Medicine by Alexandros G.Sfakianakis: 05/11/17

Πέμπτη 11 Μαΐου 2017

AHNAK suppresses tumour proliferation and invasion by targeting multiple pathways in triple-negative breast cancer

Abstract

Background

AHNAK, also known as desmoyokin, is a giant protein with the molecular size of approximately 700 kDa and exerts diverse functions in different types of cancer.

Results

In the present study, we demonstrated that AHNAK mRNA levels were down-regulated in 7 out of 8 human breast cancer cell lines, especially in triple - negative breast cancer (TNBC) cell lines. Moreover, in patients with TNBC, the expression of AHNAK gene was inversely correlated with the tumor status (P = 0.015), lymph node status (P < 0.001), lymph node (LN) infiltration (P < 0.001) and TNM stage (P < 0.001). Moreover, down-regulated AHNAK expression was considered an independent prognostic factor associated with the poor survival of patients with TNBC. Overexpression of AHNAK in two TNBC cell lines, MDA-MB-231 and BT549, suppressed the in vitro TNBC cell proliferation and colony formation, and inhibited the in vivo TNBC xenograft growth and lung metastasis. The tumor suppressing effect of AHNAK in TNBC was associated with the AKT/MAPK signaling pathway and Wnt/β-catenin pathway. Consistent results were observed when AHNAK was knockdown in BT20 and MDA-MB-435 cells.

Conclusions

Taken together, our results suggest that AHNAK acts as a tumor suppressor that negatively regulates TNBC cell proliferation, TNBC xenograft growth and metastasis via different signaling pathways.

http://ift.tt/2q82a5z

Lysophosphatidylcholine acyltransferase 1 upregulation and concomitant phospholipid alterations in clear cell renal cell carcinoma

Abstract

Background

The involvement of lipid metabolism in tumourigenesis and the progression of clear cell renal cell carcinoma (ccRCC) have been reported. However, the role of phospholipid profile alterations in ccRCC has not yet been systematically explored. In the present study, we compared the phospholipid compositions between ccRCC and paired normal renal tissues.

Methods

The phospholipid compositions of paired ccRCC and normal renal tissues were evaluated using liquid chromatography tandem mass spectrometry (LC/MS/MS). To evaluate the mRNA and protein levels of lysophosphatidylcholine acyltransferase (LPCAT), which converts lysophosphatidylcholine (LPC) to phosphatidylcholine (PC), qRT-PCR, western blotting and immunohistochemistry were performed. The correlations of LPCAT1 expression with clinicopathological features and prognosis were assessed. In addition, siRNAs were used to knockdown LPCAT1 expression in ccRCC cell lines, and its effect on cell proliferation, cell cycle, migration and invasion were investigated.

Results

The phospholipid compositions of ccRCC and normal renal tissues were significantly different. Multiple LPC species were decreased and corresponding PC species were increased in cancer tissues. The mRNA and protein levels of LPCAT1 were up-regulated in ccRCC tissues compared with normal renal tissues, and LPCAT1 expression was significantly correlated with unfavourable pathological features (higher tumour grade, higher TNM stage and larger tumour size) and overall survival. In cell line experiments, LPCAT1 knockdown depleted PCs, inhibited cell proliferation, migration and invasion and induced cell cycle arrest at the G0/G1 phase.

Conclusion

Selective changes in PC and LPC composition were observed in ccRCC tissues. The overexpression of LPCAT1 promotes the development and progression of ccRCC, likely through the conversion of LPC to PC.

http://ift.tt/2r6KFzz

Patients in prehospital transport to the emergency department: a cohort study of risk factors for 7-day mortality.

Background: Ambulance transfer is the first contact with the healthcare system for many patients in emergency conditions. We aimed to identify prognostic risk factors accessible in the prehospital phase that indicate an increased risk of 7-day mortality. Patients and methods: We included patients aged 18 years or older, transferred by ambulance to the emergency department at Odense University Hospital, from 1 April 2012 to 30 September 2014. We carried out multivariate logistic regressions, adjusted for age and sex, to describe the relationship between vital sign values recorded in the prehospital setting and 7-day mortality. Results: A total of 32 076 ambulance transfers were recorded. Of these, 20 328 were first-time transfers, including 2692 that received assistance from a physician-staffed mobile emergency care unit (MECU). The 7-day mortality was 5.3% [95% confidence interval (CI): 5.0-5.6]. The risk of death increased with age. The odds ratios (ORs) were 2.0 (95% CI: 1.1-3.5) for ages 30-44 years and 7.3 (95% CI: 4.5-11) for ages 45-69 years compared with the 18-29-year-olds. All abnormal vital sign values were associated with increased 7-day mortality. Glasgow Coma Score of less than 14 had the strongest association (OR: 17, 95% CI: 14.7-19.7). MECU assistance showed an adjusted OR of 5.3 (95% CI: 4.6-6.1). Conclusion: The overall 7-day mortality was 5.3%, but differed in the two subgroups, with 15.4% in the MECU-assisted ambulance transfers and 3.8% in non-MECU-assisted transfers. Older age and Glasgow Coma Scores below 14 were the strongest of factors associated significantly with 7-day mortality. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2qb7MJZ

A rapid gene sequencing panel strategy to facilitate precision neonatal medicine

http://ift.tt/2r8BtLR

Male child with somatic mosaic Osteopathia Striata with Cranial Sclerosis caused by a novel pathogenic AMER1 frameshift mutation

Osteopathia striata with cranial sclerosis (OSCS; OMIM #300373) is a rare X-linked dominant condition caused by mutations in the AMER1 gene (also known as WTX or FAM123B). It is a condition which usually affects females in whom the clinical phenotype can be extremely variable. Conversely affected males typically die in utero or during the neonatal period [Perdu et al. (); Clinical Genetics 80: 383-388; Vasiljevic et al. (); Prenatal Diagnosis 35: 302-304]. There have been a small number of reported cases of surviving males, including three patients who are somatic mosaic for the condition [Chénier, Noor, Dupuis, Stavropoulos, & Mendoza-Londono, (); American Journal of Medical Genetics Part A 158A: 2946-2952; Holman et al. (); American Journal of Medical Genetics Part A 155A: 2397-2408; Joseph, Shoji, & Econs, (); The Journal of Clinical Endocrinology and Metabolism 95: 1506-1507]. We report a case of a male child who has proven somatic mosaicism for OSCS associated with a novel pathogenic frameshift mutation, c.607_611delAGGCC (p.Arg203 fs) in AMER1. We describe the multisystemic clinical features which include macrocephaly with ventriculomegaly and requirement for ventriculoperitoneal shunt, cleft palate, and respiratory difficulties after birth requiring tracheostomy insertion, persistent patent ductus arteriosus, failure to thrive and gastrostomy insertion, growth retardation, ophthalmoplegia, kidney malformation, cryptorchidism, and developmental delay. The use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism in rare conditions.

http://ift.tt/2qyKPU3

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center

Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p < .004 for all). The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations, and academic goals for individuals with JS.

http://ift.tt/2qyZ2kf

Current FDA-approved injection pattern versus targeted peripheral nerve–directed injection pattern. The current FDA-approved injection pattern includes chemodenervation of 7 head and neck muscle groups (A–C). The total units of BOTOX injected for each site bilaterally include: corrugators 10U, procerus 5U, frontalis 20U (A), temporalis 40U (B), occipitalis 30U, cervical paraspinal 20U, and trapezius 30U (C). By comparison, peripheral nerve–directed BOTOX injection targets fewer sites with a smaller total quantity of BOTOX (D–F). The total units of BOTOX injected for each site bilaterally include: supraorbital nerve/supratrochlear nerve 25U (D), zygomaticotemporal nerve 37.5U (E), and greater occipital nerve 50U (F). Source Targeted Peripheral Nerve-directed Onabotulinumtoxin A Injection for Effective Long-term Therapy for Migraine Headache

http://otorhinolaryngology-crete.blogspot.com/2017/05/current-fda-approved-injection-pattern.html

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

6948891480

alsfakia@gmail.com

Autologous Platelet-rich Plasma Glue : Seroma and hematoma formations are the most common complications after plastic surgery. The aim of this study was to assess the efficacy of autologous platelet-rich plasma (A-PRP) glue to reduce postoperative wound complications and improve surgical outcomes.

http://otorhinolaryngology-crete.blogspot.com/2017/05/autologous-platelet-rich-plasma-glue.html

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

6948891480

alsfakia@gmail.com

The effect of insulin administration on c-peptide in critically ill patients with type 2 diabetes

In critically ill patients with permissive hyperglycemia, it is uncertain whether exogenous insulin administration suppresses or enhances c-peptide secretion (a marker of pancreatic beta-cell response). We aim...

http://ift.tt/2qZNCFD

Quality assurance trials for Ki67 assessment in pathology

Abstract

Ki67 is a broadly used proliferation marker in surgical pathology with an obvious need for standardization to improve reproducibility of assessment. Here, we present results of the so far only existing round robin tests on Ki67, organized annually in Germany, Austria, and Switzerland from 2010 to 2015 with up to 160 participating laboratories (QuIP). In each quality assessment trial, eight probes from each breast cancer, neuroendocrine tumor, and malignant lymphoma were compiled on a tissue microarray (TMA). TMAs were stained in the participants' laboratories with antibodies and procedures also applied in their daily routine. Participating pathologists were expected to assign Ki67 values to one of four different categories for each tumor type. All local stainings and evaluations were reassessed by the organizing panel and compared to a preset standard. On average, 95% of participants reached the benchmark of over 80% concordance rates with the Ki67 category pre-established by the panel. Automatization and type of antibody did not affect the success rate. Concordance rates differed between tumor entities being highest in each tumor type with either very high or very low labeling indices. Lower rates were seen for intermediate Ki67 levels. Staining quality improved during the observation period as did inter-observer concordance with 85% of participants achieving excellent agreement (kappa > 0.8) in the first year and over 95% in 2015. In conclusion, regular external quality assurance trials have been established as a tool to improve the reproducibility and reliability of the prognostic and predictive proliferation marker Ki67.

http://ift.tt/2pEQ9Bb

Donor selection for ex vivo expanded natural killer cells as adoptive cancer immunotherapy

Future Oncology Ahead of Print.

http://ift.tt/2r007kR

Novel translational therapeutic strategy by sequencing primary liver cancer genomes

Future Oncology Ahead of Print.

http://ift.tt/2pERfgn

Does physical activity improve survival and mortality among patients with different types of cancer?

