells that stop our body's natural defenses from tumors. VTX-0811 is a new drug that targets these cells and turns them from allies of cancer to fighters against it. Preclinical tests show that it works in the lab on human cells and tumors and is safe and efficacious in animals. The results are promising and pave the way for human trials to see if VTX-0811 can become a new powerful weapon against cancer. Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance. [ABSTRACT FROM AUTHOR]

Intrauterine fetal demise (IUFD) – fetal loss after 20 weeks – affects 6 pregnancies per 1,000 live births in the United States, and the majority are of unknown etiology. Maternal systemic regulatory T cell (Treg) deficits have been implicated in fetal loss, but whether mucosal immune cells at the maternal-fetal interface contribute to fetal loss is under-explored. We hypothesized that the immune cell composition and function of the uterine mucosa would contribute to the pathogenesis of IUFD. To investigate local immune mechanisms of IUFD, we used the CBA mouse strain, which naturally has mid-late gestation fetal loss. We performed a Treg adoptive transfer and interrogated both pregnancy outcomes and the impact of systemic maternal Tregs on mucosal immune populations at the maternal-fetal interface. Treg transfer prevented fetal loss and increased an MHC-IIlow population of uterine macrophages. Single-cell RNAsequencing was utilized to precisely evaluate the impact of systemic Tregs on uterine myeloid populations. A population of C1q+, Trem2+, MHC-IIlow uterine macrophages were increased in Treg-recipient mice. The transcriptional signature of this novel uterine macrophage subtype is enriched in multiple studies of human healthy decidual macrophages, suggesting a conserved role for these macrophages in preventing fetal loss. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer remains the most frequent cause of cancer morbidity, the second most frequent cause of cancer mortality in men in the developed world and is an exemplar of a heterogeneous disease. Stemness phenotypes and lineage plasticity have been highlighted as key drivers of heterogeneity observed both across patients and within the same patient. However, markers that indicate the presence or absence of these events remain to be identified. Next-generation sequencing has proven to be a beneficial approach to distinguish predictive and prognostic biomarkers in various diseases, including prostate cancer. This review explores measurable metrics that can reliably reflect lineage plasticity at the genomic, transcriptomic, and epigenomic levels, as well as bioinformatic tools that can be used to identify measures of lineage-plasticity in prostate cancer, in order to inform preclinical and clinical research. Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic cells to undergo phenotypic changes under microenvironmental pressures by switching between developmental cell states. What remains to be elucidated is how to identify measurements of lineage plasticity, how to implement them to inform preclinical and clinical research, and, further, how to classify patients and inform therapeutic strategies in the clinic. Recent research has highlighted the crucial role of next-generation sequencing technologies in identifying potential biomarkers associated with lineage plasticity. Here, we review the genomic, transcriptomic, and epigenetic events that have been described in PCa and highlight those with significance for lineage plasticity. We further focus on their relevance in PCa research and their benefits in PCa patient classification. Finally, we explore ways in which bioinformatic analyses can be used to determine lineage plasticity based on large omics analyses and algorithms that can shed light on upstream and downstream events. Most importantly, an integrated multiomics approach may soon allow for the identification of a lineage plasticity signature, which would revolutionize the molecular classification of PCa patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer continues to exhibit increasing incidence and mortality worldwide. Subsequently, there has been a concomitant effort to development novel therapeutics that effectively target and treat these malignancies. This paper aims to provide a thorough review of the available immunotherapy treatments that target liver cancer, with a specific focus on the role and potential therapeutic strategies available to the interventional radiologist. The underlying biochemical and molecular mechanisms underlying these diseases are discussed to highlight the specific targets for immunotherapy, the clinical efficacy and safety of available pharmaceutical treatments are analyzed, and future advancements in the field, such as combination therapies and personalized medicine, are explored as they pertain to the immunotherapy of liver cancer. Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise in minimally invasive locoregional therapy, as the bulk of these tumors are usually in the liver. The aim of this review is to highlight the immunological therapeutic targets for primary liver cancers, the available immune-based approaches, and the contributions that interventional radiology can provide in the care of these patients. [ABSTRACT FROM AUTHOR]

Purpose: Initial military training (IMT) is a transitionary period wherein immune function may be suppressed and infection risk heightened due to physical and psychological stress, communal living, and sleep deprivation. This study characterized changes in biomarkers of innate and adaptive immune function, and potential modulators of those changes, in military recruits during IMT. Methods: Peripheral leukocyte distribution and mitogen-stimulated cytokine profiles were measured in fasted blood samples, Epstein–Barr (EBV), varicella zoster (VZV), and herpes simplex 1 (HSV1) DNA was measured in saliva by quantitative polymerase chain reaction as an indicator of latent herpesvirus reactivation, and diet quality was determined using the healthy eating index measured by food frequency questionnaire in 61 US Army recruits (97% male) at the beginning (PRE) and end (POST) of 22-wk IMT. Results: Lymphocytes and terminally differentiated cluster of differentiation (CD)4+ and CD8+ T cells increased PRE to POST, whereas granulocytes, monocytes, effector memory CD4+ and CD8+ T cells, and central memory CD8+ T cells decreased (P ≤ 0.02). Cytokine responses to anti-CD3/CD28 stimulation were higher POST compared with PRE, whereas cytokine responses to lipopolysaccharide stimulation were generally blunted (P < 0.05). Prevalence of EBV reactivation was higher at POST (P = 0.04), but neither VZV nor HSV1 reactivation was observed. Diet quality improvements were correlated with CD8+ cell maturation and blunted proinflammatory cytokine responses to anti-CD3/CD28 stimulation. Conclusions: Lymphocytosis, maturation of T-cell subsets, and increased T-cell reactivity were evident POST compared with PRE IMT. Although EBV reactivation was more prevalent at POST, no evidence of VZV or HSV1 reactivation, which are more common during severe stress, was observed. Findings suggest increases in the incidence of EBV reactivation were likely appropriately controlled by recruits and immune-competence was not compromised at the end of IMT. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the availability of numerous therapeutic approaches, pancreatic ductal adenocarcinoma still stands as one of the most fatal cancers worldwide. Nanoliposomes could potentially be helpful in improving the pharmacokinetic and anticancer efficacy of drug molecules. Gemcitabine is the first line of therapy, but due to its hydrophilic nature, entrapment within nanoliposomes is very limited. To overcome this problem, we explored the lipophilic form of gemcitabine, i.e., Gemcitabine Elaidate. The present study is aimed towards investigating the antitumor activity of Gemcitabine Elaidate and further designing an appropriate nano-liposomal formulation in combination with Palmitoyl-DL-carnitine chloride as a Protein kinase C (PKC) inhibitor. Our combination therapy in a nano-liposomal carrier resulted in enhanced cellular uptake, inhibition of angiogenesis potential and augmented anticancer potency in both 2D and 3D in vitro models of pancreatic tumors. The promising results indicate the successful development of a nano-liposomal carrier incorporating Gemcitabine Elaidate and Palmitoyl-DL-carnitine chloride as a more effective approach for the treatment of pancreatic cancer by overcoming the key drawbacks of the current first-line therapy. Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC. [ABSTRACT FROM AUTHOR]

