Top 10 Myths Regarding the Diagnosis and Treatment of Cellulitis

Publication date: Available online 3 July 2017
Source:The Journal of Emergency Medicine
Author(s): Erin K. McCreary, Melissa E. Heim, Lucas T Schulz, Robert Hoffman, Jeffrey Pothof, Barry Fox
BackgroundCellulitis is commonly treated in the emergency department (ED). Patients who present with cellulitis incur significant health care costs and may be overtreated with antibiotics. The accurate diagnosis and treatment of cellulitis plays an important role in cost-effective, high-quality medical care, as well as appropriate antibiotic utilization.ObjectiveWe aim to describe common fallacies regarding cellulitis. We present 10 myths that result in misdiagnosis, overtreatment, or inappropriate empiric management of cellulitis. Clinical presentation, including swelling and redness, is explored in depth, along with incidence of community-acquired methicillin-resistance Staphylococcus aureus, management of tick bites, and effective antibiotic therapy for cellulitis.DiscussionPatients are often treated for cellulitis unnecessarily or inappropriately. Awareness of these myths will help guide providers in clinical decision making in order to effectively tailor treatment for these infections.ConclusionsCellulitis is not as simple as it might seem, and is commonly misdiagnosed in the ED. Noninfectious causes of local symptoms, including lymphedema, venous stasis, and deep vein thrombosis need to be considered. Cellulitis should be treated with empiric antimicrobial therapy based on patient risk factors and regional susceptibility patterns. This review will assist providers in managing cellulitis and avoiding treatment errors that lead to high costs, unwanted side effects for patients, and overuse of antibiotics.



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Back Pain in a Healthy Teenager

Publication date: Available online 4 July 2017
Source:The Journal of Emergency Medicine
Author(s): Kelly Gardner, Sigmund Kharasch, Ali Raja, Rene Balza, Kriti Bhatia, Emily S. Miller




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Preface

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Platelets and cancer angiogenesis nexus

Abstract

There has been remarkable insight into the importance of platelets in a wide range of pathophysiologic events, including inflammation and cancer progression. Thrombocytosis in cancer patients is a common finding. Tumor cells induce platelet activation and subsequent aggregation through direct and indirect mechanisms. Platelets are recognized to contribute to metastatic dissemination. There is plenty of evidence that components of the hemostatic system contribute to the process of angiogenesis. Furthermore, there are accumulated data on the substantial influence of blood platelets in the process of blood vessel formation during malignancy. Platelets appear to be the main physiologic transporters of proangiogenic and antiangiogenic factors. Moreover, they influence the process of angiogenesis through platelet-derived microparticles, microRNA, lipids, and variety of surface receptors. Platelets contribute to early and late stages of angiogenesis. Available data support the overall stimulatory effect of platelets on tumor angiogenesis. It raises the possibility that interfering with platelet function may be an effective antineoplastic treatment strategy.

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Journal of the History of Medicine and Allied Sciences