Future Oncology Ahead of Print.

http://ift.tt/2qZZPdA

The underestimated role of somatostatin analogs in the NETTER-1 trial

Future Oncology Ahead of Print.

http://ift.tt/2pEZwRz

Venetoclax for the treatment of patients with chronic lymphocytic leukemia

Future Oncology Ahead of Print.

http://ift.tt/2qZEGQY

Advances in Microbiology Vol.7,No.4 (April 2017)

The PafR Gene Is Required for Antifungal Activity of Strain MS82 against Mycogone perniciosa
Pseudomonas fluorescens, Antifungal Activity, Mycogone perniciosa, Mutagenesis
Paper Information Full Paper: PDF (Size:526KB)
DOI: 10.4236/aim.2017.74018

Genomic Recombination Enhances Pathogenic Factors in the Periodontopathogenic Bacterium Eikenella corrodens
Eikenella corrodens, Genomic Recombination, Biofilm, Hemolysis, Hemagglutination
Paper Information Full Paper: PDF (Size:1783KB)
DOI: 10.4236/aim.2017.74019

Antibiotic Resistance of Helicobacter pylori and Eradication Rate in Japanese Pediatric Patients
Resistance, Eradication Rate, Susceptibility Test, Clarithromycin, Metronidazole
Paper Information Full Paper: PDF (Size:568KB)
DOI: 10.4236/aim.2017.74020

A Retrospective Analysis of Three Non-Invasive Tests for Initial Diagnosis of Helicobacter pylori Infection in Children
Accuracy, Non-Invasive Tests, Urea Breath Test, Stool Antigen Test, Serum Antibody Test
Paper Information Full Paper: PDF (Size:390KB)
DOI: 10.4236/aim.2017.74021

Isolation and Identification of Potential Probiotic Bacteria from Cattle Farm Soil in Dibrugarh District
Probiotic, Soil, Cattle Farm, Enterococcus faecium, Bacillus spp.
Paper Information Full Paper: PDF (Size:378KB)
DOI: 10.4236/aim.2017.74022

Characterization of Amylase from Some Aspergillus and Bacillus Species Associated with Cassava Waste Peels
Amylase, Bacillus, Aspegillus, Enzyme Activity
Paper Information Full Paper: PDF (Size:411KB)
DOI: 10.4236/aim.2017.74023

Partial Purification and Characterization of Cellulase Produced by Bacillus sphaericus CE-3
Cellulase, Bacillus sphaericus CE-3, Untreated Sawdust, Catalytic Activity
Paper Information Full Paper: PDF (Size:433KB)
DOI: 10.4236/aim.2017.74024

Molecular and Phenotypical Characterization of Mannheimia haemolytica Isolated from Goats in Baghdad Province
Mannhimia haemolytica, Goats, Polymerase Chain Reaction (PCR), Baghdad
Paper Information Full Paper: PDF (Size:537KB)
DOI: 10.4236/aim.2017.74025

Activation without Proteolysis of Anti-σ Factor RsiV of the Extracytoplasmic Function σ Factor σ^V in a Glucolipid-Deficient Mutant of Bacillus subtilis
Anti-σ Factor, Bacillus subtilis, ECF σ Factor, Glucolipid, RsiV, σ^V, UgtP
Paper Information Full Paper: PDF (Size:554KB)
DOI: 10.4236/aim.2017.74026

Symbiotic, Hypocholesterolemic and Antioxidant Effects of Potential Probiotic Lactobacilli Strains Isolated from Tunisian Camel Milk
Probiotic, Prebiotic, Cholesterol Removal, Bile Salt Deconjugation, Antioxidant Activity, functiOnal Food
Paper Information Full Paper: PDF (Size:756KB)
DOI: 10.4236/aim.2017.74027

http://ift.tt/1lkzXmf

Neoadjuvant Trials in ER+ Breast Cancer: A Tool for Acceleration of Drug Development and Discovery [Reviews]

Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple-negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long-term patient benefit. For estrogen receptor–positive (ER⁺) breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long-term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neoadjuvant endocrine therapy for ER⁺/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery.

Significance: Neoadjuvant endocrine therapy is an excellent platform for the development of investigational drugs, triaging of novel combinations, biomarker validation, and discovery of mechanisms of drug resistance. This review summarizes the clinical and investigational benefits of this approach, with a focus on how to best integrate predictive biomarkers into novel clinical trial designs. Cancer Discov; 7(6); 1–14. ©2017 AACR.

http://ift.tt/2r5OO6U

Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS-specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole-genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well-known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2, and LSAMP are located. Certain genomic features, such as transposable elements and non-B DNA-forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage pattern – chromothripsis – has been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS-specific fragility pattern provides novel clues for understanding the biology of osteosarcoma. This article is protected by copyright. All rights reserved.

http://ift.tt/2pDSbRn

Role of Radiation Therapy in the Treatment of Hodgkin Lymphoma

Abstract

Radiation therapy has historically been the pillar of curative treatment for Hodgkin lymphoma (HL). With improved efficacy of systemic therapy and the ever-increasing recognition of treatment-related morbidity in long-term survivors, the role of radiotherapy has evolved significantly. Modern combined modality therapy (CMT) with multi-agent chemotherapy followed by involved site radiation therapy (ISRT) to initially involved sites of disease remains the gold standard for the majority of patients with HL. Reduction of long-term treatment-related toxicity has become the major driver in clinical trial design for early-stage HL while improved disease-specific survival remains the goal in patients with more advanced and unfavorable disease. This review will address the data supporting the use of radiotherapy in HL as well as specific methods for reducing late toxicity from radiotherapy.

http://ift.tt/2pq80Qk

Efficacy and Safety of Manual Partial Red Cell Exchange in the Management of Severe Complications of Sickle Cell Disease in a Developing Country

Introduction. The realization of red cell exchange (RCE) in Africa faces the lack of blood, transfusion safety, and equipment. We evaluated its efficacy and safety in severe complications of sickle cell disease. Patients and Method. Manual partial RCE was performed among sickle cell patients who had severe complications. Efficacy was evaluated by clinical evolution, blood count, and electrophoresis of hemoglobin. Safety was evaluated on adverse effects, infections, and alloimmunization. Results. We performed 166 partial RCE among 44 patients including 41 homozygous (SS) and 2 heterozygous composites SC and 1 S/β0-thalassemia. The mean age was 27.9 years. The sex ratio was 1.58. The regression of symptoms was complete in 100% of persistent vasoocclusive crisis and acute chest syndrome, 56.7% of intermittent priapism, and 30% of stroke. It was partial in 100% of leg ulcers and null in acute priapism. The mean variations of hemoglobin and hematocrit rate after one procedure were, respectively, +1.4 g/dL and +4.4%. That of hemoglobin S after 2 consecutive RCE was −60%. Neither alloimmunization nor viral seroconversion was observed. Conclusion. This work shows the feasibility of manual partial RCE in a low-resource setting and its efficacy and safety during complications of SCD outside of acute priapism.

http://ift.tt/2q4i3ty

Metabolic Syndrome and Aggressive Prostate Cancer at Initial Diagnosis

Horm Metab Res
DOI: 10.1055/s-0043-109866

Links between metabolic syndrome and prostate cancer after androgen deprivation therapy are emerging. The aim of the research was to investigate the association of metabolic syndrome and aggressive prostate malignancy, at initial diagnosis, without the influence of hormonal treatment. Retrospective analysis of 133 patients with prostate tumor diagnosis between 2007 and 2009 was conducted. Patients with prostate cancer were subdivided in 2 groups according to Gleason score: Gleason score≥7 as high-grade prostate tumor (Group 1) and <7 (Group 2) as low-grade prostate tumor. Metabolic syndrome was defined according to International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute definition. Metabolic syndrome was significantly associated with aggressive prostate cancer (OR 1.87, p<0.05) and a reduced risk of low-grade prostate cancer (OR 0.53, p<0.05) at initial diagnosis, without the influence of endocrine therapy. In our study, patients with metabolic syndrome were more likely to present with more aggressive prostate carcinoma vs. patients without metabolic syndrome. Further research should elucidate these relations in larger samples to confirm these associations and to stabilize future prevention and therapeutic strategies.
[...]