Introduction: Medical abortion is a safe, effective, and often preferred method of terminating an unintended pregnancy, but access can be made difficult by the laws of a state. Despite modern efforts to prevent unintended pregnancies in the U.S., they comprise almost half of pregnancies and 95% of abortions, signifying that abortion is a necessary and desired healthcare service. This study's purpose is to describe the proliferation of American medical abortion access laws between 2000 and 2018.Methods: Policy surveillance methods were used in 2018 to collect 7 types of U.S. medical abortion access restriction laws in place as of December 1, 2018. Statutory histories were reviewed in 2019 to record the laws' years of enactment, substantive amendment, and repeal.Results: A total of 35 states restricted medical abortion access as of 2018. Medical abortion laws increased from 16 in 2000 to 96 by 2018, and only 1 was repealed. A total of 25 states had multiple laws restricting medical abortion access in 2018. Medical abortion access laws surged from 2010 to 2017, but none were passed in 2018. Medical abortion access is generally most restricted in Midwestern and Southern states and least restricted in Western and Northeastern states.Conclusions: Although evidence demonstrates medical abortion's safety and efficacy, its access is increasingly limited by law in many states. Further research examining the impacts of these laws on women's health and the consequences of unintended births on women, children, families, and society is needed. [ABSTRACT FROM AUTHOR]

Sepsis remains a major cause of death in the United States and worldwide, and costs associated with treating septic patients place a large burden on the healthcare industry. Patients who survive the acute phase of sepsis display long-term impairments in immune function due to reductions in numbers and function of many immune cell populations. This state of chronic immunoparalysis renders sepsis survivors increasingly susceptible to infection with newly or previously encountered infections. CD4 T cells play important roles in the development of cellular and humoral immune responses following infection. Understanding how sepsis impacts the CD4 T cell compartment is critical for informing efforts to develop treatments intended to restore immune system homeostasis following sepsis. This review will focus on the current understanding of how sepsis impacts the CD4 T cell responses, including numerical representation, repertoire diversity, phenotype and effector functionality, subset representation (e.g., Th1 and Treg frequency), and therapeutic efforts to restore CD4 T cell numbers and function following sepsis. Additionally, we will discuss recent efforts to model the acute sepsis phase and resulting immune dysfunction using mice that have previously encountered infection, which more accurately reflects the immune system of humans with a history of repeated infection throughout life. A thorough understanding of how sepsis impacts CD4 T cells based on previous studies and new models that accurately reflect the human immune system may improve translational value of research aimed at restoring CD4 T cell-mediated immunity, and overall immune fitness following sepsis. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma. [ABSTRACT FROM AUTHOR]

Cardiovascular Disease (CVD) is a leading cause of mortality within the United States. Current treatments being administered to patients who suffered a myocardial infarction (MI) have increased patient survival, but do not facilitate the replacement of damaged myocardium. Recent studies demonstrate that stem cell-based therapies promote myocardial repair; however, the poor engraftment of the transferred stem cell populations within the infarcted myocardium is a major limitation, regardless of the cell type. One explanation for poor cell retention is attributed to the harsh inflammatory response mounted following MI. The inflammatory response coupled to cardiac repair processes is divided into two distinct phases. The first phase is initiated during ischemic injury when necrosed myocardium releases Danger Associated Molecular Patterns (DAMPs) and chemokines/cytokines to induce the activation and recruitment of neutrophils and pro-inflammatory M1 macrophages (MΦs); in turn, facilitating necrotic tissue clearance. During the second phase, a shift from the M1 inflammatory functional phenotype to the M2 anti-inflammatory and pro-reparative functional phenotype, permits the resolution of inflammation and the establishment of tissue repair. T-regulatory cells (Tregs) are also influential in mediating the establishment of the pro-reparative phase by directly regulating M1 to M2 MΦ differentiation. Current studies suggest CD4+ T-lymphocyte populations become activated when presented with autoantigens released from the injured myocardium. The identity of the cardiac autoantigens or paracrine signaling molecules released from the ischemic tissue that directly mediate the phenotypic plasticity of T-lymphocyte populations in the post-MI heart are just beginning to be elucidated. Stem cells are enriched centers that contain a diverse paracrine secretome that can directly regulate responses within neighboring cell populations. Previous studies identify that stem cell mediated paracrine signaling can influence the phenotype and function of immune cell populations in vitro , but how stem cells directly mediate the inflammatory microenvironment of the ischemic heart is poorly characterized and is a topic of extensive investigation. In this review, we summarize the complex literature that details the inflammatory microenvironment of the ischemic heart and provide novel insights regarding how paracrine mediated signaling produced by stem cell-based therapies can regulate immune cell subsets to facilitate pro-reparative myocardial wound healing. [ABSTRACT FROM AUTHOR]

