Evaluation of the predictive value of Gensini score on determination of severity of coronary artery disease in cases with left bundle branch block

Abstract

Left bundle branch block (LBBB) is one of the features which predicts severe organic heart disease. In this study, we aimed to examine the predictive role of Gensini score as marker of severity of coronary artery disease (CAD) in patients with LBBB and its relationship with other CAD risk factors and complications. We have included patients who referred to our center for selective coronary angiography with transient and or permanent LBBB on their surface electrocardiography (ECG). Cases with pacemaker rhythm and known non-CAD related causes of LBBB pattern on surface ECG were excluded from this study. Demographic variables and clinical features were studied. To determine severity of CAD, Gensini score was measured. The relationship between presence of CAD and deteriorated ejection fraction has been demonstrated by previous works, but we found no association between severity of CAD and degree of ejection fraction deterioration. This might imply to the role of non-CAD factors toward reduction of ejection fraction. In cases with hypertension in the setting of LBBB, higher Gensini scores were seen regardless of ventricular ejection fraction. Thus, earlier screening for possible CAD in cases with LBBB and hypertension seems rational.

https://ift.tt/2rm0zZo

The Safety Assessment of Toxic Metals in Commonly Used Pharmaceutical Herbal Products and Traditional Herbs for Infants in Jordanian Market

Abstract

The objective of this study was to assess the levels of contamination by toxic metals (Pb, Al, Ni, Cd and As) that may be present in 25 infant pharmaceutical herbal products and 15 traditional herbs in Jordan. Both products and medicinal herbs are currently prescribed by paediatricians. They are available as over-the-counter medicines and are sold the in herbal market, ensuring easy accessibility for parents. Inductively coupled plasma-optical emission spectroscopy (ICP-OES), with limit of detections (LODs) of 0.10, 1.00, 0.20, 0.15 and 2.00 mg.kg⁻¹ for Pb, Al, Ni, Cd and As respectively, was employed to measure the levels of toxic metals in the samples. Pb, Al and Ni were detected in 88, 76 and 4% of the analysed samples of pharmaceutical herbal products and in 93, 87 and 13% of the analysed samples of traditional herbs, respectively. Neither Cd or As were detected in all analysed samples. The data obtained were subsequently compared by referral to the acceptable limits of toxic heavy metals according to World Health Organisation (WHO) standards. Largely, the results showed acceptable toxic metal levels in the finished pharmaceutical products and the traditional medicinal herbs for infants. One exception to this was Persian Thyme (Satureja thymbra) with Pb content of 41.18 mg.kg⁻¹. Also, the daily intake of detected metals through pharmaceutical herbal products was found to be lower than the daily tolerable intake limit set by the regulatory bodies, except of 8% of products that exceeded the tolerable daily intake of Pb set by US FDA, as compared to traditional medicinal herbs, where the tolerable daily intake for Pb, Al and Ni were exceeded in 40, 60 and 8% of the analysed herbs, respectively. The results obtained revealed that the excessive use of medicinal plants as alternative medicine should be used with caution keeping in mind the safety factor in infants.

https://ift.tt/2jv7MCb

Management and grading of EGFR inhibitor-induced cutaneous toxicity

Future Oncology, Ahead of Print.


https://ift.tt/2FId9Xr

Systematic review on the efficacy and safety of immune checkpoint inhibition in renal cell carcinoma

Future Oncology, Ahead of Print.


https://ift.tt/2KDh3Vd

DNA Repair in the Archaea – an emerging picture

Abstract

There has long been a fascination in the DNA Repair pathways of archaea, for two main reasons. Firstly, many archaea inhabit extreme environments where the rate of physical damage to DNA is accelerated. These archaea might reasonably be expected to have particularly robust or novel DNA repair pathways to cope with this. Secondly, the archaea have long been understood to be a lineage distinct from the bacteria, and to share a close relationship with the eukarya, particularly in their information processing systems. Recent discoveries suggest the eukarya arose from within the archaeal domain, and in particular from lineages related to the TACK superphylum and Lokiarchaea. Thus, archaeal DNA repair proteins and pathways can represent a useful model system. This review focuses on recent advances in our understanding of archaeal DNA repair processes including Base Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR) and Double Strand Break Repair (DSBR). These advances are discussed in the context of the emerging picture of the evolution and relationship of the three domains of life.

https://ift.tt/2JW8H9X

Aspects of Modern Biobank Activity – Comprehensive Review

Abstract

Biobanks play an increasing role in contemporary research projects. These units meet all requirements to regard them as a one of the most innovative and up-to-date in the field of biomedical research. They enable conducting wide-scale research by the professional collection of biological specimens and correlated clinical data. Pathology units may be perceived roots of biobanking. The review aims at describing the concept of biobanks, their model of function and scientific potential. It comprises the division of biobanks, sample preservation methods and IT solutions as well as guidelines and recommendations for management of a vast number of biological samples and clinical data. Therefore, appropriate standard operating procedures and protocols are outlined. Constant individualization of diagnostic process and treatment procedures creates the niche for translational units. Thus, the role of biobanks in personalized medicine was also specified. The exceptionality of biobanks poses some new ethical-legal issues which have various solutions, in each legal system, amongst the world. Finally, distribution and activity of European biobanks are mentioned.

https://ift.tt/2JU9icp

Q&A: Ned Sharpless on His Vision for NCI [News in Depth]

Addressing the challenges of the cancer research landscape requires innovative thinking.

https://ift.tt/2jAcbE9

Kelch-Like Protein 6 Negatively Regulates NF-{kappa}B Activation in Lymphoma [Research Watch]

KLHL6 loss promotes NF-B activation to drive DLBCL proliferation.

https://ift.tt/2FK3gbu

CXCR4 Antagonism Has Antitumor Activity in Combination with Eribulin [Research Watch]

The CXCR4 antagonist balixafortide plus eribulin achieves responses in metastatic breast cancer.

https://ift.tt/2KBu7u8

I-Motif DNA Structures May Regulate Promoters and Telomeres [Research Watch]

I-motif DNA structures form in the nuclei of human cells in a cell-cycle and pH dependent manner.

https://ift.tt/2FK1I1z

A Cryo-EM Structure Elucidates the Human Telomerase Holoenzyme [Research Watch]

The bilobal telomerase structure has a catalytic core lobe and a H/ACA ribonucleoprotein lobe.

https://ift.tt/2jtYFBA

Carboxyamidotriazole Orotate plus TMZ Is Safe and Active in Glioblastoma [Research Watch]

Carboxyamidotriazole orotate (CTO) plus temozolomide (TMZ) was well tolerated in patients with glioma.

https://ift.tt/2FKEsQN

Pharmacists Can Play Role in Identifying Frailty

FRIDAY, May 4, 2018 -- As the number of older people in the United States continues to increase, pharmacists and health care professionals need to recognize and address the health care challenges associated with age, including frailty, according to...

https://ift.tt/2IfNVEU

Many Organizations Not Meeting Trial Reporting Requirements

FRIDAY, May 4, 2018 -- Many organizations are not meeting the trial registration and results reporting requirements clarified by "The Final Rule," which had a compliance date of April 18, 2017, according to a study published online May 1 in BMC...

https://ift.tt/2HRuenC

Low Neighborhood Walkability Increases Risk of Asthma in Kids

FRIDAY, May 4, 2018 -- Children living in neighborhoods with low walkability are at increased risk of asthma, according to a study published online April 17 in the Annals of the American Thoracic Society. Elinor Simons, M.D., Ph.D., from the...