New issue alert     Volume 72 Issue 3   July 2017           Articles       "One Simply Doesn't Arbitrate Authorship of Thoughts": Socialized Medicine, Medical McCarthyism, and the Publishing ofRural Health and Medical Care (1948)     J. T. H. Connor     "Forgotten" Chapters in the History of Transcervical Sterilization: Carl Clauberg and Hans-Joachim Lindemann     Sabine Hildebrandt; Susan Benedict; Erin Miller; Michael Gaffney; Michael A. Grodin     "Enquire into All the Circumstances of the Patient Narrowly": John Rutherford's Clinical Lectures in Edinburgh, 1749–53     Stephen C. Craig     "His Native, Hot Country" 1: Racial Science and Environment in Antebellum American Medical Thought     Christopher D. Willoughby     Book Reviews       Catherine L. Thompson. Patient Expectations: How Economics, Religion, and Malpractice Shaped Therapeutics in Early America     Matthew Reeves     Heather H. Vacek. Madness: American Protestant Responses to Mental Illness     Joseph Williams     Anna Katharina Schaffner. Exhaustion: A History     Susan K. Cahn     Fenneke Sysling. Racial Science and Human Diversity in Colonial Indonesia     Susie Protschky     Karen Kruse Thomas. Health and Humanity: A History of the Johns Hopkins Bloomberg School of Public Health, 1935-1985     Karen L. Walloch     Susanne M. Klausen. Abortion Under Apartheid: Nationalism, Sexuality, and Women's Reproductive Rights in South Africa     Rachel Sandwell     Richard H. Nollan. Blood Picture: L. W. Digg's Sickle Cell Anemia, and the South's First Blood Bank     Michael A. Flannery     Shelley Z. Reuter. Testing Fate: Tay-Sachs Disease and the Right to Be Responsible     Adam Turner     Luis A. Campos. Radium and the Secret of Life     Jeffrey Womack     Helen Zoe Veit. Modern Food, Moral Food: Self Control, Science, and the Rise of Modern American Eating in the Early Twentieth Century     Anna Zeide     Courtney Q. Shah. Sex Ed, Segregated: The Quest for Sexual Knowledge in Progressive-Era America     Alexandra Lord     Raúl Necochea López. A History of Family Planning in Twentieth-Century Peru     Jeannie Samuel     Michael Helquist. Marie Equi: Radical Politics and Outlaw Passions     Jacqueline D. Antonovich

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease

Abstract

In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron–exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P = 0.048) and healthy controls (P = 0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P = 0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency = 0.025 vs. <0.001; P = 0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding domain (P = 0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.

Telomere length was reduced in individuals who developed hepatocellular carcinoma in nonalcoholic fatty liver (NAFLD-HCC) versus those with cirrhosis and healthy controls, independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD patients affected by primary liver cancer, predominantly in females and specifically in the N-terminal template-binding domain. In conclusion, shorter telomeres and enrichment of hTERT rare germline mutations are associated with NAFLD-HCC.

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Structural biology: Past, present, and future

Publication date: 25 September 2017
Source:New Biotechnology, Volume 38, Part A
Author(s): Peter B. Moore
In March 2014, a symposium was held at Aarhus University to commemorate the 40th anniversary of the founding of its Division of Biostructural Chemistry by Professor Brian Clark. This article is a lightly edited version of the talk the author gave to open that event. It consists of some reflections about the discipline known as structural biology, and some comments about the author's interactions with Professor Clark and the Division of Biostructural Chemistry over the years.



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Microarray technology for identification of human papilloma virus subtype in oropharyngeal squamous cell carcinoma

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BOC is a modifier gene in holoprosencephaly

Abstract

Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a complex etiology. Heterozygous, loss-of-function mutations in the Sonic hedgehog (SHH) pathway are associated with HPE. However, mutation carriers display highly variable clinical presentation, leading to an "autosomal dominant with modifier" model, in which the penetrance and expressivity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers have not been identified. Boc encodes a SHH co-receptor and is a silent HPE modifier gene in mice. Here, we report identification of missense BOC variants in HPE patients. Consistent with these alleles functioning as HPE modifiers, individual variant BOC proteins had either loss- or gain-of-function properties in cell-based SHH signaling assays. Therefore, in addition to heterozygous loss-of-function mutations in specific SHH pathway genes and an ill-defined environmental component, our findings identify a third variable in HPE: low frequency modifier genes, BOC being the first identified.

This article is protected by copyright. All rights reserved

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Top 10 Myths Regarding the Diagnosis and Treatment of Cellulitis