Historical uranium (U) mining in the Southwestern United States resulted in significant environmental contamination throughout this region and presents a significant risk of chronic metal exposure and toxicity for communities living in close proximity to mine waste sites. Uranium exposure is associated with numerous deleterious health effects including immune dysfunction; however, its effects on the immune system have yet to be fully characterized. We recently published that drinking water exposure to U, in the form of uranyl acetate (UA), results in low overall tissue retention of U (<0.01%), with very little accumulation in immune organs (blood, bone marrow, spleen, and thymus) of male and female mice. In the present study we characterized the immunotoxicity of U, in the form of UA, following a 60-day drinking water exposure to 5 and 50 ppm in male and female C57BL/6J mice. The following immunotoxicity endpoints were evaluated: hematology, immune tissue weights and total cell recoveries, immunophenotying of the spleen and thymus, and immune cell function (lymphocyte mitogenesis and T-dependent antibody response). Uranium exposure had subtle impacts on the immune endpoints evaluated, likely due to low U accumulation at these sites. The only significant alterations were a slight decrease in the percentages of splenic natural killer T-cells and macrophages in exposed male mice. Despite minimal immunological effects, this study highlights the importance of investigating toxicological endpoints in both sexes and developing accurate animal models that model epidemiological exposures in the future. • Drinking water uranium exposure (uranyl acetate) produced minimal immunotoxicity in male or female C57BL/6J mice. • Innate immune cell subsets were slightly reduced in male, but not female mice. • Mature splenic lymphocyte function was not significantly altered in male or female mice. [ABSTRACT FROM AUTHOR]

Background: Syphilis affects approximately 11 million people each year globally, and is the third most prevalent sexually transmitted bacterial infection in the United States. Inability to independently culture and genetically manipulate Treponema pallidum subsp. pallidum, the causative agent of this disease, has hindered our understanding of the molecular mechanisms of syphilis pathogenesis. Here, we used the non-infectious and poorly adherent B314 strain of the Lyme disease-causing spirochete, Borrelia burgdorferi, to express two variants of a known fibronectin-binding adhesin, Tp0136, from T. pallidum SS14 and Nichols strains. Using this surrogate system, we investigated the ability of Tp0136 in facilitating differential binding to mammalian cell lines offering insight into the possible role of this virulence factor in colonization of specific tissues by T. pallidum during infection. Principal findings: Expression of Tp0136 could be detected on the surface of B. burgdorferi by indirect immunofluorescence assay using sera from a secondary syphilis patient that does not react with intact B314 spirochetes transformed with the empty vector. Increase in Tp0136-mediated adherence of B314 strain to human epithelial HEK293 cells was observed with comparable levels of binding exhibited by both Tp0136 alleles. Adherence of Tp0136-expressing B314 was highest to epithelial HEK293 and C6 glioma cells. Gain in binding of B314 strain expressing Tp0136 to purified fibronectin and poor binding of these spirochetes to the fibronectin-deficient cell line (HEp-2) indicated that Tp0136 interaction with this host receptor plays an important role in spirochetal attachment to mammalian cells. Furthermore, preincubation of these cell lines with fibronectin-binding peptide from Staphylococcus aureus FnbA-2 protein significantly inhibited binding of B314 expressing Tp0136. Conclusions: Our results show that Tp0136 facilitates differential level of binding to cell lines representing various host tissues, which highlights the importance of this protein in colonization of human organs by T. pallidum and resulting syphilis pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: To examine the cytotoxicity of epigenetic drugs independently and in combination with chemotherapy on ovarian cancer cells Caov-3, and to investigate their ability to acquire chemoresistance in omental microenvironments and whether epigenetic drugs can counteract this chemoresistance.Methods: A pilot study was conducted in Cooper University Hospital, NJ, USA from August 1 to October 31, 2017, among women undergoing surgeries for uterine and ovarian cancer. Cytotoxicity assays using IC50 values of epigenetic drugs and paclitaxel and cisplatin were performed on Caov-3. Omental adipose-derived stem cells (OASCs) were isolated from omentum with/without metastases. Caov-3 was cultured with OASCs' conditioned medium and subjected to different drugs. Cell viability and secretome was measured using MTT and Elisa, respectively.Results: Three women met the eligibility criteria and were included in the study. Epigenetic drugs alone or in combination with chemotherapy showed 85%-94% increased cytotoxicity against Caov-3 (P≤0.005). Metastatic OASCs conditioned medium showed up to 27-fold increase in tumorigenic factors and promoted chemoresistance (28%-35%; P < 0.050) against chemotherapy. Epigenetic therapy resulted in up to a 40-fold reversal in this chemoresistance.Conclusion: Epigenetic therapies could have an important role in treating a subgroup of ovarian cancer patients that demonstrate resistance to first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Alcohol use disorders (AUDs), which include alcohol abuse and dependence, are among the most common types of neuropsychiatric disorders in the United States (U.S.). Approximately 14% of the U.S. population is affected in a single year, thus placing a tremendous burden on individuals from all socioeconomic backgrounds. Animal models have been pivotal in revealing the basic mechanisms of how alcohol impacts neuronal function, yet there are currently limited effective therapies developed based on these studies. This is mainly due to a limited understanding of the exact cellular and molecular mechanisms underlying AUDs in humans, which leads to a lack of targeted therapeutics. Furthermore, compounding factors including genetic background, gene copy number variants, single nucleotide polymorphisms (SNP) as well as environmental and social factors that affect and promote the development of AUDs are complex and heterogeneous. Recent developments in stem cell biology, especially the human induced pluripotent stem (iPS) cell development and differentiation technologies, has provided us a unique opportunity to model neuropsychiatric disorders like AUDs in a manner that is highly complementary to animal studies, but that maintains fidelity with complex human genetic contexts. Patient-specific neuronal cells derived from iPS cells can then be used for drug discovery and precision medicine, e.g. for pathway-directed development in alcoholism. Here, we review recent work employing iPS cell technology to model and elucidate the genetic, molecular and cellular mechanisms of AUDs in a human neuronal background and provide our perspective on future development in this direction. [ABSTRACT FROM AUTHOR]