https://ift.tt/2wdLRbS

Online Review of Cosmetic Breast Surgery Extends to Surgeon, Staff

FRIDAY, May 4, 2018 -- Good cosmetic results are not the only factor mentioned in online breast augmentation reviews of plastic surgeons, according to a study published in the May issue of Plastic and Reconstructive Surgery. Robert G. Dorfman, from...

https://ift.tt/2HUSx06

Emotional Intelligence Predictors in Radiation Therapists ID'd

FRIDAY, May 4, 2018 -- Some factors that predict radiation therapists' emotional intelligence (EI) can be addressed, according to a study published online April 23 in the Journal of Medical Radiation Sciences. Trakis Stami, from the St. George...

https://ift.tt/2HRSR3G

Impact of the treatment of pancreatic exocrine insufficiency on survival of patients with unresectable pancreatic cancer: a retrospective analysis

Abstract

Background

Malnutrition and weight loss are commonly observed in patients with pancreatic cancer and contribute to poor survival. Pancreatic exocrine insufficiency (PEI), which can be caused by ductal obstruction by a tumor, causes maldigestion and malabsorption of nutrients, thus contributing to malnutrition in these patients. In this study, we evaluated the effects of pancreatic enzyme replacement therapy (PERT) on survival in patients with unresectable pancreatic cancer.

Methods

A retrospective analysis was conducted on a database of patients with unresectable, pathologically confirmed pancreatic cancer. All patients were evaluated for palliative chemotherapy and received the optimal palliative care. Patients were divided into two groups: Group 1 received standard therapy; Group 2 underwent additional evaluation of the pancreatic function and therapy with PERT, if needed. Survival (median and 95% confidence interval [CI]) was analyzed using Kaplan–Meier and Cox regression; groups were compared using the log-rank test.

Results

Overall, 160 patients with unresectable pancreatic cancer were included in the analysis (mean age: 70.5 years [range 28–100]; gender: 57.5% male; tumor stage: 78.7% Stage IV). Eighty-six patients (53.75%) were in Group 1 and 74 (46.25%) were in Group 2. Age, gender, tumor size, location and stage, weight loss, and serum CA 19–9 were similar between groups. Ninety-three (58.1%) patients received palliative chemotherapy; 46.5% in Group 1 and 71.6% in Group 2 (P < 0.001). Forty-nine (66.2%) patients in Group 2 and none in Group 1 received PERT. Survival in Group 2 (189 days, 95% CI 167.0–211.0 days) was significantly longer than in Group 1 (95.0 days, 95% CI 75.4–114.6 days) (HR 2.117, 95% CI 1.493–3.002; P < 0.001). Chemotherapy and PERT were significantly and independently associated with longer survival in a model controlled by age and tumor stage. In patients with significant weight loss at diagnosis (> 10% bodyweight within 6 months), PERT was associated with longer survival (HR 2.52, 95% CI 1.55–4.11; P < 0.001).

Conclusions

In patients with unresectable pancreatic cancer, PERT in patients with PEI was associated with longer survival compared with those not receiving PERT, especially in those experiencing significant weight loss. This finding should guide future prospective clinical trials of similar interventions.

https://ift.tt/2rmVTT6

Neuropilin-1 promotes the oncogenic Tenascin-C/ integrin β3 pathway and modulates chemoresistance in breast cancer cells

Abstract

Background

Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, however transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored.

Methods

BT-474 NRP-1 variant cells were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell line. RNA sequencing and qRT-PCR were conducted to identify differentially expressed genes. The role of an upregulated oncogene, Tenascin C (TNC) and its associated pathway was investigated by siRNA-mediated knockdown. Resistant variants of the control and BT-474 NRP-1 cells were generated by sequential treatment with four cycles of Adriamycin/Cyclophosphamide (4xAC) followed by four cycles of Paclitaxel (4xAC + 4xPAC).

Results

NRP-1 overexpression increased cellular tumorigenic behavior. RNA sequencing identified upregulation of an oncogene, Tenascin-C (TNC) and downregulation of several tumor suppressors in BT-474 NRP-1 cells. Additionally, protein analysis indicated activation of the TNC-associated integrin β3 (ITGB3) pathway via focal adhesion kinase (FAK), Akt (Ser473) and nuclear factor kappa B (NF-kB) p65. siRNA-mediated TNC knockdown ablated the migratory capacity of BT-474 NRP-1 cells and inactivated FAK/Akt473 signaling. NRP-1 overexpressing cells downregulated breast cancer resistance protein (BCRP/ABCG2). Consequently, sequential treatment with Adriamycin/Cyclophosphamide (AC) cytotoxic drugs to generate resistant cells indicated that BT-474 NRP-1 cells increased sensitivity to treatment by inactivating NRP-1/ITGB3/FAK/Akt/NF-kB p65 signaling compared to wild-type BT-474 resistant cells.

Conclusions

We thus report a novel mechanism correlating high baseline NRP-1 with upregulated TNC/ITGB3 signaling, but decreased ABCG2 expression, which sensitizes BT-474 NRP-1 cells to Adriamycin/Cyclophosphamide. The study emphasizes on the targetability of the NRP-1/ITGB3 axis and its potential as a predictive biomarker for chemotherapy response.

https://ift.tt/2wfy5FP

Metabolomic profiles in breast cancer:a pilot case-control study in the breast cancer family registry

Abstract

Background

Metabolomics is emerging as an important tool for detecting differences between diseased and non-diseased individuals. However, prospective studies are limited.

Methods

We examined the detectability, reliability, and distribution of metabolites measured in pre-diagnostic plasma samples in a pilot study of women enrolled in the Northern California site of the Breast Cancer Family Registry. The study included 45 cases diagnosed with breast cancer at least one year after the blood draw, and 45 controls. Controls were matched on age (within 5 years), family status, BRCA status, and menopausal status. Duplicate samples were included for reliability assessment. We used a liquid chromatography/gas chromatography mass spectrometer platform to measure metabolites. We calculated intraclass correlations (ICCs) among duplicate samples, and coefficients of variation (CVs) across metabolites.

Results

Of the 661 named metabolites detected, 338 (51%) were found in all samples, and 490 (74%) in more than 80% of samples. The median ICC between duplicates was 0.96 (25th – 75th percentile: 0.82–0.99). We observed a greater than 20% case-control difference in 24 metabolites (p < 0.05), although these associations were not significant after adjusting for multiple comparisons.

Conclusions

These data show that assays are reproducible for many metabolites, there is a minimal laboratory variation for the same sample, and a large between-person variation. Despite small sample size, differences between cases and controls in some metabolites suggest that a well-powered large-scale study is likely to detect biological meaningful differences to provide a better understanding of breast cancer etiology.

https://ift.tt/2rnz5mj

Systematic review of self-reported cognitive function in cancer patients following chemotherapy treatment

Abstract

Purpose

Cognitive symptoms are common in cancer patients, with up to 70% reporting cognitive symptoms following chemotherapy. These symptoms can have a major impact on how an individual functions in all aspects of their lives. This review evaluates self-reported cognitive function and its associations with neuropsychological tests and patient-reported outcomes in adult cancer patients who received chemotherapy treatment for a solid cancer.

Methods

A search of multiple databases (Medline, Ovid at Nursing, PsycINFO, Allied and Complementary Medicine) from 1936 to 2017 was conducted, identifying 1563 unique articles, of which 101 met inclusion criteria.