Publication date: Available online 3 July 2017
Source:The Journal of Emergency Medicine
Author(s): Erin K. McCreary, Melissa E. Heim, Lucas T Schulz, Robert Hoffman, Jeffrey Pothof, Barry Fox
BackgroundCellulitis is commonly treated in the emergency department (ED). Patients who present with cellulitis incur significant health care costs and may be overtreated with antibiotics. The accurate diagnosis and treatment of cellulitis plays an important role in cost-effective, high-quality medical care, as well as appropriate antibiotic utilization.ObjectiveWe aim to describe common fallacies regarding cellulitis. We present 10 myths that result in misdiagnosis, overtreatment, or inappropriate empiric management of cellulitis. Clinical presentation, including swelling and redness, is explored in depth, along with incidence of community-acquired methicillin-resistance Staphylococcus aureus, management of tick bites, and effective antibiotic therapy for cellulitis.DiscussionPatients are often treated for cellulitis unnecessarily or inappropriately. Awareness of these myths will help guide providers in clinical decision making in order to effectively tailor treatment for these infections.ConclusionsCellulitis is not as simple as it might seem, and is commonly misdiagnosed in the ED. Noninfectious causes of local symptoms, including lymphedema, venous stasis, and deep vein thrombosis need to be considered. Cellulitis should be treated with empiric antimicrobial therapy based on patient risk factors and regional susceptibility patterns. This review will assist providers in managing cellulitis and avoiding treatment errors that lead to high costs, unwanted side effects for patients, and overuse of antibiotics.



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Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome

ABSTRACT

Germline mutations in the tumor suppressor gene PTEN predispose to subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and autism. Evidence-based classification of PTEN variants as either deleterious or benign is urgently needed for accurate molecular diagnosis and gene-informed genetic counseling. We studied 34 different germline PTEN intronic variants from 61 Cowden syndrome patients, characterized their PTEN mRNA processing and analyzed PTEN expression and downstream readouts of P-AKT and P-ERK1/2. While we found that many mutations near splice junctions result in exon skipping, we also identified the presence of cyptic splicing that resulted in premature termination or a shift in isoform usage. PTEN protein expression is significantly lower in the group with splicing changes while P-AKT, but not P-ERK1/2, is significantly increased. Our observations of these PTEN intronic variants should contribute to the determination of pathogenicity of PTEN intronic variants and aid in genetic counseling.

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Viagra dosage recommendation - Pfizer viagra official website - Antioch Herald

Antioch Herald

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New role of LRP5, associated with non-syndromic autosomal recessive hereditary hearing loss

Abstract

Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. And at least 50% of hearing loss are due to a genetic etiology. Although hundreds of genes have been reported, there were still hundreds of related deafness genes to be found. Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with post-lingual non-syndromic sensorineural hearing loss. Whole-exome sequencing identified lipoprotein receptor-related protein 5 (LRP5), a member of the low-density lipoprotein receptor family, as the causative gene in this family. In the zebrafish model, lrp5 downregulation using morpholinos led to significant abnormalities in zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. Rescue experiments showed that LRP5 mutation is associated with hearing loss. Knocking down lrp5 in zebrafish results in reduced expression of several genes linked to Wnt signaling pathway and decreased cell proliferation when compared with those in wild type zebrafish. In conclusion, the LRP5 mutation influences cell proliferation through the Wnt signaling pathway, thereby reducing the number of supporting cells and hair cells and leading to non-syndromic hearing loss in this Chinese family.

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NAP1L1 regulates NF-κB signaling pathway acting on anti-apoptotic Mcl-1 gene expression

Publication date: Available online 4 July 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Toshiaki Tanaka, Yasukazu Hozumi, Mitsuyoshi Iino, Kaoru Goto
Nuclear factor-κB (NF-κB) participates in apoptosis signaling pathway under various pathophysiological conditions. It exerts transcriptional control on the anti-apoptotic Bcl-2 family, such as Bcl-2, Bcl-xl, and Mcl-1, which act on the mitochondrial outer membrane. Previously, we described that NF-κB is negatively regulated by diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates a lipid second messenger diacylglycerol. DGKζ downregulation enhances inhibitors of NF-κB α (IκBα) degradation and p65 subunit phosphorylation, leading to enhanced NF-κB transcriptional activity. Transcriptional machinery is tightly regulated by assembly/disassembly and modification of nucleosomal components. Of those, the human NAP1-like protein (NAP1L) family functions in the transport, assembly/disassembly of nucleosome core particles. We previously identified NAP1L1 and NAP1L4 as novel DGKζ binding partners, but the mechanism by which NAP1Ls are involved in NF-κB signaling pathway remains unclear. Here we show that knockdown of NAP1L1 suppresses IκBα degradation and nuclear transport of p65 subunit after treatment with TNF-α stimulation, leading to attenuation of the NF-κB transcriptional activity, whereas NAP1L4 knockdown remains silent. Moreover, ChIP assay reveals that NAP1L1 knockdown attenuates p65 binding to the Mcl-1 promoter after TNF-α stimulation. This attenuation leads to reduced expression of anti-apoptotic Mcl-1, thereby decreasing the mitochondrial membrane potential and subsequent apoptosis after treatment with TNF-α and CHX. Collectively, results of this study suggest that NAP1L1 downregulation renders the cell vulnerable to apoptotic cell death through attenuation of NF-κB transcriptional activity on the anti-apoptotic Mcl-1 gene.