Although spongiotic (eczematous), psoriatic and cutaneous skin infections are among the most common in dermatology consultations, melanocytic lesions - including the different types of nevi and melanomas - are among those that cause a great deal of concern and stress to patients and their clinicians. A diagnosis of benign melanocytic nevus carries a very good prognosis. However, a diagnosis of melanoma might indicate more aggressive treatment, lifelong surveillance and a worse prognosis. Differentiating between these conditions is not always a straightforward process for clinicians and pathologists. Therefore, knowledge of melanoma mimickers is very important for clinicians in general, and dermatologists and pathologists in particular. In this review, we called attention to some of the more frequent benign but unusual melanocytic lesions that are of diagnostic concern for clinicians evaluating these cutaneous proliferations. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential. [ABSTRACT FROM AUTHOR]

In efforts to develop a unique pedagogy for underrepresented high school and undergraduate students, we developed a pilot study to determine the effectiveness of vertically integrating STEM research education from high school students through Ph.D. candidates. The interdisciplinary research project's overarching goal is to assess the impact of environmental pollutants (specifically, platinum group elements found in road dust) on eukaryotic and prokaryotic cells and develop computational models to predict the outcomes of exposure. Ultimately, the project involves elements of fate and transport of platinum group elements in soil, water, and air and their impacts on environmental microbiology, eukaryotic cell signaling, and environmental computational modeling. Our vertically integrated and aligned mentorship model paired high school students with undergraduates, M.S. students, and Ph.D. students in various laboratories. To complement their laboratory research exposure, students also attended professional development seminars on résumé preparation, literature mining/searching, preparation of manuscripts, presentation of data, and critical reading of peer-reviewed articles. Our pilot study was very successful in exposing future STEM workers (high school students and college undergraduates) to meaningful research experiences that they translated into seven poster and oral presentations, three review articles (in preparation), three journal articles, and improved attitudes toward STEM careers. [ABSTRACT FROM AUTHOR]

The prevalence of obesity over the last several decades in the United States has tripled among children and doubled among adults. Obesity increases the incidence and progression of multiple myeloma (MM), yet the molecular mechanisms by which adipocytes contribute to cancer development and patient prognosis have yet to be fully elucidated. Here, we obtained human adipose-derived stem cells (ASCs) from twenty-nine normal (BMI = 20-25 kg/m(2)), overweight (25-30 kg/m(2)), obese (30-35 kg/m(2)), or super obese (35-40 kg/m(2)) patients undergoing elective liposuction. Upon differentiation, adipocytes were co-cultured with RPMI-8226 and NCI-H929 MM cell lines. Adipocytes from overweight, obese and super obese patients displayed increased PPAR-gamma, cytochrome C, interleukin-6, and leptin protein levels, and decreased fatty acid synthase protein. 8226 MM cells proliferated faster and displayed increased pSTAT-3/STAT-3 signaling when cultured in adipocyte conditioned media. Further, adipocyte conditioned media from obese and super obese patients significantly increased MM cell adhesion, and conditioned media from overweight, obese and super obese patients enhanced tube formation and expression of matrix metalloproteinase-2. In summary, our data suggest that adipocytes in the MM microenvironment contribute to MM growth and progression and should be further evaluated as a possible therapeutic target. [ABSTRACT FROM AUTHOR]

In April 2015, the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases hosted an experts technical consultation on bacterial vaginosis (BV), where data regarding controversies over the pathogenesis of BV were discussed. The discussion on the epidemiology and pathogenesis of BV is presented here, and several hypotheses on its pathogenesis are critiqued. Rigorous hypothesis-driven studies are needed to ultimately determine the cause of BV. This information is vital for the prevention and control of this important infection and its adverse public health consequences. [ABSTRACT FROM AUTHOR]

Breast cancer is the second leading cause of cancer-related death in women in the United States and discovery and development of safe chemopreventive drugs is urgently needed. The fruit pomegranate (Punica granatum) is gaining importance because of its various health benefits. This study was initiated to investigate chemopreventive potential of a pomegranate emulsion (PE) against 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary carcinogenesis. The animals were orally administered with PE (0.2–5.0 g/kg), starting 2 wk before and 16 wk following DMBA treatment. PE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden, and reversed histopathological changes. PE dose-dependently suppressed cell proliferation and induced apoptosis in mammary tumors. Immunohistochemical studies showed that PE increased intratumor Bax, decreased Bcl2 and manifested a proapoptotic shift in Bax/Bcl2 ratio. In addition, our gene expression study showed PE-mediated upregulation of Bad, caspase-3, caspase-7, caspase-9, poly (ADP ribose) polymerase and cytochromecin mammary tumors. Thus, PE exerts chemoprevention of mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis mediated through upregulation of Bax and downregulation of Bcl2 in concert with caspase cascades. Pomegranate bioactive phytoconstituents could be developed as a chemopreventive drug to reduce the risk of breast cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer (PrCa) is the most common type of cancer among men in the United States. The metastatic and advanced PrCa develops drug resistance to current regimens which accounts for the poor management. microRNAs (miRNAs) have been well-documented for their diagnostic, prognostic, and therapeutic roles in various human cancers. Recent literature confirmed that microRNA-205 (miR-205) has been established as one of the tumor suppressors in PrCa. miR-205 regulates number of cellular functions, such as proliferation, invasion, migration/metastasis, and apoptosis. It is also evident that miR-205 can serve as a key biomarker in diagnostic, prognostic, and therapy of PrCa. Therefore, in this review, we will provide an overview of tumor suppressive role of miR-205 in PrCa. This work also outlines miR-205's specific role in targeted mechanisms for chemosensitization and radiosensitization in PrCa. A facile approach of delivery paths for successful clinical translation is documented. Together, all these studies provide a novel insight of miR-205 as an adjuvant agent for reducing the widening gaps in clinical outcome of PrCa patients. [ABSTRACT FROM AUTHOR]