Results

Of the 101 included studies, 48 (47%) were cross-sectional and 38 (38%) longitudinal in design, with 12 (12%) randomised controlled trials. A minority (26%) incorporated a healthy control arm in the study design, whilst the majority (79%) were in women with breast cancer. There was diversity in the assessment of self-reported cognitive symptoms. A total of 43 of 44 studies that sought an association between self-reported cognitive function and patient-reported outcomes found a moderate to strong association. Overall, 31 studies showed a lack of association between self-reported cognitive symptoms and neuropsychological results, whilst 14 studies reported a significant association between the two, but the association was often restricted to limited cognitive domains.

Conclusion

The review found widespread heterogeneity in the assessment of self-reported cognitive symptoms and consistently absent or weak association with neuropsychological test scores.

Implications for Cancer Survivors

This research highlights the need for a standardised approach to measurement of self-reported cognitive symptoms in cancer patients.

https://ift.tt/2HPLdXl

Ivermectin resistance in intestinal parasites of camels in a private farm at Assiut, Egypt

Abstract

Recently, anthelmintic resistance becomes a growing problem in veterinary medicine in all domestic animals including camels. There was a little documented research on parasitic resistance especially in camels in Egypt. Therefore, this study was designed to investigate resistance to ivermectin in one-humped camels (Camelus dromedarius) in a private farm at Assiut Governorate, Egypt. These camels were regularly receiving injectable ivermectin at 0.2 mg/kg bodyweight once every month and suffered from emaciation and loss of condition. Fecal samples were collected from all camels in the farm (number = 40) and examined directly by sedimentation and flotation techniques. Fecal egg counts were also determined by using McMaster slide. Thirty-one out of 40 (77.5%) examined camels were infected with eggs of different helminth genera and coccidian oocysts. Eimeria spp. were the most prevalent (55%) either in single or mixed infested cases, followed by Trichostrongylus spp. (45%), Trichuris spp. (35%), Ascaris spp. (5%), and Moniezia spp. (5%). According to the infestation type, the infested cases divided into single and mixed cases. Single infested cases (n = 13; 32.5%) was lower than the mixed (two (9; 22.5%) or three (9; 22.5%)) ones. Severity of infestation was estimated by fecal egg count and most of cases showed mild infestation except for Eimeria spp.-infested cases, which showed severe infestation. The present study concluded that misuse of ivermectin as anthelmintic drug has led to the development of parasitic resistance in the examined camels especially with the nematode worm Trichostrongylus spp.

https://ift.tt/2rnqL63

Sequential Treatment Escalation with Dapagliflozin and Saxagliptin Improves Beta Cell Function in Type 2 Diabetic Patients on Previous Metformin Treatment: An Exploratory Mechanistic Study

Horm Metab Res
DOI: 10.1055/a-0591-9442

We investigated the effect of sequential treatment escalation with dapagliflozin and saxagliptin on beta cell function in patients with T2DM insufficiently controlled on metformin monotherapy during a hyperglycaemic clamp investigation. Twenty-six patients (19 males, age 63.5±7.0 years; duration of diabetes 8.8±4.7 years; HbA1c 63.9±15.8 mmol/mol; mean±SD) were enrolled in the study. During a first treatment period (TP1) all patients received 10 mg dapagliflozin for one month, followed by the addition of 5 mg saxagliptin or placebo for another month (TP2). At baseline and at the end of each treatment period, fasting glucose and insulin levels were analysed, and a hyperglycaemic clamp with the measurement of plasma C-peptide, insulin, proinsulin, and glucagon was performed. Treatment with dapagliflozin reduced fasting glucose levels and insulin resistance (TP1). Within the hyperglycaemic clamp, C-peptide and insulin concentrations increased after the addition of dapagliflozin in TP1 (0.48±0.45 nmol*h/l; 6.24±17.9 mU*h/l) and further improved after the addition of saxagliptin in TP2 (0.38±0.34 nmol*h/l; 6.59±10.15 mU*h/l). Acute insulin response did not change after the addition of dapagliflozin (TP1), but significantly improved after the addition of saxagliptin in TP2 (0.89±0.76 mU*h/l). Both drugs improved the C-peptide/proinsulin ratio. After the addition of saxagliptin, the glucagon/insulin ratio significantly declined (TP2). Treatment escalation with dapagliflozin and saxagliptin exhibit additive effects on beta cell capacity, and improves alpha and beta cell integrity.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

https://ift.tt/2FIBlJ3

Pancreatic Beta-Cell Proliferation Induced by Estradiol-17β is Foxo1 Dependent

Horm Metab Res
DOI: 10.1055/a-0603-3969

Estradiol-17β (E2) and the Foxo1 transcription factor have each been implicated in the regulation of β-cell proliferation. Interaction between Foxo1and estrogen receptor alpha (ERα), effecting cell cycle, has been demonstrated in breast cancer cells, but has not been studied thus far in β-cells. Using human islets and the INS1-E β-cell line, this study investigated the contribution of Foxo1 to E2-mediated β-cell replication. Foxo1 expression was knocked down in INS1-E cells using siRNA and Foxo1 activity was inhibited in human islets with a specific Foxo1 inhibitor (AS1842856). Cells were treated with E2 and the ERα agonist PPT and evaluated for proliferation by 3[H]-thymidine incorporation and for transcriptional activity through the estrogen response element by the luciferase assay. As Foxo1 activity is regulated by post-translational modifications, the effect of E2 on phosphorylation was also assessed. In INS1-E cells, knock down of Foxo1 abrogated the proliferative response to E2 and PPT. In human islets, inhibition of Foxo1 abrogated E2-mediated proliferation and attenuated the response to PPT. Foxo1 knock down and inhibition reduced activity through the estrogen response element by 25% (p<0.05) and 50% (p<0.01) respectively, in INS1-E cells. E2 increased Foxo1 phosphorylation in a time dependent manner in INS1-E and human islets (p<0.01, p<0.05, respectively). These findings suggest that Foxo1 is involved in E2-mediated proliferation in INS1-E cells and human islets. This may have implications vis-à-vis variations in circulating endogenous E2 concentrations in diabetes.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

https://ift.tt/2jzZcCp

Neonatal Thyrotoxicosis with Tricuspid Valve Regurgitation and Hydrops in a Preterm Infant Born to a Mother with Graves' Disease

AJP Rep 2018; 08: e85-e88
DOI: 10.1055/s-0038-1645879

Neonatal hyperthyroidism is rare disorder due to the passage of thyroid receptor antibodies (TRBs) from the mother to the fetus. Neonatal thyrotoxicosis can present in several ways and if unrecognized, can be fatal. We present a preterm neonate who developed fetal hydrops and tricuspid regurgitation in utero. The mother had a history of treated Grave's disease. The infant responded to maternal treatment antenatally and postnatal anti-thyroid treatment, with resolution of both the tricuspid regurgitation and hydrops. To our knowledge, this is the first case report of tricuspid regurgitation associated with fetal and neonatal thyrotoxicosis. Our case also highlights the importance of obtaining a detailed and accurate history in a mother with previous Grave's disease, even if treated.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

https://ift.tt/2jvc4tp

Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population

Abstract

Otosclerosis is a common form of hearing loss which typically presents in young adults. The disease has a familial, monogenic form and a non-familial form with a more complex aetiology. A previous genome wide association study identified evidence that variants within RELN are associated with the condition. Other genes in which an association has been reported include BMP2, COL1A1, FGF2, PPP2R5B and TGFB1. However, follow up studies have often failed to replicate initial positive results. The aim of this study was to establish if an association exists between eight single nucleotide polymorphisms (SNPs) in these six previously implicated genes and otosclerosis in a British case–control cohort (n = 748). Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found (p = 0.034), this association was strongest amongst non-familial cases (p = 0.011). No evidence of an association was detected with variants in COL1A1, FGF2, BMP2, and PPP2R5B. No association between variation in RELN and otosclerosis was observed in the whole cohort. However, a significant association (p = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients. Additionally, we identify expression of one RELN transcript in 51 of 81 human stapes tested, clarifying previous conflicting data as to whether RELN is expressed in the affected tissue. Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis and support a relationship between RELN and familial otosclerosis only, which may explain previous variable replications.