Article in Thieme eJournals:
Table of contents | Abstract | Full text

http://ift.tt/2ppTCYA

Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects

To evaluate the serum levels of zonulin, which regulates tight junctions between enterocytes and is a physiological modulator controlling intestinal permeability, in patients with autism spectrum disorders (ASDs).

http://ift.tt/2q9Pl8Q

Impact of iron deficiency anemia on CD4 and CD8-T lymphocytes among preschool-school children

Abstract

Iron is a basic element at cellular and molecular levels for proper development and effective function of the immune system. Children with iron deficiency are more susceptible to infections and have many alterations to their immune profile. The current study investigates the quantitative changes for CD4 and CD8 T-lymphocytes among symptomatic and asymptomatic iron deficient children. Flow cytometry using conjugated monoclonal antibodies was used for assessment of the CD4 and CD8 T-lymphocyte subsets among 30 asymptomatic iron deficient children, 28 iron deficiency anemia (IDA) symptomatic children, and 30 healthy children. A significant decline of CD4+ lymphocyte percentage was observed among both asymptomatic and symptomatic iron deficient children when compared to the control group. The percentage of CD8+ lymphocytes increased among both iron deficient groups. The current study concludes that symptomatic and asymptomatic iron deficient children have an alteration of CD4 and CD8 cell ratios. Early diagnosis and treatment of asymptomatic iron deficiency are mandatory to prevent functional deterioration of cell-mediated immunity.

http://ift.tt/2pDyJ7j

Provider Perspectives Regarding Resuscitation Decisions for Neonates and Other Vulnerable Patients

To use structured surveys to assess the perspectives of pediatric residents and neonatal nurses on resuscitation decisions for vulnerable patients, including neonates.

http://ift.tt/2q7boih

Cystic adventitial disease of the common femoral vein

We present the case of a 46-year-old commercial pilot with a history of unilateral leg swelling following a flight to Geneva. Although initial clinical examination suggested a deep vein thrombosis, the swelling only partially resolved with anticoagulation and further imaging suggested the presence of adventitial cystic disease (ACD). The patient underwent initial anticoagulation to allow any thrombus to be lysed, followed by excision of the ACD from the venous wall and venous reconstruction. Following the excision of the ACD, providing the patient remains asymptomatic and further imaging finds normal venous anatomy, we hope the patient will discontinue anticoagulation and return to flying.

http://ift.tt/2q9XlGT

Bilateral corneal injury after face-paint application to upper eyelids

A 40-year-old woman with no known medical conditions or allergies presented with severely painful, watery eyes and blurred vision. She reported topical application of face-paint onto both upper eyelids prior to attending a Halloween party. She subsequently noticed a burning sensation, epiphora and misty vision within a few hours. On examination, bilateral large corneal epithelial defects were highlighted with fluorescein dye under cobalt-blue light. Antibiotic ointment, mydriatic and sodium ascorbate 10% eye-drops were given, and patient was advised to keep the eyelids shut to promote healing. No corneal defects were visible by day 4 and the patient was discharged with vision recovering to normal levels.

http://ift.tt/2q7aC4R

Mixed cryoglobulinemia: a diagnostic and therapeutic challenge

Mixed cryoglobulinemia is frequently secondary to hepatitis C virus infection. Diagnosis and therapeutic management are challenging, depending on the spectrum and severity of manifestations, as well as on the presence of comorbidities. We describe a case of a 79-year-old woman with a non-cirrhotic hepatitis C virus infection presenting with weakness, arthralgias, purpuric rash with left leg ulcerative lesions, bilateral peripheral sensorimotor polyneuropathy, renal impairment and cardiac failure. The investigation was compatible with a severe type II mixed cryoglobulinemia with multisystemic involvement, including a low-grade B cell lymphoma and concomitant intestinal tuberculosis. Initial management with immunosuppressive therapy with glucocorticoids to control symptoms and simultaneous tuberculosis treatment was required. Unavailability of adequate antiviral treatment led to the need to control the severity of systemic manifestations with rituximab, before the effective aetiological treatment with sofosbuvir and ledipasvir was possible, allowing the definitive resolution of the disease.

http://ift.tt/2qaj29P

A rare view: giant liver abscess with underlying liver metastases

Description

Liver abscess (LA) refers to a suppurated cavity caused by the invasion of liver parenchyma, most commonly by Gram-negative bacteria. Although rare, it is potentially life-threatening. Giant LA (>10 cm) is even more uncommon.1 Symptoms and signs are non-specific and the diagnosis relies essentially on imaging with ultrasound (US) and CT scan. Treatment is based on antimicrobials, abscess drainage and approach to the underlying disease.2 For pyogenic LA, prompt initiation of empirical broad-spectrum intravenous antibiotics,2 usually a third-generation cephalosporin plus metronidazole, is essential with subsequent adjustment to culture and sensitivity, usually for 10–14 days, depending on clinical and radiological response. Together with CT scan or US-guided percutaneous catheter drainage (PD), it is the initial treatment of choice.1 However, large LA >5 cm predicts failure of PD and the need for surgical drainage.3 Malignancy and multiloculation are also risk factors for therapy...

http://ift.tt/2q7cCdo

Vitamin A deficiency due to chronic malabsorption: an ophthalmic manifestation of a systemic condition

A 47-year-old woman presented with a 4-week history of progressive loss of vision, first manifesting as night blindness. Additionally, the patient reported frequent severe episodes of diarrhoea over the past month. Her medical history included end-stage renal failure for which she was currently on haemodialysis after a failed renal transplant, chronic pancreatitis and autonomic diabetes mellitus. Ophthalmological examination revealed severe bilateral corneal xerosis, bilateral Bitot's spots and inferior ulceration of the right cornea. A diagnosis of xerophthalmia due to vitamin A deficiency was made, most likely due to the presence of small intestinal bacterial overgrowth and the patient's chronic malabsorptive state. Standard management using oral vitamin A tablets was ineffective, resulting in the patient requiring intravenous supplementation. The extent of visual deterioration on presentation and the difficulties encountered managing the patient resulted in the patient's vision failing to improve.

http://ift.tt/2qa5NWs

Ian Freckelton QC, Scholarly misconduct – law, regulation, and practice

http://ift.tt/2r544AO

Comorbid conditions delay diagnosis of colorectal cancer: a cohort study using electronic primary care records

http://ift.tt/2q8jtCN

Mutation status among patients with sinonasal mucosal melanoma and its impact on survival

http://ift.tt/2q8gryM

Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma

http://ift.tt/2pElxQD

Randomized evaluation of cognitive-behavioral therapy and graded exercise therapy for post-cancer fatigue.

To evaluate the outcomes of a randomized controlled trial, which assigned patients with post-cancer fatigue (PCF) to education, or 12-weeks of integrated cognitive-behavioral therapy (CBT) and graded exercise therapy (GET).

http://ift.tt/2r5lRYU

AST to Platelet Ratio Index and fibrosis 4 calculator scores for non-invasive assessment of hepatic fibrosis in patients with non-alcoholic fatty liver disease

Liver fibrosis is the single most important prognostic factor in patients with non-alcoholic fatty liver disease (NAFLD). The predictive value of the AST to Platelet Ratio Index (APRI) score, originally developed for fibrosis assessment in HCV patients, is much less known in the context of NAFLD patients.

http://ift.tt/2pDnX0R

Retraction Note: Anti-cancer effects of grailsine-al-glycoside isolated from Rhizoma Sparganii

http://ift.tt/2q9ZOAO

Changes in resting-state directed connectivity in cortico-subcortical networks correlate with cognitive function in Parkinson’s disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by prominent motor symptoms, as well as a wide range of non-motor disturbances in early disease stages, among which cognitive dysfunction (Chaudhuri et al., 2006; Dickson et al., 2009). Over time, dementia develops in up to 75% of PD patients (Aarsland and Kurz. 2010), contributing significantly to an impaired quality of life and putting a heavy burden on caregivers (Aarsland et al., 1999; Schrag et al., 2006). The pathophysiological mechanisms underlying cognitive decline and conversion to PD dementia (PDD) are not well understood.

http://ift.tt/2q6WrNo

Heart rate changes according to the complexity of motor events in REM sleep behavior disorder

Reduced Heart Rate Variability (HRV) is considered a marker of autonomic system dysfunction in REM sleep behavior disorder (RBD) (Fantini et al. 2002; Sorensen et al. 2012). Blunted Heart Rate (HR) response was described in RBD and Parkinson's Disease (PD) patients following limb movements during sleep (Fantini et al. 2002; Sorensen et al. 2012) and in PD after arousals (Sorensen et al. 2012). We found no study on the effect of RBD motor events (ME) on HR. RBD related ME can be classified in two types: short lasting, small amplitude, non-purposeful movements and complex, scenic ones, in which patients enact the content of their dreams, usually negative or violent (Frauscher et al.

http://ift.tt/2qalkWo

Motor unit number estimation (MUNE): An important – though imperfect – measure receives some needed scholarship

"MUNE has the potential to serve as the most sensitive quantitative measure of early disease progression in ALS." (Shefner and Gooch, 2003)

http://ift.tt/2q72ykB

Evoked potentials recorded during routine EEG predict outcome after perinatal asphyxia

Hypoxic-ischaemic encephalopathy (HIE) due to perinatal asphyxia occurs in approximately 2,5 per 1000 live full-term births (Graham et al., 2008), and is one of the leading causes of neonatal deaths and severe neurodevelopmental compromise (Lai and Yang, 2011). Recent data show that even when treated with therapeutic hypothermia (TH), 40-50% of newborns with moderate-to-severe HIE will die or develop with severe handicap (Tagin et al., 2012).

http://ift.tt/2qalixK

Response to Letter: Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

http://ift.tt/2ppEUkd

Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients

Purpose: HSV1716 is an oncolytic herpes simplex virus-1 (HSV-1) studied in adults via injection into the brain and superficial tumors. To determine the safety of administering HSV1716 to pediatric patients with cancer, we conducted a phase I trial of image-guided injection in young patients with relapsed or refractory extracranial cancers.

Experimental Design: We delivered a single dose of 10⁵ to 10⁷ infectious units of HSV1716 via computed tomography–guided intratumoral injection and measured tumor responses by imaging. Patients were eligible for up to three more doses if they achieved stable disease. We monitored HSV-1 serum titers and shedding by PCR and culture.

Results: We administered a single dose of HSV1716 to eight patients and two doses to one patient. We did not observe any dose-limiting toxicities. Adverse events attributed to virus included low-grade fever, chills, and mild cytopenias. Six of eight HSV-1 seronegative patients at baseline showed seroconversion on day 28. Six of nine patients had detectable HSV-1 genomes by PCR in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had transient focal increases in metabolic activity on ¹⁸fluorine-deoxyglucose PET, consistent with inflammatory reactions. In one case, the same geographic region that flared later appeared necrotic on imaging. No patient had an objective response to HSV1716.