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Back Pain in a Healthy Teenager

Publication date: Available online 4 July 2017
Source:The Journal of Emergency Medicine
Author(s): Kelly Gardner, Sigmund Kharasch, Ali Raja, Rene Balza, Kriti Bhatia, Emily S. Miller




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Modeling of Patient-Derived Xenografts in Colorectal Cancer

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2–82.6) vs. biopsy 35% (95% CI: 22.1%–50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435–42. ©2017 AACR.

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Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421–34. ©2017 AACR.

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TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing

Treatment of triple-negative breast cancer (TNBC) has been challenging, and paclitaxel resistance is one of the major obstacles to the better prognosis. Deregulation of alternative splicing (AS) may contribute to tumor progression and chemotherapy resistance. Human AS factor TRA2 has two separate gene paralogs encoding TRA2A and TRA2B proteins. TRA2B is associated with cancer cell survival and therapeutic sensitivity. However, the individual role of TRA2A in cancer progression has not been reported. Here we report that TRA2A facilitates proliferation and survival and migration and invasion of TNBC cells. In addition, TRA2A promotes paclitaxel resistance of TNBC by specifically controlling cancer-related splicing, which is independent of other splicing factors. TRA2A overexpression could promote AS of CALU, RSRC2, and PALM during paclitaxel treatment of TNBC cells. The isoform shift of RSRC2 from RSRC2s to RSRC2l leads to a decreased RSRC2 protein expression, which could contribute to TNBC paclitaxel resistance. TRA2A can regulate RSRC2 AS by specifically binding upstream intronic sequence of exon4. Strikingly, TRA2A expression is increased dramatically in patients with TNBC, and has a close relationship with decreased RSRC2 expression; both are associated with poor survival of TNBC. Collectively, our findings suggest that paclitaxel targets the TRA2A–RSRC2 splicing pathway, and deregulated TRA2A and RSRC2 expression may confer paclitaxel resistance. In addition to providing a novel molecular mechanism of cancer-related splicing dysregulation, our study demonstrates that expression of TRA2A in conjunction with RSRC2 may provide valuable molecular biomarker evidence for TNBC clinical treatment decisions and patient outcome. Mol Cancer Ther; 16(7); 1377–88. ©2017 AACR.

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Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein Kinase Activation

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer. Mol Cancer Ther; 16(7); 1224–35. ©2017 AACR.

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NKG2D Ligand-Targeted Bispecific T-Cell Engagers Lead to Robust Antitumor Activity against Diverse Human Tumors