https://ift.tt/2KxMoIJ

(OA02) Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer

Immune checkpoint inhibitors (ICIs) are commonly used for treatment of advanced stage non-small cell lung cancer (NSCLC) and numerous clinical studies are examining combinations of ICIs with radiotherapy (RT). Standard-of-care response assessment is CT imaging, which is typically performed no earlier than 2-3 months after treatment initiation due to delayed radiographic responses and occasional pseudoprogression. Improved methods of response assessment would be useful clinically and in trials combining ICIs and RT.

https://ift.tt/2HQLiWL

Usefulness of controlled attenuation parameter for detecting increased arterial stiffness in general population

Liver fibroscan has recently been suggested as an alternative method to measure liver steatosis noninvasively. In this study, we evaluated usefulness of controlled attenuation parameter (CAP) for detecting increased arterial stiffness in general population.

https://ift.tt/2jzPAYl

Small-vessel intestinal vasculitis as an initial manifestation of systemic lupus erythematosus

https://ift.tt/2wdis1n

Inter-replicon Gene Flow Contributes to Transcriptional Integration in the Sinorhizobium meliloti Multipartite Genome

Integration of newly acquired genes into existing regulatory networks is necessary for successful horizontal gene transfer (HGT). Ten percent of bacterial species contain at least two DNA replicons over 300 kilobases in size, with the secondary replicons derived predominately through HGT. The Sinorhizobium meliloti genome is split between a 3.7 Mb chromosome, a 1.7 Mb chromid consisting largely of genes acquired through ancient HGT, and a 1.4 Mb megaplasmid consisting primarily of recently acquired genes. Here, RNA-sequencing is used to examine the transcriptional consequences of massive, synthetic genome reduction produced through the removal of the megaplasmid and/or the chromid. Removal of the pSymA megaplasmid influenced the transcription of only six genes. In contrast, removal of the chromid influenced expression of ~8% of chromosomal genes and ~4% of megaplasmid genes. This was mediated in part by the loss of the ETR DNA region whose presence on pSymB is due to a translocation from the chromosome. No obvious functional bias among the up-regulated genes was detected, although genes with putative homologs on the chromid were enriched. Down-regulated genes were enriched in motility and sensory transduction pathways. Four transcripts were examined further, and in each case the transcriptional change could be traced to loss of specific pSymB regions. In particularly, a chromosomal transporter was induced due to deletion of bdhA likely mediated through 3-hydroxybutyrate accumulation. These data provide new insights into the evolution of the multipartite bacterial genome, and more generally into the integration of horizontally acquired genes into the transcriptome.

https://ift.tt/2jyBNkp

Inducible Genome Editing with Conditional CRISPR/Cas9 Mice

Genetically engineered mouse models (GEMMs) are powerful tools by which to probe gene function in vivo, obtain insight into disease etiology, and identify modifiers of drug response. Increased sophistication of GEMMs has led to the design of tissue-specific and inducible models in which genes of interest are expressed or ablated in defined tissues or cellular subtypes. Here we describe the generation of a transgenic mouse harboring a doxycycline-regulated Cas9 allele for inducible genome engineering. This model provides a flexible platform for genome engineering since editing is achieved by exogenous delivery of sgRNAs and should allow for the modeling of a range of biological and pathological processes.

https://ift.tt/2FHC1yx

Robust {Phi}C31-Mediated Genome Engineering in Drosophila melanogaster Using Minimal attP/attB Phage Sites

Effective genome engineering should lead to a desired locus change with minimal adverse impact to the genome itself. However, flanking loci with site-directed recombinase recognition sites, such as those of the phage C31 integrase, allows for creation of platforms for cassette exchange and manipulation of genomic regions in an iterative manner, once specific loci have been targeted. Here we show that a genomic locus engineered with inverted minimal phage C31 attP/attB sites can undergo efficient recombinase-mediated cassette exchange (RMCE) in the fruit fly Drosophila melanogaster.

https://ift.tt/2jwNZCi

Vps74 Connects the Golgi Apparatus and Telomeres in Saccharomyces cerevisiae

In mammalian cell culture, the Golgi apparatus fragment upon DNA damage. GOLPH3, a Golgi component, is a phosphorylation target of DNA-PK after DNA damage and contributes to Golgi fragmentation. The function of the yeast (Saccharomyces cerevisiae) ortholog of GOLPH3, Vps74, in the DNA damage response has been little studied, although genome-wide screens suggested a role at telomeres. In this study we investigated the role of Vps74 at telomeres and in the DNA damage response. We show that Vps74 decreases the fitness of telomere defective cdc13-1 cells and contributes to the fitness of yku70 cells. Importantly, loss of Vps74 in yku70 cells exacerbates the temperature dependent growth defects of these cells in a Chk1 and Mec1-dependent manner. Furthermore, Exo1 reduces the fitness of vps74yku70 cells suggesting that ssDNA contributes to the fitness defects of vps74yku70 cells. Systematic genetic interaction analysis of vps74, yku70 and yku70vps74 cells suggests that vps74 causes a milder but similar defect to that seen in yku70 cells. vps74 cells have slightly shorter telomeres and loss of VPS74 in yku70 or mre11 cells further shortens the telomeres of these cells. Interestingly, loss of Vps74 leads to increased levels of Stn1, a partner of Cdc13 in the CST telomere capping complex. Overexpression of Stn1 was previously shown to cause telomere shortening, suppression of cdc13-1 and enhancement of yku70 growth defects, suggesting that increased levels of Stn1 may be the route by which Vps74 affects telomere function. These results establish Vps74 as a novel regulator of telomere biology.

https://ift.tt/2FJw6Jn

The Draft Genome of the Invasive Walking Stick, Medauroidea extradendata, Reveals Extensive Lineage-Specific Gene Family Expansions of Cell Wall Degrading Enzymes in Phasmatodea

Plant cell wall components are the most abundant macromolecules on Earth. The study of the breakdown of these molecules is thus a central question in biology. Surprisingly, plant cell wall breakdown by herbivores is relatively poorly understood, as nearly all early work focused on the mechanisms used by symbiotic microbes to breakdown plant cell walls in insects such as termites. Recently, however, it has been shown that many organisms make endogenous cellulases. Insects, and other arthropods, in particular have been shown to express a variety of plant cell wall degrading enzymes in many gene families with the ability to break down all the major components of the plant cell wall. Here we report the genome of a walking stick, Medauroidea extradentata, an obligate herbivore that makes uses of endogenously produced plant cell wall degrading enzymes. We present a draft of the 3.3Gbp genome along with an official gene set that contains a diversity of plant cell wall degrading enzymes. We show that at least one of the major families of plant cell wall degrading enzymes, the pectinases, have undergone a striking lineage-specific gene family expansion in the Phasmatodea. This genome will be a useful resource for comparative evolutionary studies with herbivores in many other clades and will help elucidate the mechanisms by which metazoans breakdown plant cell wall components.