Propolis or bee glue has been used for centuries for various purposes and is especially important in human health due to many of its biological and pharmacological properties. In this work we showed quorum sensing inhibitory (QSI) activity of ten geographically distinct propolis samples from the United States using the acyl-homoserine lactone- (AHL-) dependent Chromobacterium violaceum strain CV026. Based on GC-MS chemical profiling the propolis samples can be classified into several groups that are as follows: (1) rich in cinnamic acid derivatives, (2) rich in flavonoids, and (3) rich in triterpenes. An in-depth analysis of the propolis from North Carolina led to the isolation and identification of a triterpenic acid that was recently isolated from Hondurian propolis (Central America) and ethyl ether of p-coumaric alcohol not previously identified in bee propolis. QSI activity was also observed in the second group US propolis samples which contained the flavonoid pinocembrin in addition to other flavonoid compounds. The discovery of compounds that are involved in QSI activity has the potential to facilitate studies that may lead to the development of antivirulence therapies that can be complementary and/or alternative treatments against antibiotic resistant bacterial pathogens and/or emerging pathogens that have yet to be identified. [ABSTRACT FROM AUTHOR]

The article examines several features of rheumatoid arthritis (RA) which is a type of inflammatory arthritis that has unclear etiology. Topics include RA's clinical manifestations, predisposing factors, and epidemiology. Also discussed is the differential diagnoses that mimic RA as well as its work-up and treatment. It also details a method for RA diagnosis which involves radiographic imaging.

Walnuts contain many bioactive components that may slow cancer growth. A previous report showed that a diet supplemented with walnuts decreased the tumor size formed by MDA-MB-231 human cancer cells injected into nude mice. However, the mechanism of action was never determined. We characterized the effects of a methanol extract prepared from walnuts on human MDA-MB-231, MCF7, and HeLa cells. The extract was cytotoxic to all cancer cells. We identified compounds from the methanol extract that induced this cytotoxicity. The predominant compounds were Tellimagrandin I and Tellimagrandin II, members of the ellagitannin family. We also show a walnut extract decreases the intracellular pH, depolarizes the mitochondrial membrane with release of cytochrome c and phosphatidylserine flipping. The antimitogenic effects of walnut extract were associated with a twofold reduction of mitochondria respiration. These results suggest impairment of mitochondrial function and apoptosis as relevant mechanism of anticancer effects of the walnut extract. [ABSTRACT FROM PUBLISHER]

The American Diabetes Association emphasizes the importance of individualized patient care in the management of diabetes. One of the important considerations in choosing an antihyperglycemic agent is its side-effect and safety profile. This article reviews the common and clinically significant side effects of each class of agents, including ways to prevent and overcome their occurrence. [ABSTRACT FROM AUTHOR]

Biologic therapies represent a drug class toward which there is continued development and production in a number of disease states. The development of an approval pathway allowing for the introduction of biosimilars into the US pharmaceutical market poses new challenges for health care systems and institutions. The potential difference in cost is a major driver for the development and use of biosimilars in practice. The manufacturing process for biosimilar compounds is complicated and requires specific detailing of each step, including development of the large-molecular component. Requirements for safe manufacturing of these therapies are crucial, as downstream effects may influence clinical efficacy and immunological properties. As these therapies enter the US marketplace, health care professionals will be asked to take prudent measures as they consider and evaluate these therapies for substitution into their formularies. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis. [ABSTRACT FROM AUTHOR]

Normal aging is marked by dysregulated immune function or immunosenescence. However, there is considerable variation in the degree to which adults are susceptible or resilient to immune dysregulation and disease. Stress is an important factor that can further alter the aging immune system. In this chapter, we review research that shows how stress can enhance age-related immune dysregulation in a variety of clinically relevant ways. We then explore what factors promote resilience to the negative immunological consequences of stress and aging. Finally, we take a lifespan perspective to examine evidence to suggest that some of the most important factors that augment or assuage an older adult's capacity for resilience to age and stress-related immune dysregulation develop long before he or she reaches older adulthood. [ABSTRACT FROM AUTHOR]

Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most commonly diagnosed cancer and second most common cause of cancer deaths in American men. Its long latency, slow progression, and high incidence rate make prostate cancer ideal for targeted chemopreventative therapies. Therefore, chemoprevention studies and clinical trials are essential for reducing the burden of prostate cancer on society. Epidemiological studies suggest that tea consumption has protective effects against a variety of human cancers, including that of the prostate. Laboratory and clinical studies have demonstrated that green tea components, specifically the green tea catechin (GTC) epigallocatechin gallate, can induce apoptosis, suppress progression, and inhibit invasion and metastasis of prostate cancer. Multiple mechanisms are involved in the chemoprevention of prostate cancer with GTCs; understanding and refining models of fundamental molecular pathways by which GTCs modulate prostate carcinogenesis is essential to apply the utilization of green tea for the chemoprevention of prostate cancer in clinical settings. The objective of this article is to review and summarize the most current literature focusing on the major mechanisms of GTC chemopreventative action on prostate cancer from laboratory, in vitro, and in vivo studies, and clinical chemoprevention trials. [ABSTRACT FROM AUTHOR]