Conclusions: Intratumoral HSV1716 is safe and well-tolerated without shedding in children and young adults with late-stage, aggressive cancer. Viremia consistent with virus replication and transient inflammatory reactions hold promise for future HSV1716 studies. Clin Cancer Res; 1–9. ©2017 AACR.

http://ift.tt/2ppRVKJ

Forthcoming Issues

The Treatment of Myeloid Malignancies with Kinase Inhibitors

http://ift.tt/2qxmDSi

Contributors

GEORGE P. CANELLOS, MD

http://ift.tt/2r71ScY

Staging in Esophageal and Gastric Cancers

Gastric and esophageal tumors have a poor prognosis; approximately 15% of patients are alive at 10 years following diagnosis. Surgical resection plus adjunctive chemotherapy or chemoradiotherapy is curative in approximately 50% of patients with operable disease, but is also associated with significant morbidity. Therefore, accurate preoperative staging is required to spare patients unnecessary toxicity and futile surgery. This review evaluates the sensitivity and specificities of the modalities used to stage patients with gastroesophageal cancer. Staging techniques reviewed include CT, PET, MRI, EUS, and laparoscopy. The article concludes with suggestions on appropriate staging tools according to site and stage of disease.

http://ift.tt/2qxnIcx

Update on Gastroesophageal Adenocarcinoma Targeted Therapies

Gastroesophageal cancer (GEC) remains a major cause of cancer-related mortality worldwide. Although the incidence of distal gastric adenocarcinoma (GC) is declining in the United States, proximal esophagogastric junction adenocarcinoma (EGJ) incidence is rising. GC and EGJ, together, are treated uniformly in the metastatic setting as GEC. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to date—only first-line anti-HER2 therapy for ERBB2 amplification and second-line anti-VEGFR2 therapy. This article reviews aberrations in epidermal growth factor receptor, MET, and ERBB2, their therapeutic implications, and future directions in targeting these pathways.

http://ift.tt/2r6USgp

Upper Gastrointestinal Malignancies

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

http://ift.tt/2qxsXJj

Manish A. Shah

http://ift.tt/2r72MGp

Copyright

ELSEVIER

http://ift.tt/2qxsUgB

Index

Note: Page numbers of article titles are in boldface type.

http://ift.tt/2r6Ocin

HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity

Abstract

Background

Hematological and neurological expressed 1 (HN1) is upregulated in many tumors, but the role of HN1 in breast cancer progression and its regulatory mechanism have not been well understood.

Methods

To study the role of HN1 in the initiation and progression of breast cancer, we examined HN1 levels in breast cancer cells and tissues and analyzed the relationship between HN1 levels and patient survival. We used mammosphere formation assay, side population analysis, wound healing assay, transwell assay, soft agar formation assay, and xenografted tumor model to determine the effect of HN1 on the expansion of breast cancer stem cells, and the migration, invasion and tumorigenesis of breast cancer. To determine whether HN1 regulates MYC, we used quantitative real-time PCR and Western blot analysis to assess the expression of MYC and their targeted genes to determine the phenotype caused by knockdown of MYC in breast cancer cell with HN1 overexpression.

Results

In this study, we found that HN1 was upregulated in breast cancer tissues. Patients with high levels of HN1 expression had significantly shorter survival than those with low HN1 expression. In breast cancer cell line, ectopic overexpression of HN1 not only promoted the expansion of breast cancer stem cells, but also promoted cell migration, invasion, and tumorigenesis, while knockdown of HN1 reduced these effects. Furthermore, there was a positive correlation between MYC (also known as c-MYC) level and HN1 level, mechanism analysis suggested HN1 promoted the expression of MYC and its targeted genes like CDK4, CCND1, p21, CAV1, and SFRP1. Downregulation of MYC abrogated the effect of HN1 overexpression in breast cancer cell lines.

Conclusion

Taken together, these data reveal that HN1 promotes the progression of breast cancer by upregulating MYC expression, and might be a therapeutic target for breast cancer.

http://ift.tt/2q9JJeJ

Neuroendocrine carcinoma of the breast: a review of 126 cases in China

http://ift.tt/2r6LJnO

Issue Information

http://ift.tt/2qx7Oix

Vitamin D deficiency among smear positive pulmonary tuberculosis patients and their tuberculosis negative household contacts in Northwest Ethiopia: a case–control study

Vitamin D is a fat-soluble vitamin that increases the immunity against tuberculosis (TB), decreases the re-activation of latent TB and reduces the severity of active TB disease. Epidemiological studies on the ...

http://ift.tt/2r6ILjo

Perkins P, Cooksley CD and Cox JD. Breast cancer: Is ethnicity an independent prognostic factor for survival? Cancer. 1996;78:1241-1247.

http://ift.tt/2q7TbAG

Facile Preparation of Ultrafine Aluminum Hydroxide Particles with or without Mesoporous MCM-41 in Ambient Environments

An ultrafine aluminum hydroxide nanoparticle suspension was prepared via the controlled titration of [Al(H2O)]3+ with L-arginine to pH 4.6 with and without cage-effect confinement within mesoporous channels of MCM-41.

http://ift.tt/2qxgMw5

Validation of SDM-Q-Doc Questionnaire to measure shared decision-making physician’s perspective in oncology practice

Abstract

Objective

The aim of this study was to analyze the psychometric properties of the Shared Decision-Making Questionnaire–Physician version (SDM-Q-Doc) in a sample of medical oncologists who provide adjuvant treatment to patients with non-metastatic resected cancer and the correlations between the total SDM-Q-Doc score and physician satisfaction with the information provided.

Methods

Prospective, observational and multicenter study in which 32 medical oncologists and 520 patients were recruited. The psychometric properties, dimensionality, and factor structure of the SDM-Q-Doc were assessed.

Results

Exploratory factor analyses suggested that the most likely solution was two-dimensional, with two correlated factors: one factor regarding information and another one about treatment. Confirmatory factor analysis based on cross-validation showed that the fitted two-dimensional solution provided the best fit to the data. Reliability analyses revealed good accuracy for the derived scores, both total and sub-scale, with estimates ranging from 0.81 to 0.89. The results revealed significant correlations between the total SDM-Q-Doc score and physician satisfaction with the information provided (p < 0.01); between information sub-scale scores (factor 1) and satisfaction (p < 0.01), and between treatment sub-scale scores (factor 2) and satisfaction (p < 0.01). Medical oncologists of older age and those with more years of experience showed more interest in the patient preferences (p = 0.026 and p = 0.020, respectively). Patient age negatively correlated with SDM information (p < 0.01) and physicians appear to provide more information to young patients.

Conclusion

SDM-Q-Doc showed good psychometric properties and could be a helpful tool that examines physician's perspective of SDM and as an indicator of quality and satisfaction in patients with cancer.

http://ift.tt/2pDRV5A

Cancer subtypes in aetiological research

Abstract

Researchers often attempt to categorize tumors into more homogeneous subtypes to better predict prognosis or understand pathogenic mechanisms. In clinical research, typically the focus is on prognosis: the tumor subtypes are intended to be associated with specific responses to treatment and/or different clinical outcomes. In aetiological research, the focus is on identifying distinct pathogenic mechanisms, which may involve different risk factors. We used directed acyclic graphs to present a framework for considering potential biases arising in aetiological research of tumor subtypes, when there is incomplete correspondence between the identified subtypes and the underlying pathogenic mechanisms. We identified two main scenarios: (1) weak effect, when the tumor subtypes are identified through combinations of characteristics and some of these characteristics are affected by factors that are unrelated with the underlying pathogenic mechanisms; and (2) lack of causality, when the set of characteristics corresponds with a mechanism that is actually not a cause of the tumor of interest. Examples of the magnitude of bias that can be introduced in these situations are provided. Although categorization of tumors into homogenous subtypes may have important implications for aetiological research and identification of risk factors, the characteristics used to classify tumors into subtypes should be as close as possible to the actual pathogenic mechanisms to avoid interpretative biases. Whenever our knowledge of these mechanisms is limited, research into risk factors for tumor subtypes should first aim to causally link the characteristics to the pathogenic mechanisms.

http://ift.tt/2q7QUFS

Intralesional interleukin-2 for unresectable mucosal melanoma refractory to nivolumab

http://ift.tt/2q6EPB3

Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies

Abstract

Adoptive cell therapies with chimeric antigen receptor (CAR) engineered T cells (CAR-T) and immune checkpoint inhibition (ICI)-based cancer immunotherapies have lately shown remarkable success in certain tumor types. CAR-T cell-based therapies targeting CD19 can now induce durable remissions as well as prolong disease-free survival of patients with CD19 positive treatment refractory B cell malignancies and ICI-based therapies with humanized monoclonal antibodies against the T cell inhibitory receptors CTLA-4 and PD-1 as well as against the PD-1 ligand, PD-L1, can now achieve durable remissions as well as prolongation of life of a sizeable fraction of patients with melanoma and Hodgkin's lymphoma and non-small cell cancers. Most importantly, these immuno-therapeutic treatment modalities have raised the possibility of achieving long-term "containment" as well as "cures" for certain types of cancer. While this represents major advances in cancer immunotherapy, both modalities come with considerable toxicities, including fatalities. Although more work will be needed to bring CAR-T cell-based therapies to the bedside for most major cancers and a good deal more will be needed to make ICI—alone or in combination with other treatment modalities—work more consistently and across most major cancers, these two treatment modalities stand out as superb examples of successful translation of bench research to the bedside as well as represent real progress in the field of cancer immunotherapy.

http://ift.tt/2q9V7as

Validation of the prognostic value of new sub-stages within the AJCC 8th edition of non-small cell lung cancer

Abstract

Background

The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for non-small cell lung cancer (NSCLC) has been released. The current study tried to validate the prognostic significance of the new system among patients registered within the surveillance, epidemiology and end results (SEER) database.

Methods

SEER database (2010–2013) has been accessed through SEER*Stat program and AJCC 8th edition stages were reconstructed utilizing the collaborative stage descriptions. Overall and lung cancer-specific survival analyses according to both 7th and 8th editions were conducted through Kaplan–Meier analysis and multivariate analysis was conducted through a Cox proportional hazard model.

Results

A total of 127,096 patients with NSCLC were identified in the period from 2010 to 2013. For overall survival assessment according to the 8th edition, P values for all pair-wise comparisons among different stages were significant (<0.0001) except for the comparisons between stage IB and IIA (P = 0.146); stage IIA and IIB (P = 0.165). For lung cancer-specific survival according to the 8th edition, P values for all pair-wise comparisons among different stages were significant (<0.001). Among patients with stage I disease, multivariate analysis for factors affecting overall and lung cancer-specific survival among patients with stage I disease was conducted. The following factors were associated with worse overall and lung cancer-specific survival: age ≥70 years, more advanced stage, male gender, squamous histology, no surgery and no radiotherapy (P < 0.0001 for all factors).