https://ift.tt/2jux9Eb

Russian Doll Genes and Complex Chromosome Rearrangements in Oxytricha trifallax

Ciliates have two different types of nuclei per cell, with one acting as a somatic, transcriptionally active nucleus (macronucleus; abbr. MAC) and another serving as a germline nucleus (micronucleus; abbr. MIC). Furthermore, Oxytricha trifallax undergoes extensive genome rearrangements during sexual conjugation and post-zygotic development of daughter cells. These rearrangements are necessary because the precursor MIC loci are often both fragmented and scrambled, with respect to the corresponding MAC loci. Such genome architectures are remarkably tolerant of encrypted MIC loci, because RNA-guided processes during MAC development reorganize the gene fragments in the correct order to resemble the parental MAC sequence. Here, we describe the germline organization of several nested and highly scrambled genes in Oxytricha trifallax. These include cases with multiple layers of nesting, plus highly interleaved or tangled precursor loci that appear to deviate from previously described patterns. We present mathematical methods to measure the degree of nesting between precursor MIC loci, and revisit a method for a mathematical description of scrambling. After applying these methods to the chromosome rearrangement maps of O. trifallax we describe cases of nested arrangements with up to five layers of embedded genes, as well as the most scrambled loci in O. trifallax.

https://ift.tt/2FKe8pX

QTL Mapping of Genome Regions Controlling Manganese Uptake in Lentil Seed

This study evaluated Mn concentration in the seeds of 120 RILs of lentil developed from the cross "CDC Redberry" x "ILL7502". Micronutrient analysis using atomic absorption spectrometry indicated mean seed manganese (Mn) concentrations ranging from 8.5 to 26.8 mg/kg, based on replicated field trials grown at three locations in Turkey in 2012 and 2013. A linkage map of lentil was constructed and consisted of seven linkage groups with 5,385 DNA markers. The total map length was 973.1 cM, with an average distance between markers of 0.18 cM. A total of 6 QTL for Mn concentration were identified using composite interval mapping (CIM). All QTL were statistically significant and explained 15.3–24.1% of the phenotypic variation, with LOD scores ranging from 3.00 to 4.42. The high-density genetic map reported in this study will increase fundamental knowledge of the genome structure of lentil, and will be the basis for the development of micronutrient-enriched lentil genotypes to support biofortification efforts.

https://ift.tt/2KCfA1t

Distinguishing Among Evolutionary Forces Acting on Genome-Wide Base Composition: Computer Simulation Analysis of Approximate Methods for Inferring Site Frequency Spectra of Derived Mutations

Inferred ancestral nucleotide states are increasingly employed in analyses of within- and between -species genome variation. Although numerous studies have focused on ancestral inference among distantly related lineages, approaches to infer ancestral states in polymorphism data have received less attention. Recently developed approaches that employ complex transition matrices allow us to infer ancestral nucleotide sequence in various evolutionary scenarios of base composition. However, the requirement of a single gene tree to calculate a likelihood is an important limitation for conducting ancestral inference using within-species variation in recombining genomes. To resolve this problem, and to extend the applicability of ancestral inference in studies of base composition evolution, we first evaluate three previously proposed methods to infer ancestral nucleotide sequences among within- and between-species sequence variation data. The methods employ a single allele, bifurcating tree, or a star tree for within-species variation data. Using simulated nucleotide sequences, we employ ancestral inference to infer fixations and polymorphisms. We find that all three methods show biased inference. We modify the bifurcating tree method to include weights to adjust for an expected site frequency spectrum, "bifurcating tree with weighting" (BTW). Our simulation analysis show that the BTW method can substantially improve the reliability and robustness of ancestral inference in a range of scenarios that include non-neutral and/or non-stationary base composition evolution.

https://ift.tt/2FJTaYs

Genome-Wide Analysis of Mycoplasma bovirhinis GS01 Reveals Potential Virulence Factors and Phylogenetic Relationships

Mycoplasma bovirhinis is a significant etiology in bovine pneumonia and mastitis, but our knowledge about the genetic and pathogenic mechanisms of M. bovirhinis is very limited. In this study, we sequenced the complete genome of M. bovirhinis strain GS01 isolated from the nasal swab of pneumonic calves in Gansu, China, and we found that its genome forms a 847,985 bp single circular chromosome with a GC content of 27.57% and with 707 protein-coding genes. The putative virulence determinants of M. bovirhinis were then analyzed. Results showed that three genomic islands and 16 putative virulence genes, including one adhesion gene enolase, seven surface lipoproteins, proteins involved in glycerol metabolism, and cation transporters, might be potential virulence factors. Glycerol and pyruvate metabolic pathways were defective. Comparative analysis revealed remarkable genome variations between GS01 and a recently reported HAZ141_2 strain, and extremely low homology with others mycoplasma species. Phylogenetic analysis demonstrated that M. bovirhinis was most genetically close to M. canis, distant from other bovine Mycoplasma species. Genomic dissection may provide useful information on the pathogenic mechanisms and genetics of M. bovirhinis.

https://ift.tt/2KBdb6U

Improved Genome Assembly and Annotation for the Rock Pigeon (Columba livia)

The domestic rock pigeon (Columba livia) is among the most widely distributed and phenotypically diverse avian species. C. livia is broadly studied in ecology, genetics, physiology, behavior, and evolutionary biology, and has recently emerged as a model for understanding the molecular basis of anatomical diversity, the magnetic sense, and other key aspects of avian biology. Here we report an update to the C. livia genome reference assembly and gene annotation dataset. Greatly increased scaffold lengths in the updated reference assembly, along with an updated annotation set, provide improved tools for evolutionary and functional genetic studies of the pigeon, and for comparative avian genomics in general.

https://ift.tt/2FLGYWX

A Strategy To Isolate Modifiers of Caenorhabditis elegans Lethal Mutations: Investigating the Endoderm Specifying Ability of the Intestinal Differentiation GATA Factor ELT-2

The ELT-2 GATA factor normally functions in differentiation of the C. elegans endoderm, downstream of endoderm specification. We have previously shown that, if ELT-2 is expressed sufficiently early, it is also able to specify the endoderm and to replace all other members of the core GATA-factor transcriptional cascade (END-1, END-3, ELT-7). However, such rescue requires multiple copies (and presumably overexpression) of the end-1p::elt-2 cDNA transgene; a single copy of the transgene does not rescue. We have made this observation the basis of a genetic screen to search for genetic modifiers that allow a single copy of the end-1p::elt-2 cDNA transgene to rescue the lethality of the end-1end-3 double mutant. We performed this screen on a strain that has a single copy insertion of the transgene in an end-1end-3 background. These animals are kept alive by virtue of an extrachromosomal array containing multiple copies of the rescuing transgene; the extrachromosomal array also contains a toxin under heat shock control to counterselect for mutagenized survivors that have been able to lose the rescuing array. A screen of ~14,000 mutagenized haploid genomes produced 17 independent surviving strains. Whole genome sequencing was performed to identify genes that incurred independent mutations in more than one surviving strain. The C. elegans gene tasp-1 was mutated in four independent strains. tasp-1 encodes the C. elegans homolog of Taspase, a threonine-aspartic acid protease that has been found, in both mammals and insects, to cleave several proteins involved in transcription, in particular MLL1/trithorax and TFIIA. A second gene, pqn-82, was mutated in two independent strains and encodes a glutamine-asparagine rich protein. tasp-1 and pqn-82 were verified as loss-of-function modifiers of the end-1p::elt-2 transgene by RNAi and by CRISPR/Cas9-induced mutations. In both cases, gene loss leads to modest increases in the level of ELT-2 protein in the early endoderm although ELT-2 levels do not strictly correlate with rescue. We suggest that tasp-1 and pqn-82 represent a class of genes acting in the early embryo to modulate levels of critical transcription factors or to modulate the responsiveness of critical target genes. The screen's design, rescuing lethality with an extrachromosomal transgene followed by counterselection, has a background survival rate of <10^–4 without mutagenesis and should be readily adapted to the general problem of identifying suppressors of C. elegans lethal mutations.