About one third of acquired immunodeficiency syndrome cases in the USA have been attributed to the use of injected addictive drugs, frequently involving opioids like heroin and morphine, establishing them as significant predisposing risk factors for contracting human immunodeficiency virus type 1 (HIV-1). Accumulating evidence from in vitro and in vivo experimental systems indicates that opioids act in concert with HIV-1 proteins to exacerbate dysregulation of neural and immune cell function and survival through diverse molecular mechanisms. In contrast, the impact of opioid exposure and withdrawal on the viral life cycle and HIV-1 disease progression itself is unclear, with conflicting reports emerging from the simian immunodeficiency virus and simian-human immunodeficiency virus infection models. However, these studies suggest a potential role of opioids in elevated viral production. Because human microglia, astrocytes, CD4+ T lymphocytes, and monocyte-derived macrophages express opioid receptors, it is likely that intracellular signaling events triggered by morphine facilitate enhancement of HIV-1 infection in these target cell populations. This review highlights the biochemical changes that accompany prolonged exposure to and withdrawal from morphine that synergize with HIV-1 proteins to disrupt normal cellular physiological functions especially within the central nervous system. More importantly, it collates evidence from epidemiological studies, animal models, and heterologous cell systems to propose a mechanistic link between such physiological adaptations and direct modulation of HIV-1 production. Understanding the opioid-HIV-1 interface at the molecular level is vitally important in designing better treatment strategies for HIV-1-infected patients who abuse opioids. [ABSTRACT FROM AUTHOR]

Garcinol, or polyisoprenylated benzophenone, isolated from the rind of fruiting bodies of Garcinia indica, has been used in traditional medicine for its potential antiinflammatory and antioxidant properties. The objective of this study was to investigate the effect of garcinol on pancreatic cancer (PaCa) cell viability and proliferation. For this, 2 human PaCa cell lines, BxPC-3 and Panc-1, with wild and mutant k-ras, respectively, were treated with garcinol (0-40 μM). Garcinol significantly (P < 0.05) inhibited cell growth (trypan blue exclusion) by induction of apoptosis in a dose- and time-dependent manner. Flow cytometric analysis revealed G0-G1 phase cell cycle arrest in both cell lines. The molecular mechanism of garcinol's action on PaCa cells was investigated by targeting signaling moieties involved in apoptosis (X-IAP, cIAP, caspase-3, 9, and PARP cleavage), transcription factor NF-κB, believed to contribute toward a chemoresistance phenotype in pancreatic tumors, and molecules associated with neovascularization and metastasis (MMP-9, VEGF, IL-8, and PGE2). Garcinol significantly (P < 0.05) augmented antiproliferative, proapoptotic, antimetastatic, and antiangiogenic effects in both PaCa cell types relative to untreated cells. These effects were more pronounced in Panc-1. This is the first report on the therapeutically relevant effect of garcinol in PaCa. Further studies are warranted, based on our findings. [ABSTRACT FROM AUTHOR]

Our aim was to investigate the effect of several dietary polyphenols on uptake of 14C-butyrate (14C-BT) by Caco-2 cells and try to correlate this effect with the modulation of the anticarcinogenic effect of BT in these cells. Acutely, uptake of 14C-BT (10 μM) was decreased by resveratrol, quercetin, myricetin, and chrysin, and increased by xanthohumol, catechin, and epicatechin; and uptake of 14C-BT (20 mM) was reduced by resveratrol, quercetin, myricetin, chrysin, EGCG, and epicatechin. Resveratrol acts as a competitive inhibitor of 14C-BT uptake. Chronically, quercetin and EGCG increased uptake of 14C-BT (10 μM), whereas myricetin, rutin, chrysin, and xanthohumol decreased it. Moreover, catechin (1 μM), quercetin, myricetin, rutin, EGCG, and chrysin increased uptake of 14C-BT (20 mM), whereas catechin (0.1 μM) decreased it. EGCG, myricetin, and catechin decreased MCT1 mRNA expression, while chrysin increased it; quercetin, rutin, and xanthohumol had no effect. BT (5 mM; 48 h) markedly decreased cellular viability and proliferation and increased cell differentiation and apoptosis. In general, combination of polyphenolic compounds with BT did not significantly modify these changes. In conclusion, changes in uptake of BT induced by polyphenols do not correlate with changes on the effect of BT upon cell viability, cell proliferation, differentiation, and apoptosis. [ABSTRACT FROM AUTHOR]

The article focuses on researcher Peter Agre's discovery of cellular water channels and for elucidating their ultra structure and function. Agre and colleagues found that the protein that had been synthesized by the oocytes after gene transfer could be defined as a water channel protein and it was named as aquaporin. The role of aquaporins provides an insight into the function of the blood brain barrier in preterm infants.

The article offers information on a research program sponsored by the U.S. Department of Energy which aims to gain a better understanding of how low-dose radiation affects cellular functioning. Three implementation challenges are discussed including one that involves explaining low-dose effects in a systems biology model, another that arises when issues of population susceptibility are juxtaposed against molecular and mechanistic studies, and another one that concerns integrating the results of radiation epidemiology.