Conclusion

This SEER analysis supports the prognostic significance of the added sub-stages described within AJCC 8th edition stages I and III. Further work is needed to incorporate molecular markers and personalize the future editions of the AJCC staging system.

http://ift.tt/2q7Z2pD

Utility of urinary circulating tumor DNA for EGFR mutation detection in different stages of non-small cell lung cancer patients

Abstract

Purpose

Non-invasive methods of molecular profiling for non-small cell lung cancer (NSCLC) are useful for monitoring disease progression. The aim of the current study was to ascertain if transrenal DNA is sensitive for clinical correlation and EGFR detection in NSCLC patients.

Methods

160 patients at various stages of the disease participated and samples were collected prospectively at 2-month intervals. A baseline sample was taken before treatment commencement. To ascertain the sensitivity of transrenal DNA, we compared its results with plasma DNA. ddPCR was used to profile the urine and blood samples for key EGFR mutations.

Results

Using tumor tissues as references, our study showed good concordance in EGFR mutations with transrenal DNA before treatment. Results were highly matching in late-stage NSCLC patients, with stage III/IV patients yielding an agreement of more than 90%. The assay was also sensitive to detect early-stage patients after surgical procedures. Profiles were highly concordant with results derived from plasma DNA, demonstrating the specificity of transrenal DNA assays. Serial monitoring of these patients showed stable molecular signatures and correlated to different treatments. Survival analysis showed good prognostic utility for late-stage patients with high transrenal DNA variations and patients that acquired T790M mutation.

Conclusion

The study demonstrated the feasibility of using transrenal DNA in mutation profiling for different stages of NSCLC patients. It highlights the importance of continual monitoring and has potential clinical utility in the clinical management of NSCLC.

http://ift.tt/2q7UT5n

Intralesional interleukin-2 for unresectable mucosal melanoma refractory to nivolumab

http://ift.tt/2q6EPB3

Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies

Abstract

http://ift.tt/2q9V7as

Accelerating drug development by efficiently using emerging PK/PD data from an adaptable entry-into-human trial: example of lumretuzumab

Abstract

Purpose

This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens.

Methods

Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens.

Results

The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400–2000 mg q2w in combination regimens were consistent with the model predictions.

Conclusion

PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.

http://ift.tt/2qXHZaY

MDA-MET-conditioned-medium augments the chemoattractant-dependent migration of MDA-MET cells towards hFOB-conditioned medium and increases collagenase activity

Abstract

Background

Metastasis of breast cancer displays site-specificity towards bone. Recently, studies have emerged indicating that primary tumors may remotely influence creation of a pre-metastatic niche. In this study, we used human fetal osteoblastic cells and MDA-MET, a metastatic and preferentially bone homing derivative of the breast cancer cell line MDA-MB-231. We examined 1) whether secreted factors from MDA-MET cells increase generation of chemoattractants by human foetal osteoblastic cells 2) whether MDA-MET cells were responsive to these chemoattractants and 3) the identity of these chemoattractants.

Methods

Human foetal osteoblastic cells were treated with conditioned medium of MDA-MET cells for 24 hours and then washed with phosphate-buffered saline. Serum-free replacement medium was conditioned by treated hFOB cells for 18 hours, before its use in in vitro quantification of MDA-MET migration. We also quantified collagen levels and collagenase activity in conditioned medium from human foetal osteoblastic cells.

Results

Conditioned medium from human foetal osteoblastic cells that had been treated with MDA-MET-conditioned medium attracted more MDA-MET cells than hFOB cells pre-exposed to their own medium. This conditioned medium had increased collagenase activity. The addition of bacterial collagenase removed the ability of conditioned medium from human foetal osteoblastic cells to attract MDA-MET cells.

Conclusions

Our data suggest that an increase in collagenase activity in osteoblastic cells induced by their exposure to breast cancer cell–secreted factors may increase their ability to attract breast cancer cells.

http://ift.tt/2qwVChK

Metastatic non-muscle invasive bladder cancer with meningeal carcinomatosis: case report of an unexpected response

Abstract

Background

Non-muscle invasive bladder cancer (NMIBC) is usually treated with local therapy including transurethral resection of the bladder tumor and intravesical therapy depending on the stage of the tumor. NMIBC is a rarely a metastatic diseases with lymph node invasion in less of 10%. In the other hand meningeal carcinomatosis is a rare location for metastases with extremely poor outcomes. We described a case report of a patient presenting a metastatic disease to bones and meninges, several years after the treatment of NMIBC, which had been in complete response (CR) for 4 years after chemotherapy treatment.

Case presentation

A 63-years old men was treated by TURBT in 2008 for a high grade NMIBC, pT1b. Three years later he presented an acute binocular diplopy with right trochlear nerve paralysis, and labial hypoesthesia. Brain scan and MRI were performed finding a clivus infiltration and a pachymeningitis. A vertebral biopsy was performed finding an invasive carcinoma, CK7+/CK20+, TTF1-, PSA-, Thyroglobulin- and GATA3+. The metastatic event was in relation to the high grade NMIBC treated 3 years previously. Palliative chemotherapy was started with cisplatin gemcitabine. After 6 cycles and to date, 4 years later, the patient is therefore considered in complete response.

Conclusion

Metastasis in non-muscle invasive urothelial carcinoma is rare. Meningeal carcinomatosis outcome is poor, usually appearing in widely metastatic and progressive cancers but also because most systemic agents fail to pass the blood-brain barrier and penetrate into the cerebrospinal fluid. We described an unexpected response with complete response after chemotherapy for meningeal carcinomatosis of non muscle invasive urothelial carcinoma.

http://ift.tt/2r6ow5j

Analysis of Chromosome Segregation, Histone Acetylation, and Spindle Morphology in Horse Oocytes

This manuscript describes an experimental approach to morphologically and biochemically characterize horse oocytes. Specifically, the present work illustrates how to collect immature and mature horse oocytes by ultrasound-guided ovum pick-up (OPU) and how to investigate chromosome segregation, spindle morphology, global histone acetylation, and mRNA expression.

http://ift.tt/2q6CtSO

CRNDE Expression Positively Correlates with EGFR Activation and Modulates Glioma Cell Growth

Abstract

Background

The long non-coding RNA CRNDE has emerged as an important regulator in carcinogenesis and cancer progression. While CRNDE has previously been found to be the most highly upregulated lncRNA in glioma, detailed information on its roles in regulating cancer cell growth remains limited.

Objective

In the present study, we aimed at exploring the functional roles and underlying mechanisms of CRNDE in glioma.

Methods

We applied microarray data analysis to determine the prognostic significance of CRNDE in glioma patients and its correlation with epidermal growth factor receptor (EGFR) activation. EGFR inhibition was used to confirm the role of EGFR in regulating CRNDE expression. Functional studies were performed upon CRNDE silencing to explore its role in gliomagenesis.

Results

We confirm that CRNDE acts as an oncogene that is highly up-regulated in glioma, and high CRNDE expression correlates with poor prognosis in glioma patients. We further demonstrate that the expression of CRNDE correlates with EGFR activation. EGF and EGFR tyrosine kinase inhibitor (TKI) enhance and block the up-regulation of CRNDE expression, respectively, suggesting that EGFR signaling may positively regulate CRNDE expression. Functional assays show that CRNDE depletion inhibits glioma cell growth both in vitro and in vivo, and is associated with induced cellular apoptosis with decreased Bcl2/Bax ratio.

Conclusions

Our findings suggest that the aberrant expression of CRNDE may be mediated by activated EGFR signaling and play significant roles in gliomagenesis.

http://ift.tt/2q6CTZd

Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer

http://ift.tt/2poYkWd

Cardiac safety, efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study

Abstract

Purpose

Cardiotoxicity is a side effect of trastuzumab. We assessed efficacy and cardiac safety of CMF with trastuzumab (CMF+T) in HER2-positive metastatic breast cancer patients (MBC).

Methods

In this phase II study, centrally confirmed, previously treated HER2-positive MBC patients with measurable disease (per RECIST v 1.0) were enrolled. Initially, patients were randomized between 8 CMF cycles alone or combined with trastuzumab during chemotherapy, followed by 3-weekly trastuzumab maintenance till progression. A protocol amendment dropped the CMF arm and thereafter all patients received CMF+T. Translational research for prediction of treatment benefit was performed through serial serum HER2-shed antigen assessments.

Results

Ninety patients (CMF: 19; CMF+T: 71) were enrolled between 2002 and 2006. Median age was 54 years. 42 patients had prior chemotherapy (33 with anthracyclines) and 41/71 patients who received CMF+T continued trastuzumab monotherapy for a median duration of 40 weeks. Overall response rate was 50% for CMF+T (35/70) and 32% for CMF (6/19). Median duration of response was 10.3 months and 5.4 months, respectively. Median progression-free survival was 9.4 months (95% CI 8.1–11.6) and 4.8 months (95% CI 2.8–7.9), respectively. In the CMF+T arm, 13(18%) patients had an absolute LVEF decline, including 3 patients developing any grade of New York Heart Association cardiac dysfunction. Patients with an increase of 30% over baseline shed antigen had a higher progression risk (95% CI 7.6, 3.9–14.8).

Conclusions

CMF+T is effective, with an acceptable cardiotoxicity profile. LVEF declines were mostly asymptomatic and occurred irrespective of previous anthracycline exposure. CMF+T can be considered for these patients, if other cytotoxics are contraindicated.

http://ift.tt/2r4CG60

Cost-effectiveness of palbociclib plus letrozole versus letrozole alone as a first-line treatment in women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. Revised results for the Swiss health care setting

http://ift.tt/2r4OWDN

FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer

Abstract

Purpose

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin β1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin β1 (ITGB1) gene expression have not been well elucidated.

Methods

Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin β1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin β1 gene and drives its expression.

Results

We demonstrated that FOXM1 directly binds to the promoter of integrin β1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells.