https://ift.tt/2jxChHI

Rapid Multiplex Small DNA Sequencing on the MinION Nanopore Sequencing Platform

Real-time sequencing of short DNA reads has a wide variety of clinical and research applications including screening for mutations, target sequences and aneuploidy. We recently demonstrated that MinION, a nanopore-based DNA sequencing device the size of a USB drive, could be used for short-read DNA sequencing. In this study, an ultra-rapid multiplex library preparation and sequencing method for the MinION is presented and applied to accurately test normal diploid and aneuploidy samples' genomic DNA in under three hours, including library preparation and sequencing. This novel method shows great promise as a clinical diagnostic test for applications requiring rapid short-read DNA sequencing.

https://ift.tt/2FJw5Fj

Cold Shock as a Screen for Genes Involved in Cold Acclimatization in Neurospora crassa

When subjected to rapid drops of temperature (cold shock), Neurospora responds with a temporary shift in its morphology. This report is the first to examine this response genetically. We report here the results of a screen of selected mutants from the Neurospora knockout library for alterations in their morphological response to cold shock. Three groups of knockouts were selected to be subject to this screen: genes previously suspected to be involved in hyphal development as well as knockouts resulting in morphological changes; transcription factors; and genes homologous to E. coli genes known to alter their expression in response to cold shock. A total of 344 knockout strains were subjected to cold shock. Of those, 118 strains were identified with altered responses. We report here the cold shock morphologies and GO categorizations of strains subjected to this screen. Of strains with knockouts in genes associated with hyphal growth or morphology, 33 of 131 tested (25%) showed an altered response to cold shock. Of strains with knockouts in transcription factor genes, 30 of 145 (20%) showed an altered response to cold shock. Of strains with knockouts in genes homologous to E. coli genes which display altered levels of transcription in response to cold shock, a total of 55 of 68 tested (81%) showed an altered cold shock response. This suggests that the response to cold shock in these two organisms is largely shared in common.

https://ift.tt/2jxgBLZ

Haplotype-Based Genome-Wide Prediction Models Exploit Local Epistatic Interactions Among Markers

Genome-wide prediction approaches represent versatile tools for the analysis and prediction of complex traits. Mostly they rely on marker-based information, but scenarios have been reported in which models capitalizing on closely-linked markers that were combined into haplotypes outperformed marker-based models. Detailed comparisons were undertaken to reveal under which circumstances haplotype-based genome-wide prediction models are superior to marker-based models. Specifically, it was of interest to analyze whether and how haplotype-based models may take local epistatic effects between markers into account. Assuming that populations consisted of fully homozygous individuals, a marker-based model in which local epistatic effects inside haplotype blocks were exploited (LEGBLUP) was linearly transformable into a haplotype-based model (HGBLUP). This theoretical derivation formally revealed that haplotype-based genome-wide prediction models capitalize on local epistatic effects among markers. Simulation studies corroborated this finding. Due to its computational efficiency the HGBLUP model promises to be an interesting tool for studies in which ultra-high-density SNP data sets are studied. Applying the HGBLUP model to empirical data sets revealed higher prediction accuracies than for marker-based models for both traits studied using a mouse panel. In contrast, only a small subset of the traits analyzed in crop populations showed such a benefit. Cases in which higher prediction accuracies are observed for HGBLUP than for marker-based models are expected to be of immediate relevance for breeders, due to the tight linkage a beneficial haplotype will be preserved for many generations. In this respect the inheritance of local epistatic effects very much resembles the one of additive effects.

https://ift.tt/2FKze7F

Fast Ordered Sampling of DNA Sequence Variants

Explosive growth in the amount of genomic data is matched by increasing power of consumer-grade computers. Even applications that require powerful servers can be quickly tested on desktop or laptop machines if we can generate representative samples from large data sets. I describe a fast and memory-efficient implementation of an on-line sampling method developed for tape drives 30 years ago. Focusing on genotype files, I test the performance of this technique on modern solid-state and spinning hard drives, and show that it performs well compared to a simple sampling scheme. I illustrate its utility by developing a method to quickly estimate genome-wide patterns of linkage disequilibrium (LD) decay with distance. I provide open-source software that samples loci from several variant format files, a separate program that performs LD decay estimates, and a C++ library that lets developers incorporate these methods into their own projects.

https://ift.tt/2jwjY5O

Comparison of the Relative Potential for Epigenetic and Genetic Variation To Contribute to Trait Stability

The theoretical ability of epigenetic variation to influence the heritable variation of complex traits is gaining traction in the study of adaptation. This theory posits that epigenetic marks can control adaptive phenotypes but the relative potential of epigenetic variation in comparison to genetic variation in these traits is not presently understood. To compare the potential of epigenetic and genetic variation in adaptive traits, we analyzed the influence of DNA methylation variation on the accumulation of chemical defense compounds glucosinolates from the order Brassicales. Several decades of work on glucosinolates has generated extensive knowledge about their synthesis, regulation, genetic variation and contribution to fitness establishing this pathway as a model pathway for complex adaptive traits. Using high-throughput phenotyping with a randomized block design of ddm1 derived Arabidopsis thaliana epigenetic Recombinant Inbred Lines, we measured the correlation between DNA methylation variation and mean glucosinolate variation and within line stochastic variation. Using this information, we identified epigenetic Quantitative Trait Loci that contained specific Differentially Methylated Regions associated with glucosinolate traits. This showed that variation in DNA methylation correlates both with levels and variance of glucosinolates and flowering time with trait-specific loci. By conducting a meta-analysis comparing the results to different genetically variable populations, we conclude that the influence of DNA methylation variation on these adaptive traits is much lower than the corresponding impact of standing genetic variation. As such, selective pressure on these traits should mainly affect standing genetic variation to lead to adaptation.

https://ift.tt/2FKzdR9

Comparative Transcriptomics Among Four White Pine Species

Conifers are the dominant plant species throughout the high latitude boreal forests as well as some lower latitude temperate forests of North America, Europe, and Asia. As such, they play an integral economic and ecological role across much of the world. This study focused on the characterization of needle transcriptomes from four ecologically important and understudied North American white pines within the Pinus subgenus Strobus. The populations of many Strobus species are challenged by native and introduced pathogens, native insects, and abiotic factors. RNA from the needles of western white pine (Pinus monticola), limber pine (Pinus flexilis), whitebark pine (Pinus albicaulis), and sugar pine (Pinus lambertiana) was sampled, Illumina short read sequenced, and de novo assembled. The assembled transcripts and their subsequent structural and functional annotations were processed through custom pipelines to contend with the challenges of non-model organism transcriptome validation. Orthologous gene family analysis of over 58,000 translated transcripts, implemented through Tribe-MCL, estimated the shared and unique gene space among the four species. This revealed 2025 conserved gene families, of which 408 were aligned to estimate levels of divergence and reveal patterns of selection. Specific candidate genes previously associated with drought tolerance and white pine blister rust resistance in conifers were investigated.

https://ift.tt/2KxVCF3

Effects of Larval Density on Gene Regulation in Caenorhabditis elegans During Routine L1 Synchronization

Bleaching gravid C. elegans followed by a short period of starvation of the L1 larvae is a routine method performed by worm researchers for generating synchronous populations for experiments. During the process of investigating dietary effects on gene regulation in L1 stage worms by single-worm RNA-Seq, we found that the density of resuspended L1 larvae affects expression of many mRNAs. Specifically, a number of genes related to metabolism and signaling are highly expressed in worms arrested at low density, but are repressed at higher arrest densities. We generated a GFP reporter strain based on one of the most density-dependent genes in our dataset – lips-15 – and confirmed that this reporter was expressed specifically in worms arrested at relatively low density. Finally, we show that conditioned media from high density L1 cultures was able to downregulate lips-15 even in L1 animals arrested at low density, and experiments using daf-22 mutant animals demonstrated that this effect is not mediated by the ascaroside family of signaling pheromones. Together, our data implicate a soluble signaling molecule in density sensing by L1 stage C. elegans, and provide guidance for design of experiments focused on early developmental gene regulation.

https://ift.tt/2FKTfel

Germline Variants in the POT1-Gene in High-Risk Melanoma Patients in Austria

Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n = 163) or with a positive family history (n = 133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used.