Purpose: 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) is being developed for imaging cellular proliferation. The goals were to explore the capacity of FLT-positron emission tomography (PET) to distinguish between recurrence and radionecrosis in gliomas and compare the results to those obtained with 2-fluoro-2-deoxy-D: -glucose (FDG).Procedures: Fifteen patients with tumor recurrence and four with radionecrosis, determined by clinical course and magnetic resonance imaging results, were studied by dynamic [18F]FLT-PET with arterial blood sampling. A two-tissue compartment four-rate constant model was used to determine metabolic flux (K (FLT)), blood to tissue transport (K (1)), and phosphorylation (k (3)). FDG-PET scans were obtained 75-90 min postinjection.Results: K (FLT) and k (3), but not K (1) or k (3)/k (2) + k (3), reached significance for separating the recurrence from radionecrosis groups. Standardized uptake value and visual analyses of FLT or FDG images did not reach significance.Conclusions: K (FLT) (flux) appears to distinguish recurrence from radionecrosis better than other parameters, FLT and FDG semiquantitative approaches, or visual analysis of images of either tracer. [ABSTRACT FROM AUTHOR]

Type 2 diabetes affects -7% of the population in the United States and is characterized by decreased disposal of glucose in peripheral tissues due to insulin resistance and overproduction of glucose by the liver, defects in pancreatic /3-cell function, and decreased β-cell mass. Obesity, decreased physical exercise, and consumption of foods with a high glycemic index (GI) and load are major predisposing factors in the development of type 2 diabetes. The GI is used to evaluate the rise in blood glucose levels in response to food. The GI provides an indication of the quality of carbohydrate in a food. The glycemic load (GL) is used to provide information about the quantity of carbohydrates in a food and the insulin demand. Individuals with diabetes are advised to maintain a diet of low-GL foods, because low-GL diets improve diabetes symptoms. Grapes have a mean GI and GL in the low range. Little research has been performed with grapes and/or grape products to determine the glycemic response either alone or with a meal. Grapes and other fruits contain numerous polyphenols, including the stilbene resveratrol, the flavanol quercetin, catechins, and anthocyanins that have shown potential for reducing hyperglycemia, improving β-cell function, and protecting against β-cell loss. Therefore, with a low mean GI and GL, grapes or grape products may provide health benefits to type 2 diabetics. [ABSTRACT FROM AUTHOR]

The hair cells of the larval zebrafish lateral line provide a useful preparation in which to study hair cell death and to screen for genes and small molecules that modulate hair cell toxicity. We recently reported preliminary results from screening a small-molecule library for compounds that inhibit aminoglycoside-induced hair cell death. To potentially reduce the time required for development of drugs and drug combinations that can be clinically useful, we screened a library of 1,040 FDA-approved drugs and bioactive compounds (NINDS Custom Collection II). Seven compounds that protect against neomycin-induced hair cell death were identified. Four of the seven drugs inhibited aminoglycoside uptake, based on Texas-Red-conjugated gentamicin uptake. The activities of two of the remaining three drugs were evaluated using an in vitro adult mouse utricle preparation. One drug, 9-amino-1,2,3,4-tetrahydroacridine (tacrine) demonstrated conserved protective effects in the mouse utricle. These results demonstrate that the zebrafish lateral line can be used to screen successfully for drugs within a library of FDA-approved drugs and bioactives that inhibit hair cell death in the mammalian inner ear and identify tacrine as a promising protective drug for future studies. [ABSTRACT FROM AUTHOR]

Purpose: 3'-[F-18]Fluoro-3'-deoxythymidine (FLT) is an analog of thymidine that is being developed for imaging cellular proliferation. The goal of this study was to prove that the dose of FLT used for positron emission tomography imaging produces no significant toxicity.Procedures: Twelve patients with gliomas with either recurrence or suspected radionecrosis were imaged with FLT. Before and at several time points after imaging, subjects underwent general physical and neurological examinations with review of systems and tests of hematologic, hepatic, renal, and several other metabolic parameters. Vital signs and electrocardiograms were monitored during and after the imaging session.Results: There were no significant adverse effects from FLT injected at a dose of 0.07 mCi/kg (maximum of 5 mCi) at specific activities of 1.25 Ci/micromol or higher. The FLT mass administered for imaging was 0.0001% to 0.0009% of the least toxic cumulative dose administered in clinical trials of FLT as an antiretroviral agent.Conclusions: FLT is a safe radiotracer for quantifying proliferation in the human cancer setting. [ABSTRACT FROM AUTHOR]

Background: Epithelial-mesenchymal transformations (EMT) are critical for the invasion, progression, and metastasis of epithelial carcinogenesis. The role of EMT in head and neck squamous carcinoma (HNSC) tumorigenesis remains unexplored. In the current study, the expressions of several factors associated with the induction of EMT in HNSC cell lines and tumor specimens were investigated to define their functional and pathologic role in HNSC.Methods: Eleven HNSC cell lines and 50 primary tumor tissue specimens formed the materials of this study. Western blot analysis as well as immunohistochemical, and functional techniques were used to assess the status of activated Src (p-Src), E-cadherin, and vimentin in both cell lines and tumor tissues and the results were correlated with patients' clinicopathologic parameters.Results: The results demonstrated the inverse expression of p-Src and E-cadherin in the majority of cell lines and in primary tumor tissues compared with normal squamous mucosa. Elevated levels of p-Src were accompanied by down-regulation of E-cadherin and the expression of vimentin in epithelial tumor cells. In vitro inhibition of Src led to E-cadherin reexpression and increased cell contact in squamous carcinoma cell lines. Immunophenotypic analysis of these markers in primary tumor tissues demonstrated a significant correlation between increased p-Src, decreased E-cadherin, and vimentin expression and aggressive tumor features including penetrating invasive fronts, high-grade sarcomatoid transformation, and lymph node metastasis.Conclusions: The results of the current study indicate that Src and E-cadherin may play an important role in EMT, invasion, and aggressive clinicopathologic features of HNSC. These proteins may be targeted for the therapeutic intervention of patients with HNSC. [ABSTRACT FROM AUTHOR]