Conclusion

Our study suggests that FOXM1 transcription factor regulates Integrin β1 gene expression and that FOXM1/ Integrin-β1/FAK axis may play an important role in the progression of TNBC.

http://ift.tt/2r57aVs

Aromatase expression in atypical ductal hyperplasia in women

Abstract

Purpose

To determine the levels of aromatase in atypical ductal hyperplasia (ADH) lesions, tissue surrounding the ADH, and in dense and non-dense normal breast tissue. We postulated that excess aromatase in breast tissue might, through production of increased estrogen, drive the carcinogenic process. Estrogens and their metabolites are thought to contribute to the development of breast cancer through estrogen receptor-mediated mechanisms and genotoxic effects of estrogen metabolites. ADH is a benign lesion of the breast which is associated with substantially increased risk for subsequent development of breast cancer. After 25 years, approximately 30% of women with ADH develop breast cancer. In women with three or more separate ADH lesions at the same time, 47% will develop breast cancer over that time period. Another important risk factor for breast cancer is the presence of mammographically dense breast tissue.

Methods

We utilized quantitative immunochemical analysis of aromatase in biopsy tissue to test this possibility. Previously published results comparing dense with non-dense breast tissue in normal women (Vachon et al. Breast Cancer Res Treat 125:243–252, 2011) were used for comparisons with ADH. A well-characterized histochemical H-score was employed for quantitative assessment of aromatase in the various tissue studied.

Results

The H-score of aromatase staining was statistically significantly higher (p = 0.003) in the ADH epithelium than surrounding epithelial tissue. In order of H-score from highest to lowest were ADH, issue surrounding ADH, dense normal and non-dense normal breast tissues. The levels of aromatase in a subset of women with ADH who went on to develop breast cancer were not higher than in women who did not.

Conclusions

We suggest from these studies that overexpression of aromatase in breast tissue and its resultant increase in estradiol levels may contribute to the later development of breast cancer in women with ADH.

http://ift.tt/2pp9biZ

Response

http://ift.tt/2r4Q7TM

Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression

Abstract

Purpose

Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists.

Methods

Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination. The effects on cell survival, caspase activation, and expression of TRAIL receptors and the antiapoptotic protein XIAP were determined. In addition, XIAP was silenced by RNAi in TNBC cells and the effects on sensitivity to TRAIL were determined. The antitumor effects of metformin, TRAIL, or the combination were evaluated in an orthotopic model of metastatic TNBC.

Results

Metformin sensitized diverse TNBC cells to TRAIL receptor agonists. Metformin selectively enhanced the sensitivity of transformed breast epithelial cells to TRAIL receptor agonist-induced caspase activation and apoptosis with little effect on untransformed breast epithelial cells. These effects of metformin were accompanied by robust reductions in the protein levels of XIAP, a negative regulator of TRAIL-induced apoptosis. Silencing XIAP in TNBC cells mimicked the TRAIL-sensitizing effects of metformin. Metformin also enhanced the antitumor effects of TRAIL in a metastatic murine TNBC model.

Conclusions

Our findings indicate that metformin enhances the activity of TRAIL receptor agonists, thereby supporting the rationale for additional translational studies combining these agents.

http://ift.tt/2ppjzY4

Erratum to: ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling

http://ift.tt/2r52I9i

Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience

Abstract

Aim

This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability.

Methods

163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C).

Results

RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C), p = 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis.

Conclusions

No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

http://ift.tt/2pp97Qh

Relationship of breast MRI to recurrence rates in patients undergoing breast-conservation treatment

Abstract

Purpose

The effect of pre-operative MRI on the in-breast tumor recurrence rate (IBTR) of patients undergoing breast-conservation treatment (BCT) remains uncertain. We began to routinely perform pre-operative MRI in 2006. Our goal was to determine the effect of pre-operative MRI on IBTR.

Methods

Retrospective review of a prospective database of all patients undergoing BCT (n = 1396) from 2000 to 2010. IBTR were calculated using Kaplan–Meier estimates.

Results

664 (47.6%) patients underwent pre-operative MRI. The use of MRI increased from 13.9% in 2000–2005 to 80.7% in 2006–2010. Ten percent of patients who underwent MRI were found to have an additional ipsilateral cancer, with a mean diameter of 1.6 cm. The IBTR for patients with and without MRI were 4% vs. 8% at 8 years (p = 0.04). In multivariate analysis, radiation therapy and endocrine therapy were associated with decreased IBTR, but MRI was not (RR 0.77 (0.45–1.28)). For 1030 patients with invasive cancer, the IBTR at 8 years with and without MRI was 4.2% vs. 7.3% (p = 0.28). For 366 DCIS patients with and without MRI, the IBTR was 3.6% vs. 10.9% (p = 0.06). In the subgroup of DCIS patients who did not receive radiation, the IBTR with and without MRI was 0% vs. 18.2% (p = 0.08). Patients with an additional cancer found by MRI had a higher IBTR at 8 years (10.1% vs. 3.3%, p = 0.02).

Conclusions

In a study analyzing BCT patients from one time period who rarely had a pre-operative MRI and a subsequent time period where most patients had MRI, the use of MRI was associated with a decrease in the IBTR on univariate, but not multivariate analysis. Patients who had additional cancers detected had a significantly higher IBTR.

http://ift.tt/2pp2JZv

http://ift.tt/2pCi0Bs

Announcements

http://ift.tt/2qYjRoS

Editorial Board

http://ift.tt/2pCBaHf

Subscriptions Page

http://ift.tt/2qYG7im

Back Cover

http://ift.tt/2pCzc9Z

Front Cover

http://ift.tt/2qYGolz

Phylogeography of Sophora moorcroftiana Supports Wu’s Hypothesis on the Origin of Tibetan Alpine Flora

<div class="boxTitle">Abstract</div>Wu hypothesized that the Tibetan flora originated mostly from the paleotropical Tertiary flora in the Hengduan Mountains by adapting to the cold and arid environments associated with the strong uplift of the Qinghai-Tibet Plateau (QTP). Here, we combine the phylogeographic history of Sophora moorcroftiana with that of Sophora davidii to explore the speciation of S. moorcroftiana to test this hypothesis. We collected 151 individuals from 17 populations and sequenced 2 chloroplast fragments and the internal transcribed spacer of rDNA. Five chlorotypes and 9 ribotypes were detected but no significant phylogeographic structure was revealed. The integrated results of phylogeographic studies of these 2 species clearly support the progenitor–derivative relationship between them. We infer that the western peripheral population of S. davidii migrated westwards from the Hengduan Mountains to the middle reaches of the Yarlung Zangbo River and differentiated from its ancestor in the process of adaptation to increasingly cold and arid environments with the uplift of the QTP and finally evolved into S. moorcroftiana during the Late Pliocene. In addition, our findings shed light on the idea that natural selection, as imposed by climate differentiation (especially mean diurnal range and precipitation seasonality), directly drove this peripatric speciation event after geographic isolation. The speciation of S. moorcroftiana is a strong case supporting Wu's hypothesis about the origin of Tibet's flora.

http://ift.tt/2qYK6LW

Determination of the Genetic Architecture Underlying Short Wavelength Sensitivity in Lake Malawi Cichlids

<div class="boxTitle">Abstract</div>African cichlids are an exemplary system to study organismal diversity and rapid speciation. Species differ in external morphology including jaw shape and body coloration, but also differ in sensory systems including vision. All cichlids have 7 cone opsin genes with species differing broadly in which opsins are expressed. The differential opsin expression results in closely related species with substantial differences in spectral sensitivity of their photoreceptors. In this work, we take a first step in determining the genetic basis of opsin expression in cichlids. Using a second generation cross between 2 species with different opsin expression patterns, we make a conservative estimate that short wavelength opsin expression is regulated by a few loci. Genetic mapping in 96 F2 hybrids provides clear evidence of a cis-regulatory region for SWS1 opsin that explains 34% of the variation in expression between the 2 species. Additionally, in situ hybridization has shown that SWS1 and SWS2B opsins are coexpressed in individual single cones in the retinas of F2 progeny. Results from this work will contribute to a better understanding of the genetic architecture underlying opsin expression. This knowledge will help answer long-standing questions about the evolutionary processes fundamental to opsin expression variation and how this contributes to adaptive cichlid divergence.

http://ift.tt/2pCIC5i

SOFIA: An R Package for Enhancing Genetic Visualization With Circos

<div class="boxTitle">Abstract</div>Visualization of data from any stage of genetic and genomic research is one of the most useful approaches for detecting potential errors, ensuring accuracy and reproducibility, and presentation of the resulting data. Currently software such as Circos, ClicO FS, and RCircos, among others, provide tools for plotting a variety of genetic data types in a concise manner for data exploration and presentation. However, each of the programs has 1 or more disadvantages that limit their usability in data exploration or construction of publication quality figures, such as inflexibility in formatting and configuration, reduced image quality, lack of potential for automation, or requirements of high-level computational expertise. Therefore, we developed the R package SOFIA, which leverages the capabilities of Circos by manipulating data, preparing configuration files, and running the Perl-native Circos directly from the R environment with minimal user intervention. The advantages of integrating both R and Circos into SOFIA are numerous. R is a very powerful and user-friendly programming language widely used among the genetic and genomic research community, while Circos has proven to be a novel software for arranging genomic data to create aesthetical publication quality circular figures. Producing Circos figures in R with SOFIA is simple, requires minimal coding experience, even for complex figures that incorporate high-dimensional genetic information, and allows simultaneous analysis and visual exploration of genomic and genetic data in a single programming environment.

http://ift.tt/2pCAeCO

Application of Genomic Estimation Methods of Inbreeding and Population Structure in an Arabian Horse Herd