In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counseling.

https://ift.tt/2jumt8A

H3K4 Methylation Dependent and Independent Chromatin Regulation by JHD2 and SET1 in Budding Yeast

Set1 and Jhd2 regulate the methylation state of histone H3 lysine-4 (H3K4me) through their opposing methyltransferase and demethylase activities in the budding yeast Saccharomyces cerevisiae. H3K4me associates with actively transcribed genes and, like both SET1 and JHD2 themselves, is known to regulate gene expression diversely. It remains unclear, however, if Set1 and Jhd2 act solely through H3K4me. Relevantly, Set1 methylates lysine residues in the kinetochore protein Dam1 while genetic studies of the S. pombe SET1 ortholog suggest the existence of non-H3K4 Set1 targets relevant to gene regulation. We interrogated genetic interactions of JHD2 and SET1 with essential genes involved in varied aspects of the transcription cycle. Our findings implicate JHD2 in genetic inhibition of the histone chaperone complexes Spt16-Pob3 (FACT) and Spt6-Spn1. This targeted screen also revealed that JHD2 inhibits the Nrd1-Nab3-Sen1 (NNS) transcription termination complex. We find that while Jhd2's impact on these transcription regulatory complexes likely acts via H3K4me, Set1 governs the roles of FACT and NNS through opposing H3K4-dependent and -independent functions. We also identify diametrically opposing consequences for mutation of H3K4 to alanine or arginine, illuminating that caution must be taken in interpreting histone mutation studies. Unlike FACT and NNS, detailed genetic studies suggest an H3K4me-centric mode of Spt6-Spn1 regulation by JHD2 and SET1. Chromatin immunoprecipitation and transcript quantification experiments show that Jhd2 opposes the positioning of a Spt6-deposited nucleosome near the transcription start site of SER3, a Spt6-Spn1 regulated gene, leading to hyper-induction of SER3. In addition to confirming and extending an emerging role for Jhd2 in the control of nucleosome occupancy near transcription start sites, our findings suggest some of the chromatin regulatory functions of Set1 are independent of H3K4 methylation.

https://ift.tt/2jv2o23

Phase II trial of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for untreated non-squamous non-small-cell lung cancer

Abstract

Purpose

We conducted a phase II trial to evaluate the efficacy and safety of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for advanced non-squamous non-small-cell lung cancer (NSCLC).

Methods

Patients with advanced or recurrent untreated non-squamous NSCLC received split-dose cisplatin (40 mg/m², days 1 and 8) plus pemetrexed (500 mg/m², day 1) tri-weekly. After four cycles of induction, patients without disease progression received pemetrexed maintenance until disease progression or unacceptable toxicity. The primary endpoint was the 1-year survival rate. The secondary endpoints were progression-free survival (PFS), overall survival (OS), response in induction phase, and safety.

Results

From February 2012 to September 2014, 53 assessable patients were enrolled in this study. Thirty-eight (71.7%) patients completed induction therapy, while 35 (66.0%) received maintenance therapy. The 1-year survival rate was 67.7%. The median PFS and OS were 5.3 and 18.6 months, respectively. The response rate and disease control rate (DCR) during the induction phase were 37.7 and 86.8%, respectively. Eight patients (15.1%) discontinued the therapy due to adverse events (AEs) during the induction phase, but both hematological and non-hematological AEs were infrequent.

Conclusions

Treatment with induction chemotherapy of pemetrexed plus split-dose cisplatin showed a promising 1-year survival rate, DCR, and transition rate into maintenance phase. This regimen is feasible and well-tolerated. A phase III study comparing this regimen with conventional tri-weekly regimen is warranted.

https://ift.tt/2KE9nlG

Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy

Abstract

Purpose

High activity of enzyme TOP2a in tumor cells is known to be associated with sensitivity to anthracycline chemotherapy, but 20% of such patients do not show clinical response. Tumor microenvironment, including tumor-associated macrophages (TAM), is an essential factor defining the efficiency of chemotherapy. In the present study, we analyzed the expression of M2 macrophage markers, YKL-39 and CCL18, in tumors of breast cancer patients received anthracycline-based NAC.

Methods

Patients were divided into two groups according to the level of doxorubicin sensitivity marker TOP2a: DOX-Sense and DOX-Res groups. Expression levels of TOR2a, CD68, YKL-39 and CCL18 genes were analyzed by qPCR, the amplification of TOR2a gene locus was assessed by the microarray assay. Clinical and pathological responses to neoadjuvant chemotherapy were assessed.

Results

We found that the average level of TOP2a expression in patients of DOX-Sense group was almost 10 times higher than in patients of DOX-Res group, and the expression of CD68 was 3 times higher in the DOX-Sense group compared to DOX-Res group. We demonstrated that expression levels of M2-derived cytokines but not the amount of TAM is indicative for clinical and pathological chemotherapy efficacy in breast cancer patients. Out of 8 patients from DOX-Sense group who did not respond to neoadjuvant chemotherapy (NAC), 7 patients had M2+ macrophage phenotype (YKL-39⁺CCL18⁻ or YKL-39⁻CCL18⁺) and only one patient had M2− macrophage phenotype (YKL-39⁻CCL18⁻). In DOX-Res group, out of 14 patients who clinically responded to NAC 9 patients had M2− phenotype and only 5 patients had M2+ macrophage phenotype. Among pathological non-responders in DOX-Sense group, 19 (82%) patients had M2+ tumor phenotype and only 4 (18%) patients had M2− phenotype. In DOX-Res group, all 5 patients who pathologically responded to NAC had M2 phenotype (YKL-39⁻CCL18⁻). Unlike the clinical response to NAC, the differences in the frequency of M2+ and M2− phenotypes between pathologically responding and non-responding patients within DOX-Sense and DOX-Res groups were statistically significant.

Conclusions

Thus, we showed that in patients with breast cancer who received anthracycline-containing NAC the absence of clinical response is associated with the presence of M2+ macrophage phenotype (YKL-39-CCL18 + or YKL-39 + CCL18-) based on TOP2a overexpression data.

https://ift.tt/2FJrtz3

Azospirillum: benefits that go far beyond biological nitrogen fixation

The genus Azospirillum comprises plant-growth-promoting bacteria (PGPB), which have been broadly studied. The benefits to plants by inoculation with Azospirillum have been primarily attributed to its capacity to ...

https://ift.tt/2HQUYEX

Engagement. Leadership. Advocacy.