Magnesium inadequacy affects more than half of the U.S. population and is associated with increased risk for many age-related diseases, yet the underlying mechanisms are unknown. Altered cellular physiology has been demonstrated after acute exposure to severe magnesium deficiency, but few reports have addressed the consequences of long-term exposure to moderate magnesium deficiency in human cells. Therefore, IMR-90 human fibroblasts were continuously cultured in magnesium-deficient conditions to determine the long-term effects on the cells. These fibroblasts did not demonstrate differences in cellular viability or plating efficiency but did exhibit a decreased replicative lifespan in populations cultured in magnesium-deficient compared with standard media conditions, both at ambient (20% 02) and physiological (5% 02) oxygen tension. The growth rates for immortalized IMR-90 fibroblasts were not affected under the same conditions. IMR-90 fibroblast populations cultured in magnesium-deficient conditions had increased senescence-associated ~3-galactosidase activity and increased pl6INK4a and p2lwAFl protein expression compared with cultures from standard media conditions. Telomere attrition was also accelerated in cell populations from magnesium-deficient cultures. Thus, the long-term consequence of inadequate magnesium availability in human fibroblast cultures was accelerated cellular senescence, which may be a mechanism through which chronic magnesium inadequacy could promote or exacerbate age- related disease. [ABSTRACT FROM AUTHOR]

Many of the proteins that are candidates for bioenergetic pathways involved with sulfate respiration in Desulfovibrio spp. have been studied, but complete pathways and overall cell physiology remain to be resolved for many environmentally relevant conditions. In order to understand the metabolism of these microorganisms under adverse environmental conditions for improved bioremediation efforts, Desulfovibrio vulgaris Hildenborough was used as a model organism to study stress response to nitrite, an important intermediate in the nitrogen cycle. Previous physiological studies demonstrated that growth was inhibited by nitrite and that nitrite reduction was observed to be the primary mechanism of detoxification. Global transcriptional profiling with whole-genome microarrays revealed coordinated cascades of responses to nitrite in pathways of energy metabolism, nitrogen metabolism, oxidative stress response, and iron homeostasis. In agreement with previous observations, nitrite-stressed cells showed a decrease in the expression of genes encoding sulfate reduction functions in addition to respiratory oxidative phosphorylation and ATP synthase activity. Consequently, the stressed cells had decreased expression of the genes encoding ATP-dependent amino acid transporters and proteins involved in translation. Other genes up-regulated in response to nitrite include the genes in the Fur regulon, which is suggested to be involved in iron homeostasis, and genes in the Per regulon, which is predicted to be responsible for oxidative stress response. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress are associated with cancer, atherosclerosis, and other chronic diseases. Dietary flavonoids have been reported to possess antiinflammatory and antioxidant properties, but their mechanisms of action and structure-activity relations have not been fully investigated. We hypothesized that differences in antioxidant activity between the structurally similar flavones, luteolin and chrysin (differing only in B-ring hydroxylation patterns), would differentially affect inflammation-associated Cox-2 expression and PGE2 formation. Pretreatment of RAW 264.7 macrophage-like cells with 25, 50, or 100 micromol/L concentrations of luteolin inhibited lipopolysaccharide (LPS)-induced Cox-2 protein expression (P < 0.0001). Chrysin pretreatment did not reduce LPS-induced Cox-2 protein expression at any level tested. Conversely, both luteolin and chrysin completely suppressed LPS-induced PGE2 formation (P < 0.001). Luteolin, but not chrysin, inhibited xanthine/xanthine oxidase-generated superoxide formation at 100 micromol/L in a cell-free system (P < 0.001). Although both luteolin and chrysin reduced LPS-induced hydroxyl radical formation relative to the positive control (P < 0.001), luteolin was superior to chrysin (P = 0.003). In summary, luteolin and chrysin suppressed PGE2 formation equally well, despite differential effects on Cox-2 protein expression and on superoxide and hydroxyl radical scavenging. These data indicate that flavones may display similar antiinflammatory activity via different mechanisms. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a primary cause of death in the United States, and the current obesity epidemic threatens to exacerbate its morbidity and mortality worldwide. Despite important cardiovascular treatment advances over the past few decades, new approaches are needed to curb dangerous health trends. Nuclear receptors are a superfamily of ligand-activated transcription factors. The discovery of subfamilies known as peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) as lipid-sensors that regulate lipid and glucose metabolism as well as inflammation offers new targets for nutritional and pharmacologic treatment of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor 4-alpha (HNF4A) is a transcription factor located on chromosome 20q13 that regulates expression of genes involved in glucose metabolism and homeostasis. Recently, two groups independently identified single nucleotide polymorphism (SNPs) in an alternate upstream promoter (P2) of HNF4A that were associated with type 2 diabetes in Ashkenazi Jews and Finns. We genotyped haplotype-tagging SNPs (htSNPs) across the two promoter regions and the coding region of HNF4A in individuals with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) from the Amish Family Diabetes Study (AFDS) to test for association with type 2 diabetes. In the P1 promoter region, we observed a significant association between the A allele of rs2425640 and type 2 diabetes (odds ratio [OR] 1.60, P = 0.03). Furthermore, the mean age of type 2 diabetes onset was, on average, 5.1 years earlier in those with the AA or GA genotype at SNP rs2425640 than in those with the GG genotype (57.8 vs. 62.9 years, P = 0.011). In the P2 promoter, the htSNP rs1884614 showed borderline association with both type 2 diabetes (OR 1.40, P = 0.09) and the combined type 2 diabetes/IGT trait (1.35, P = 0.07). In an expanded set of 698 nondiabetic AFDS subjects, we found association between rs1884614 and glucose area under the curve during an oral glucose tolerance test (additive model, P = 0.022; dominant model, P = 0.010). The results of this study provide evidence that variants in both the P1 and P2 promoters of HNF4A increase risk for typical type 2 diabetes. [ABSTRACT FROM AUTHOR]