<div class="boxTitle">Abstract</div>Horse breeders rely heavily on pedigrees for identification of ancestry in breeding stock. Inaccurate pedigrees may erroneously assign individuals to false lineages or breed memberships resulting in wrong estimates of inbreeding and coancestry. Moreover, discrepancies in pedigree records can lead breeders seeking to limit inbreeding into making misguided breeding decisions. Genome-wide SNPs provide a quantitative tool to aid in the resolution of lineage assignments and the calculation of genomic measures of relatedness. The aim of this project was to pilot a comparison between pedigree and genomic relatedness and inbreeding measures in a herd of 36 pedigreed Egyptian Arabian horses genotyped using the Equine SNP70 platform (Geneseek, Inc.). Moreover, we sought to estimate the minimum number of markers sufficient for genomic inbreeding calculations. Pedigree inbreeding values were moderately correlated with genomic inbreeding values (r = 0.406), whereas genomic relationships and pedigree relationships have a high correlation (r = 0.77). Although first degree relationships were successfully reconstructed, more distant relationships were difficult to resolve. Multi-dimensional scaling and clustering analysis agreed with within-herd pedigree information. In comparing the herd to a reference sample of United States, Polish, and Egyptian Arabian horses, the herd's historically recorded Egyptian lineage was successfully recovered. We conclude that genomic estimates of inbreeding and relationships are superior to their pedigree counterparts. They can be thus utilized in conservation of valuable lines of livestock, and in breeds at risk for loss of genomic diversity. We also postulate a minimum of 2000 markers in linkage equilibrium to be used for inbreeding estimation.

http://ift.tt/2pCICCk

Genes and Group Membership Predict Gidgee Skink ( Egernia stokesii ) Reproductive Pairs

<div class="boxTitle">Abstract</div>Due to their role in mate choice, disease resistance and kin recognition, genes of the major histocompatibility complex (MHC) are good candidates for investigating genetic-based mate choice. MHC-based mate choice is context dependent and influenced by many factors including social structure. Social structure diversity makes the Egernia group of lizards suitable for comparative studies of MHC-based mate choice. We investigated mate choice in the gidgee skink (Egernia stokesii), a lizard that exhibits high levels of social group and spatial stability. Group membership was incorporated into tests of the good genes as heterozygosity and compatible genes hypotheses for adaptive (MHC) and neutral (microsatellite) genetic diversity (n = 47 individuals genotyped). Females were more likely to pair with a male with higher MHC diversity and with whom they had a lower degree of microsatellite relatedness. Males were more likely to pair with a female with higher microsatellite heterozygosity and with whom they shared a lower proportion of MHC alleles. Lizards were more likely to mate with an individual from within, rather than outside, their social group, which confirmed earlier findings for this species and indicated mate choice had already largely occurred prior to either social group formation or acceptance of an individual into an existing group. Thus, a combination of genes and group membership, rather than group membership alone, predicted mate choice in this species. This work will contribute to an enhanced understanding of squamate group formation and a deeper understanding of the evolution of sociality within all vertebrates.

http://ift.tt/2qYOLNN

Reproductive Strategy of the Polyploid Species Varronia curassavica Jacq. in Restinga Environment

<div class="boxTitle">Abstract</div>This study aimed to elucidate the breeding strategies of Varronia curassavica, an important medicinal species associated with Brazilian restinga. This was accomplished by combining phenological and genetic data. Every 2 weeks over a period of 2 years, we measured flowering and fruiting phenology to evaluate the activity and intensity of phenophases (n = 60). We evaluated the mating system, pollen ovule ratio and genotypes from progeny and mother plants using 8 nuclear microsatellite loci. We observed flowering and fruiting of V. curassavica at low intensity throughout the entire year, but with 2 distinct peaks, one of which was seasonal, corresponding to the period of gradual increase of temperature and photoperiod. Overlapping of flowering and fruiting strategies favors gene flow among different groups of individuals and between populations by attraction of fauna throughout the year. Analysis of the mating system indicates that V. curassavica is a typical outcrossed species (t^ = 0.98; pollen/ovule ratio = 7087.50). Combining phenology with genetic studies improved our understanding of the reproductive strategies of this species. The typical outcrossing system of V. curassavica reflects the existence of functional self-incompatibility mechanisms still unaffected by changes in genetic balance by polyploidy.

http://ift.tt/2pCzaPp

Genetic Diversity and Population Structure of Varronia curassavica : A Medicinal Polyploid Species in a Threatened Ecosystem

<div class="boxTitle">Abstract</div>Varronia curassavica is an important medicinal species associated with the restinga, one of the most threatened coastal ecosystems of the Atlantic Forest. These circumstances call for studies aimed at estimating effective population size and gene flow to improve conservation efforts. Hence, the present study aimed to characterize the genetic diversity, ploidy level, and population structure of this species in different areas of restinga using microsatellites. Varronia curassavica was characterized as an autotetraploid, with high genetic variability, low divergence, and no significant fixation indices, indicating the absence of, or reduced, inbreeding and genetic drift in the study area. About 44% of the alleles occurred at low frequency in adults of all populations and 41% in the progenies evaluated. Gene flow was high, consistent with outcrossing species with high dispersal capacity (Nm = 4.87). The results showed no tendency toward isolation by distance. The estimated effective size indicates that the populations studied have the potential to ensure conservation of the species in the long term. The genetic variability and population structure of V. curassavica, as determined in this study, could form the foundation for activities directed toward the sustainable use of this resource and its conservation. Even though the restinga ecosystem has suffered dramatic reductions in area, this study provides evidence that this species is resilient to anthropogenic threats to its genetic integrity, since it is a polyploid with self-incompatibility mechanisms that contribute to maintaining high genetic diversity in an panmictic meta-population along the coast of Santa Catarina.

http://ift.tt/2qYHwpg

DAMBE6: New Tools for Microbial Genomics, Phylogenetics, and Molecular Evolution

<div class="boxTitle">Abstract</div>DAMBE is a comprehensive software workbench for data analysis in molecular biology, phylogenetics, and evolution. Several important new functions have been added since version 5 of DAMBE: 1) comprehensive genomic profiling of translation initiation efficiency of different genes in different prokaryotic species, 2) a new index of translation elongation (ITE) that takes into account both tRNA-mediated selection and background mutation on codon–anticodon adaptation, 3) a new and accurate phylogenetic approach based on pairwise alignment only, which is useful for highly divergent sequences from which a reliable multiple sequence alignment is difficult to obtain. Many other functions have been updated and improved including PWM for motif characterization, Gibbs sampler for de novo motif discovery, hidden Markov models for protein secondary structure prediction, self-organizing map for nonlinear clustering of transcriptomic data, comprehensive sequence alignment, and phylogenetic functions. DAMBE features a graphic, user-friendly and intuitive interface, and is freely available from http://ift.tt/2qYUEum;

http://ift.tt/2pCz9Ll

TetraploidSNPMap: Software for Linkage Analysis and QTL Mapping in Autotetraploid Populations Using SNP Dosage Data

<div class="boxTitle">Abstract</div>An earlier software application of ours, TetraploidMap for Windows, enabled linkage analysis and quantitative trait locus interval mapping to be carried out in an experimental cross of an autotetraploid species, using both dominant markers such as amplified fragment length polymorphisms and codominant markers such as simple sequence repeats. The size was limited to 800 markers, and quantitative trait locus mapping was conducted for each parent separately due to the difficulties in obtaining a reliable consensus map for the 2 parents. Modern genotyping technologies now give rise to datasets of thousands of single nucleotide polymorphisms, and these can be scored in autotetraploid species as single nucleotide polymorphism dosages, distinguishing among the heterozygotes AAAB, AABB, and ABBB, rather than simply using the presence or absence of an allele. The dosage data is more informative about recombination and leads to higher density linkage maps. The current program, TetraploidSNPMap, makes full use of the dosage data, and has new facilities for displaying the clustering of single nucleotide polymorphisms, rapid ordering of large numbers of single nucleotide polymorphisms using a multidimensional scaling analysis, and phase calling. It also has new routines for quantitative trait locus mapping based on a hidden Markov model, which use the dosage data to model the effects of alleles from both parents simultaneously. A Windows-based interface facilitates data entry and exploration. It is distributed with a detailed user guide. TetraploidSNPMap is freely available from our GitHub repository.

http://ift.tt/2qYIwJV

Genetic Kinship Analyses Reveal That Gray’s Beaked Whales Strand in Unrelated Groups

<div class="boxTitle">Abstract</div>Some marine mammals are so rarely seen that their life history and social structure remain a mystery. Around New Zealand, Gray's beaked whales (Mesoplodon grayi) are almost never seen alive, yet they are a commonly stranded species. Gray's are unique among the beaked whales in that they frequently strand in groups, providing an opportunity to investigate their social organization. We examined group composition and genetic kinship in 113 Gray's beaked whales with samples collected over a 20-year period. Fifty-six individuals stranded in 19 groups (2 or more individuals), and 57 whales stranded individually. Mitochondrial control region haplotypes and microsatellite genotypes (16 loci) were obtained for 103 whales. We estimated pairwise relatedness between all pairs of individuals and average relatedness within, and between, groups. We identified 6 mother–calf pairs and 2 half-siblings, including 2 whales in different strandings 17 years and 1500 km apart. Surprisingly, none of the adults stranding together were related suggesting that groups are not formed through the retention of kin. These data suggest that both sexes may disperse from their mothers, and groups consisting of unrelated subadults are common. We also found no instances of paternity within the groups. Our results provide the first insights into dispersal, social organization, and the mating system in this rarely sighted species. Why whales strand is still unknown but, in Gray's beaked whales, the dead can tell us much about the living.

http://ift.tt/2pCCxG9

Population Differentiation in Common Walnut ( Juglans regia L.) across Major Parts of Its Native Range—Insights from Molecular and Morphometric Data