Two new bispecific T-cell engaging (BiTE) molecules with specificity for NKG2D ligands were developed and functionally characterized. One, huNKG2D-OKT3, was derived from the extracellular portion of the human NKG2D receptor fused to a CD3 binding single-chain variable fragment (scFv), known as OKT3. NKG2D has multiple ligands, including MICA, which are expressed by a variety of malignant cells. A second molecule, B2-OKT3, was created in the tandem scFv BiTE format that targets MICA on tumor cells and CD3 on human T cells. Both BiTEs specifically activated T cells to kill human tumor cell lines. Cytotoxicity by B2-OKT3, but not huNKG2D-OKT3, is blocked by soluble rMICA. The huNKG2D-OKT3 induced greater T-cell cytokine production in comparison with B2-OKT3. No T-cell pretreatment was required for IFN production upon coculture of B2-OKT3 or huNKG2D-OKT3 with T cells and target cells. The effector memory T-cell compartment was the primary source of IFN, and culture of T cells and these BiTEs with plate-bound rMICA showed ligand density–dependent production of IFN from both CD4⁺ and CD8⁺ T cells. There was 2-fold more IFN produced per CD8⁺ T cell and 5-fold greater percentage of CD8⁺ T cells producing IFN compared with CD4⁺ T cells. In addition, both BiTEs elicited significant antitumor responses against human metastatic melanoma tumor samples using autologous or healthy donor T cells. These data demonstrate the robust antitumor activity of these NKG2D ligand–binding bispecific proteins and support their further development for clinical use. Mol Cancer Ther; 16(7); 1335–46. ©2017 AACR.

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Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Cancer cells are highly reliant on NAD⁺-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD⁺ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD⁺, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD⁺ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45. ©2017 AACR.

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A Novel Galectin-1 Inhibitor Discovered through One-Bead Two-Compound Library Potentiates the Antitumor Effects of Paclitaxel in vivo

Through the one-bead two-compound (OB2C) ultra–high-throughput screening method, we discovered a new small-molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC/MS-MS indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells) in vitro. Furthermore, in vivo therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice. Our results presented here indicate that the OB2C combinatorial technology is a highly efficient drug screening platform, and LLS2 discovered through this method can be further optimized for anticancer drug development. Mol Cancer Ther; 16(7); 1212–23. ©2017 AACR.

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Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton tyrosine kinase (BTK)–mediated B-cell receptor signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and follicular lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy. Mol Cancer Ther; 16(7); 1246–56. ©2017 AACR.

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Lectin, Galactoside-Binding Soluble 3 Binding Protein Promotes 17-N-Allylamino-17-demethoxygeldanamycin Resistance through PI3K/Akt Pathway in Lung Cancer Cell Line

Heat shock protein 90 (HSP90) stabilizing oncoproteins has been an attractive target in cancer therapy. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, was tested in phase II/III clinical trials, but due to lack of efficacy, clinical evaluation of 17-AAG has achieved limited success, which led to resistance to 17-AAG. However, the mechanism of 17-AAG resistance has not clearly been identified. Here, we identified LGALS3BP (Lectin, galactoside-binding soluble 3 binding protein), a secretory glycoprotein, as a 17-AAG resistance factor. In the clinical reports, it was suggested that LGALS3BP was associated with low survival rate, development of cancer progression, and enhancement of metastasis in human cancers. As we confirmed that the LGALS3BP level was increased in 17-AAG–resistant cells (H1299_17R) compared with that of the parental cell line (H1299_17P), knockdown of LGALS3BP expression increased sensitivity to 17-AAG in H1299_17R cells. Overexpression of LGALS3BP also augmented PI3K/Akt and ERK signaling pathways. Furthermore, we determined that the PI3K/Akt signaling pathway was involved in LGALS3BP-mediated 17-AAG resistance in vitro and in vivo, demonstrating that LGALS3BP mediates the resistance against 17-AAG through PI3K/Akt activation rather than ERK activation. These findings suggest that LGALS3BP would be a target to overcome resistance to 17-AAG in lung cancer. For example, the combination of 17-AAG and PI3K/Akt inhibitor would effectively suppress acquired resistance to 17-AAG. In conclusion, targeting of LGALS3BP-mediated–specific survival signaling pathway in resistant cells may provide a novel therapeutic model for the cancer therapy. Mol Cancer Ther; 16(7); 1355–65. ©2017 AACR.

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Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CA^WT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257–68. ©2017 AACR.

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Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia

The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multifunctional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T cells, including in patient biopsies. Ref-1 redox function is active in leukemia T cells, regulating the Ref-1 target NF-B, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and downregulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small-molecule inhibitor for leukemia. Mol Cancer Ther; 16(7); 1401–11. ©2017 AACR.

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MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody

Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269–78. ©2017 AACR.

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Targeting Insulin Receptor in Breast Cancer Using Small Engineered Protein Scaffolds

Insulin receptor (InsR) and the type I insulin-like growth factor (IGF1R) are homologous receptors necessary for signal transduction by their cognate ligands insulin, IGF-I and IGF-II. IGF1R mAbs, intended to inhibit malignant phenotypic signaling, failed to show benefit in patients with endocrine-resistant tumors in phase III clinical trials. Our previous work showed that in tamoxifen-resistant cells, IGF1R expression was lacking, but InsR inhibition effectively blocked growth. In endocrine-sensitive breast cancer cells, insulin was not growth stimulatory, likely due to the presence of hybrid InsR/IGF1R, which has high affinity for IGF-I, but not insulin. Combination inhibition of InsR and IGF1R showed complete suppression of the system in endocrine-sensitive breast cancer cells. To develop InsR-binding agents, we employed a small protein scaffold, T7 phage gene 2 protein (Gp2) with the long-term goal of creating effective InsR inhibitors and diagnostics. Using yeast display and directed evolution, we identified three Gp2 variants (Gp2 #1, #5, and #10) with low nanomolar affinity and specific binding to cell surface InsR. These Gp2 variants inhibited insulin-mediated monolayer proliferation in both endocrine-sensitive and resistant breast cancer, but did not downregulate InsR expression. Gp2 #5 and Gp2 #10 disrupted InsR function by inhibiting ligand-induced receptor activation. In contrast, Gp2 #1 did not block InsR phosphorylation. Notably, Gp2 #1 binding was enhanced by pretreatment of cells with insulin, suggesting a unique receptor-ligand–binding mode. These Gp2 variants are the first nonimmunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling. Mol Cancer Ther; 16(7); 1324–34. ©2017 AACR.

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White matter abnormalities in mild traumatic brain injury with and without post-traumatic stress disorder: a subject-specific diffusion tensor imaging study

Abstract

Mild traumatic brain injuries (mTBIs) are often associated with posttraumatic stress disorder (PTSD). In cases of chronic mTBI, accurate diagnosis can be challenging due to the overlapping symptoms this condition shares with PTSD. Furthermore, mTBIs are heterogeneous and not easily observed using conventional neuroimaging tools, despite the fact that diffuse axonal injuries are the most common injury. Diffusion tensor imaging (DTI) is sensitive to diffuse axonal injuries and is thus more likely to detect mTBIs, especially when analyses account for the inter-individual variability of these injuries. Using a subject-specific approach, we compared fractional anisotropy (FA) abnormalities between groups with a history of mTBI (n = 35), comorbid mTBI and PTSD (mTBI + PTSD; n = 22), and healthy controls (n = 37). We compared all three groups on the number of abnormal FA clusters derived from subject-specific injury profiles (i.e., individual z-score maps) along a common white matter skeleton. The mTBI + PTSD group evinced a greater number of abnormally low FA clusters relative to both the healthy controls and the mTBI group without PTSD (p < .05). Across the groups with a history of mTBI, increased numbers of abnormally low FA clusters were significantly associated with PTSD symptom severity, depression, post-concussion symptoms, and reduced information processing speed (p < .05). These findings highlight the utility of subject-specific microstructural analyses when searching for mTBI-related brain abnormalities, particularly in patients with PTSD. This study also suggests that patients with a history of mTBI and comorbid PTSD, relative to those without PTSD, are at increased risk of FA abnormalities.