<div class="boxTitle">Abstract</div>Juglans regia is an economically highly important species for fruit and wood production in the warm temperate and subtropical zones of the Northern Hemisphere. Besides the natural influence of climatic and geomorphological barriers, its genetic structure has been strongly modified by humans and the population history is still unclear. For this reason, we investigated mainly natural walnut populations across the Eurasian continent on a molecular (44 populations, 581 trees) and morphometric level (23 populations, 1391 ripe nuts). Population genetic diversity and differentiation were examined by using 7 microsatellite loci. Morphometric characteristics of the nuts (mainly roundness index and nut density) were used to estimate trait variation and population differentiation. Highest allelic richness Rs12 = 7.05 was observed in a Pakistani and the lowest value Rs12 = 3.04 in a Kyrgyz population. The genetic differentiation among populations was high (FST = 0.217; RST = 0.530) indicating a strong phylogeographic pattern. While variation of the roundness index within single populations was high, this trait neither differentiated geographical regions nor was it associated to genetic clusters. Approximated QST based on this trait equalled FST, while approximated QST based on nut density considerably exceeded FST, indicating selection. Nut density was moderately correlated with altitude, latitude, and longitude, and differentiated populations according to their origin. Pakistani and Indian populations showed highest nut densities. These South Asian populations contain putatively ancestral nut forms, which probably have been lost in other populations as a consequence of human selection.

http://ift.tt/2qYOJFF

Genetic Structure and Phylogeography of the Leopard Cat ( Prionailurus bengalensis ) Inferred from Mitochondrial Genomes

<div class="boxTitle">Abstract</div>The Leopard cat Prionailurus bengalensis is a habitat generalist that is widely distributed across Southeast Asia. Based on morphological traits, this species has been subdivided into 12 subspecies. Thus far, there have been few molecular studies investigating intraspecific variation, and those had been limited in geographic scope. For this reason, we aimed to study the genetic structure and evolutionary history of this species across its very large distribution range in Asia. We employed both PCR-based (short mtDNA fragments, 94 samples) and high throughput sequencing based methods (whole mitochondrial genomes, 52 samples) on archival, noninvasively collected and fresh samples to investigate the distribution of intraspecific genetic variation. Our comprehensive sampling coupled with the improved resolution of a mitochondrial genome analyses provided strong support for a deep split between Mainland and Sundaic Leopard cats. Although we identified multiple haplogroups within the species' distribution, we found no matrilineal evidence for the distinction of 12 subspecies. In the context of Leopard cat biogeography, we cautiously recommend a revision of the Prionailurus bengalensis subspecific taxonomy: namely, a reduction to 4 subspecies (2 mainland and 2 Sundaic forms).

http://ift.tt/2qYMrpW

Complementary Roles of Phenotype and Genotype in Subspecies Delimitation

Recent exchanges in this journal about subspecies taxonomy (<a href="#CIT0007" class="reflinks">Fredrickson et al. 2015</a>; <a href="#CIT0030" class="reflinks">Weckworth et al. 2015</a>; <a href="#CIT0006" class="reflinks">Cronin et al. 2015</a>) signal an increased attention to this Linnaean rank, yet it is clear from some of the discourse that misconceptions about subspecies definitions persist. We emphasize that our goal is not to evaluate the validity of named subspecies of the gray wolf (Canis lupus), even if we refer to this particular example because it was the basis of the published exchange. Rather, our goals are to outline current thinking and methodology of practitioners who use subspecific taxonomy and to highlight the difficulty, short of further theory (e.g., development of a sound null model), inherent in use of neutral genetic markers to establish the validity of subspecies.

http://ift.tt/2pCqWXB

Evolutionary and Functional Mitogenomics Associated With the Genetic Restoration of the Florida Panther

<div class="boxTitle">Abstract</div>Florida panthers are endangered pumas that currently persist in reduced patches of habitat in South Florida, USA. We performed mitogenome reference-based assemblies for most parental lines of the admixed Florida panthers that resulted from the introduction of female Texas pumas into South Florida in 1995. With the addition of 2 puma mitogenomes, we characterized 174 single nucleotide polymorphisms (SNPs) across 12 individuals. We defined 5 haplotypes (Pco1–Pco5), one of which (Pco1) had a geographic origin exclusive to Costa Rica and Panama and was possibly introduced into the Everglades National Park, Florida, prior to 1995. Haplotype Pco2 was native to Florida. Haplotypes Pco3 and Pco4 were exclusive to Texas, whereas haplotype Pco5 had an undetermined geographic origin. Phylogenetic inference suggests that haplotypes Pco1–Pco4 diverged ~202000 (95% HPDI = 83000–345000) years ago and that haplotypes Pco2–Pco4 diverged ~61000 (95% HPDI = 9000–127000) years ago. These results are congruent with a south-to-north continental expansion and with a recent North American colonization by pumas. Furthermore, pumas may have migrated from Texas to Florida no earlier than ~44000 (95% HPDI = 2000–98000) years ago. Synonymous mutations presented a greater mean substitution rate than other mitochondrial functional regions: nonsynonymous mutations, tRNAs, rRNAs, and control region. Similarly, all protein-coding genes were under predominant negative selection constraints. We directly and indirectly assessed the presence of potential deleterious SNPs in the ND2 and ND5 genes in Florida panthers prior to and as a consequence of the introduction of Texas pumas. Screenings for such variants are recommended in extant Florida panthers.

http://ift.tt/2qYOJp9

Spinal osteoid osteoma: efficacy and safety of radiofrequency ablation

Abstract

Objective

The aim of this study was to evaluate the efficacy and complications of CT-guided radiofrequency ablation (RFA) of spinal osteoid osteoma (OO).

Materials and methods

Between 2002 and 2012, a total of 61 patients (46 male and 15 female, mean age 26.4 ± 12.7 years) were subjected to RFA for spinal OO. The diagnosis of OO was made after a period of pain and symptoms of 20.6 ± 14.4 months. RFA was performed under conscious sedation and local analgesia. Clinical symptoms were evaluated at 3, 6, and12 months, and at the end of the time of the present investigation. Mean follow-up was 41.5 ± 7.1 months.

Results

The primary efficacy of RFA, complete regression of symptoms, was obtained in 57 out of 61 patients (93.4%). Four out of 61 (6.5%) patients showed a relapse of OO (after 3 months); 2 out of 4 were subjected to a second RFA, the remaining ones were subjected to surgery. There was one complication (case of lower limb paresthesia for 30 days after the ablation) and one possible complication (a disc herniation).

Conclusion

CT-guided RFA is an excellent treatment for spinal OO. Our data suggest that this procedure should be considered for the first stage of therapy for this disease.

http://ift.tt/2qYFIN0

Transcranial doppler sonography is not a valid diagnostic tool for detection of basilar artery stenosis or in-stent restenosis: a retrospective diagnostic study

There are contradictory reports concerning the validity of transcranial sonography (TCD and TCCS) for examinations of the basilar artery. Here we investigated sensitivity and specificity of transcranial sonogr...

http://ift.tt/2pCk3FK

A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls

Fibromyalgia syndrome (FMS) is a chronic pain syndrome. A plausible pathogenesis of the disease is uncertain and the pursuit of measurable biomarkers for objective identification of affected individuals is a c...

http://ift.tt/2qYoSO1

Stability and relative validity of the Neuromuscular Disease Impact Profile (NMDIP)

The aim of this study was to examine the stability and relative validity (RV) of the Neuromuscular Disease Impact Profile (NMDIP) using criterion-related groups. In a previous study the NMDIP-scales showed goo...

http://ift.tt/2pCyIAt

Inkjet-printed Polyvinyl Alcohol Multilayers

An inkjet printer was used to manufacture polyvinyl alcohol multilayers. Polyvinyl alcohol water-based ink was formulated, and the main physical properties were investigated.

http://ift.tt/2poYL2R

Trends in the supply of Californias emergency departments and inpatient services, 2005-2014: a retrospective analysis

Objectives

Given increasing demand for emergency care, there is growing concern over the availability of emergency department (ED) and inpatient resources. Existing studies of ED bed supply are dated and often overlook hospital capacity beyond ED settings. We described recent statewide trends in the capacity of ED and inpatient hospital services from 2005 to 2014.

Design

Retrospective analysis.

Setting

Using California hospital data, we examined the absolute and per admission changes in ED beds and inpatient beds in all hospitals from 2005 to 2014.

Participants

Our sample consisted of all patients inpatient and outpatient) from 501 hospital facilities over 10-year period.

Outcome measures

We analysed linear trends in the total annual ED visits, ED beds, licensed and staffed inpatient hospital beds and bed types, ED beds per ED visit, and inpatient beds per admission (ED and non-ED).

Results

Between 2005 and 2014, ED visits increased from 9.8 million to 13.2 million (an increase of 35.0%, p<0.001). ED beds also increased (by 29.8%, p<0.001), with an average annual increase of 195.4 beds. Despite this growth, ED beds per visit decreased by 3.9%, from 6.0 ED beds per 10 000 ED visits in 2005 to 5.8 beds in 2014 (p=0.01). While overall admission numbers declined by 4.9% (p=0.06), inpatient medical/surgical beds per visit grew by 11.3%, from 11.6 medical/surgical beds per 1000 admissions in 2005 to 12.9 beds in 2014 (p<0.001). However, there were reductions in psychiatric and chemical dependency beds per admission, by –15.3% (p<0.001) and –22.4% (p=0.05), respectively.

Conclusions

These trends suggest that, in its current state, inadequate supply of ED and specific inpatient beds cannot keep pace with growing patient demand for acute care. Analysis of ED and inpatient supply should capture dynamic variations in patient demand. Our novel 'beds pervisit' metric offers improvements over traditional supply measures.

http://ift.tt/2pDCiLD

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Πέμπτη 11 Μαΐου 2017

Abstract

Background

Results

Conclusions

Abstract

Background

Methods

Results

Conclusion

Abstract

Abstract

Abstract

Abstract

Abstract

Background

Methods

Results

Conclusion

Abstract

Objective

Methods

Results

Conclusion

Abstract

Abstract

Abstract

Background

Methods

Results

Conclusion

Abstract

Purpose

Methods

Results

Conclusion

Abstract

Abstract

Purpose

Methods

Results

Conclusion

Abstract

Background

Methods

Results

Conclusions

Abstract

Background

Case presentation

Conclusion

Abstract

Background

Objective

Methods

Results

Conclusions

Abstract

Purpose

Methods

Results

Conclusions

Abstract

Purpose

Methods

Results

Conclusion

Abstract

Purpose

Methods

Results

Conclusions