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Screening Cleavage of Factor XIII V34X Activation Peptides by Thrombin Mutants: A Strategy for Controlling Fibrin Architecture

Publication date: Available online 4 July 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Madhavi A. Jadhav, Whitney N. Goldsberry, Sara E. Zink, Kelsey N. Lamb, Katelyn E. Simmons, Carmela M. Riposo, Boris A. Anokhin, Muriel C. Maurer
In blood coagulation, thrombin converts fibrinogen into fibrin monomers that polymerize into a clot network. Thrombin also activates Factor XIII by cleaving the R37-G38 peptide bond of the Activation Peptide (AP) segment. The resultant transglutaminase introduces covalent crosslinks into the fibrin clot. A strategy to modify clot architecture would be to design FXIII AP sequences that are easier or more difficult to be thrombin-cleaved thus controlling initiation of crosslinking. To aid in this design process, FXIII V34X (28–41) activation peptides were kinetically ranked for cleavage by wild-type thrombin and several anticoagulant mutants. Thrombin-catalyzed hydrolysis of aromatic FXIII F34, W34, and Y34 APs was compared with V34 and L34. Cardioprotective FXIII L34 remained the variant most readily cleaved by wild-type thrombin. The potent anticoagulant thrombins W215A and W215A/E217A (missing a key substrate platform for binding fibrinogen) were best able to hydrolyze FXIII F34 and W34 APs. Thrombin I174A and L99A could effectively accommodate FXIII W34 and Y34 APs yielding kinetic parameters comparable to FXIII AP L34 with wild-type thrombin. None of the aromatic FXIII V34X APs could be hydrolyzed by thrombin Y60aA. FXIII F34 and W34 are promising candidates for FXIII – anticoagulant thrombin systems that could permit FXIII-catalyzed crosslinking in the presence of reduced fibrin formation. By contrast, FXIII Y34 with thrombin (Y60aA or W215A/E217A) could help assure that both fibrin clot formation and protein crosslinking are hindered. Regulating the activation of FXIII is predicted to be a strategy for helping to control fibrin clot architecture and its neighboring environments.

Graphical abstract

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Sericin improves heart and liver mitochondrial architecture in hypercholesterolaemic rats and maintains pancreatic and adrenal cell biosynthesis

Publication date: Available online 4 July 2017
Source:Experimental Cell Research
Author(s): Sumate Ampawong, Duangnate Isarangkul, Pornanong Aramwit
Hypercholesterolaemia is well known to be associated with mitochondrial dysfunction, subsequently leading to multiple organ failure. Similar to other natural products, sericin is a candidate for adjunctive therapy in hyperlipidaemic conditions. However, the cholesterol-lowering mechanisms of sericin are multifactorial and controversial. Here, a high-cholesterol-fed rat model with or without sericin treatment was established using a dosage of 1,000mg/kg/day for 30 days. Blood lipid profiles, oxidative stress markers (superoxide dismutase, SOD; malondialdehyde, MDA; nuclear factor erythroid 2-related factor, Nrf-2), dysmorphic mitochondria in relation to fission (dynamin-related protein-1; Drp-1) and fusion (guanosine triphosphatase mutated in dominant optic atrophy; OPA-1) markers and biosynthetic markers (aquaporin, AQP-1; tubulin-4β, Tb4B) in the pancreas and adrenal gland were evaluated. The results showed that sericin reduced blood cholesterol and increased high-density lipoprotein (HDL) by acting against oxidative stress. Hypocholesterolaemic and antioxidant conditions further preserved heart and liver mitochondrial architecture; however, this protection was not exhibited in the kidney, where a high level of renal mitophagy, indicating by LC-3 up-regulation, was presented. The steps of ultrastructural alteration of mitochondria from degenerative changes to necrosis were also demonstrated. Sericin also conserved AQP-1 and Tb4B levels in the exocrine pancreatic acinar cells and zona glomerulosa cells, which were positively correlated with serum lipase, HDL, antioxidative markers and mitochondrial integrity. The present study revealed that sericin not only has antioxidant capacity but also balances pancreatic and adrenal cell biosynthesis, especially lipase activity, which may have played an important role in improving lipid dysregulation in the hypercholesterolaemic rat model, leading to the reduction of dysmorphic mitochondria, particularly in the heart and liver.

Graphical abstract

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Chronic scrotal pain in young adults

Chronic scrotal pain (CSP) is a common and well recognized symptom of young males presenting to primary care units. Historically, CSP is defined as a testicular pain lasting for over 3 months. However, its eti...

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The associations between religion, bereavement and depression among Hong Kong nurses

This paper is to examine the associations between religion, bereavement and depression among nursing professionals using a cross-sectional survey design. There is little empirical evidence in Asia suggesting t...

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A 5 year trend analysis of malaria prevalence with in the catchment areas of Felegehiwot referral Hospital, Bahir Dar city, northwest-Ethiopia: a retrospective study

Malaria is one of the killer diseases in Ethiopia and it is still the first leading cause of death in health facilities. However, there is no information yet regarding the trends of malaria prevalence at healt...

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One year symptom severity and health-related quality of life changes among Black African patients undergoing uterine fibroid embolisation

The main aim in the treatment of symptomatic fibroids by various modalities including uterine fibroid embolisation (UFE) is to alleviate symptoms and ultimately improve the quality of life. The efficacy of thi...

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The association between childcare arrangements and risk of overweight and obesity in childhood: a systematic review

Summary

Over 80% of preschool-aged children experience non-parental childcare. Childcare type has the potential to influence weight outcomes, but its impact on childhood overweight/obesity is not well established. This review aims to (i) systematically evaluate the effects of childcare type on childhood overweight/obesity risk and (ii) investigate the impact of childcare intensity and age at commencement. Five electronic databases were searched for observational studies quantifying an association between childcare type ≤5 years and weight outcomes <18 years. Twenty-four studies were included (n = 127,529 children). Thirteen studies reported increased risk of overweight/obesity in children attending informal care (n = 9) or centre care (n = 4) vs. parental care. Seven studies reported decreased risk of overweight/obesity for children in centre vs. 'non-centre' care (parental and informal). Four studies reported no association between informal or centre care and overweight/obesity. Early (<3 years) informal care, especially by a relative, was associated with increased risk of overweight/obesity. Higher intensity childcare, especially when commenced early (<1 year), increased overweight/obesity risk. Later (≥3 years) centre care was associated with decreased risk of overweight/obesity. Early informal care, earlier commencement age and higher intensity represent a risk for childhood obesity. Exploration of the obesogenic aspects of these contexts is essential to inform preventative measures.

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Endogenous hydrogen sulfide-mediated MAPK inhibition preserves endothelial function through TXNIP signaling

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Danyang Tian, Jinghui Dong, Sheng Jin, Xu Teng, Yuming Wu
Mounting evidence demonstrated deficient cystathionine-γ-lyase (CSE)/H2S implicated the development of cardiovascular disease. The present study aimed to evaluating the favorable action of CSE derived H2S on endothelial function in CSE^-/- mice. CSE^-/- mice exhibited attenuated endothelium-dependent relaxations, coupled with reduction of endothelial nitric oxide synthase (eNOS) phosphorylation at site of Ser1177, increase of thioredoxin interacting protein (TXNIP) level and MAPK phosphorylation, which were corrected by sodium hydrosulfide chronic treatment for 8 weeks. Impaired relaxations to ACh and upregulated TXNIP of CSE^-/- mice aorta were partially corrected by p38 inhibitor, extracellular regulated protein kinase (ERK) inhibitor and c-Jun N-terminal kinase (JNK) inhibitor and totally corrected by combined treatment. Pharmacological inhibition of CSE with DL-propargylglycine (PPG) in vivo and ex vivo induced endothelial dysfunction. PPG stimulated the phosphorylation of p38, JNK and ERK in human umbilical vein endothelial cells (HUVECs). MAPK inhibition by combined treatment of p38, JNK and ERK inhibitors normalized the endothelial changes of eNOS phosphorylation and TXNIP protein level in CSE^-/- mice aorta and PPG-treated HUVECs. NaHS offered similar effect with MAKP inhibitors. TXNIP siRNA prevented against endothelial function by PPG and TXNIP overexpression mimics the detrimental effect of PPG treatment on endothelial function, whereas MAPK inhibitor or NaHS has no beneficial effect. In a word, Endogenous CSE/H2S benefits against endothelial dysfunction through suppressing MAPK/TXNIP cascade. CSE deficiency and consequently lowered endogenous H2S level should be considered as risk factors and biomarkers for endothelial dysfunction.

Graphical abstract

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