Thanks to the PTs, PTAs, and students from across the country who came to Washington, DC, for the 2018 Federal Advocacy Forum!

https://www.youtube.com/watch?v=KaZXZH8HJ-I

IAED releases Performance Standards 10th Edition

Brought to you by Priority Dispatch The International Academies of Emergency Dispatch® (IAED™) ED-Q Council of Standards has approved the release of Performance Standards 10th Edition, an updated version of performance requirements for all medical, fire, and police emergency calltaking. These new standards are integrated seamlessly into AQUA® 7 Ascent and will enhance a communication center's ...

https://ift.tt/2HPJPEm

Identifying risk factors for L’Hermitte’s sign after IMRT for head and neck cancer

Abstract

Background

L'Hermitte's sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high.

Methods

One hundred seventeen patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model.

Results

Forty two patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95% CI 0.51–2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95% CI 0.051–3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95% CI 0.15–0.84}) were more likely to develop LS. Higher V_40Gy (p = 0.047, OR = 1.06 {95% CI 1.00–1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95% CI 0.92–1.00}) were associated with elevated risk of LS, with borderline significance.

Conclusions

In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.

https://ift.tt/2rm7AIT

Measuring Trans-Plasma Membrane Electron Transport by C2C12 Myotubes

The goal of this protocol is to spectrophotometrically monitor trans-plasma membrane electron transport utilizing extracellular electron acceptors and to analyze enzymatic interactions that may occur with these extracellular electron acceptors.

https://ift.tt/2HVOO26

Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids

The protocol presents the Escherichia coli-based selective pressure incorporation of non-canonical amino acids (ncAAs) into the lactococcal antimicrobial peptide nisin. Its properties can be changed during recombinant expression via substitution with desired ncAAs in defined growth media. Resulting changes in bioactivity are mapped by growth inhibition assays and fluorescence microscopy.

https://ift.tt/2jvTaTe

Neuroendocrine carcinoma of the cervix: a systematic review of the literature

Abstract

Background

Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials.

Methods

We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC.

Results

Three thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports.

Conclusion

NECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.

https://ift.tt/2juyGKv

PET/CT incidental detection of second tumor in patients investigated for pancreatic neoplasms

Abstract

Background

Positron Emission Tomography/computed tomography (PET/CT) is an imaging technique which has a role in the detection and staging malignancies (both in first diagnosis and follow-up). The finding of an unexpected region of FDG (Fluorodeoxyglucose) uptake can occur when performing whole-body FDG-PET, raising the possibility of a second primary tumor. The aim of this study was to evaluate our experience of second primary cancer incidentally discovered during PET/CT examination performed for pancreatic diseases, during the initial work-up or follow-up after surgical resection.

Methods

In this study, a retrospective evaluation of a prospectively collected data base was performed. Three hundred ninety- nine patients with pancreatic pathology were evaluated by whole body PET/CT imaging from January 2004 to December 2014. Among them, 348 patients were scanned before surgical resection and 51 during the course of their follow-up (pancreatic cancer). Median follow-up time was 29 months (range 14-124).

Results

Fifty-six patients (14%) had incidental uptake of FDG in their organs: 31 patients had focal uptake and 25 showed diffuse with or without focal uptake. All patients with focal uptake were investigated, and invasive malignancy was diagnosed in 22 patients: 14 colon, 4 lung, 1 larynx, 1 urothelial, 1 breast cancer, and 1 colon metastasis from pancreatic cancer. Twenty patients underwent resection, and 6 endoscopic removal of colonic polyps. Three patients were not operated for advanced disease, and two patients did not show any pathology (PET/CT false positive). Of the 10 patients investigated for diffuse uptake, no malignancy was found; none of these patients developed a second cancer during the follow-up.

Conclusions

As in other malignancies, unexpected FDG uptake can occur in patients having PET/CT investigation for pancreatic diseases. Focal uptake is likely to be a malignancy and deserves further investigations, although the stage and the poor prognosis of primary pancreatic cancer should be kept in mind. Some selected patients may benefit from the aggressive treatment of incidental lesions and show survival benefit.

https://ift.tt/2FJQyJX

Pancreatic ductal adenocarcinoma can be detected by analysis of volatile organic compounds (VOCs) in alveolar air

Abstract

Background

In the last decade many studies showed that the exhaled breath of subjects suffering from several pathological conditions has a peculiar volatile organic compound (VOC) profile. The objective of the present work was to analyse the VOCs in alveolar air to build a diagnostic tool able to identify the presence of pancreatic ductal adenocarcinoma in patients with histologically confirmed disease.

Methods

The concentration of 92 compounds was measured in the end-tidal breath of 65 cases and 102 controls. VOCs were measured with an ion-molecule reaction mass spectrometry. To distinguish between subjects with pancreatic adenocarcinomas and controls, an iterated Least Absolute Shrinkage and Selection Operator multivariate Logistic Regression model was elaborated.

Results

The final predictive model, based on 10 VOCs, significantly and independently associated with the outcome had a sensitivity and specificity of 100 and 84% respectively, and an area under the ROC curve of 0.99. For further validation, the model was run on 50 other subjects: 24 cases and 26 controls; 23 patients with histological diagnosis of pancreatic adenocarcinomas and 25 controls were correctly identified by the model.

Conclusions

Pancreatic cancer is able to alter the concentration of some molecules in the blood and hence of VOCs in the alveolar air in equilibrium. The detection and statistical rendering of alveolar VOC composition can be useful for the clinical diagnostic approach of pancreatic neoplasms with excellent sensitivity and specificity.

https://ift.tt/2KE8dXg

Moringa oleifera Leaves Extract Protects Titanium Dioxide Nanoparticles-Induced Nephrotoxicity via Nrf2/HO-1 Signaling and Amelioration of Oxidative Stress

Abstract

The efficacy of Moringa oleifera leaf extract (MO) in alleviating nephrotoxicity induced by titanium dioxide nanoparticles (TiO₂ NPs) was studied. Rats were divided into four groups. Group I received distilled water. Group II received TiO₂NPs. Group III received both TiO₂NPs suspension beside MO. Group IV received MO only. Kidney KIM-1, NF-кB TNF-α, and HSP-70 expression were significantly upregulated while both Nrf2 and HO-1were significantly downregulated in TiO₂NPs-treated rats. MO decreases expression of KIM-1, NF-кB, TNF-α, and HSP-70. In addition, MO has markedly upregulated the expression of Nrf2 and HO-1. In conclusion, MO can inhibit nephrotoxicity by suppressing oxidative stress and inflammation. These effects are suggested to be mediated by activating Nrf2/HO-1.The biochemical analysis and histopathological finding reinforced these results. These data support the antioxidant properties' nutraceutical role of MO against TiO₂NPs-induced toxicity.

https://ift.tt/2JTIXeo

Bottlenecks, concerns and needs in malaria operational research: the perspectives of key stakeholders in Nigeria

We conducted a study to determine stakeholders' perspective of the bottlenecks, concerns and needs to malaria operational research (MOR) agenda setting in Nigeria.

https://ift.tt/2rjB7ng

The perception of hidden curriculum among undergraduate medical students: a qualitative study

The effect of hidden curriculum on student learning has not been sufficiently recognized in most of the revised curriculums. This study is a qualitative study that measures the students' perception of hidden c...

https://ift.tt/2JVnwtB

miRNAs in platelet-poor blood plasma and purified RNA are highly stable: a confirmatory study

We wished to re-assess the relative stability of microRNAs (miRNAs) as compared with other RNA molecules, which has been confirmed in many contexts. When bound to Argonaute proteins, miRNAs are protected from ...

https://ift.tt/2rmiCi8

Psychiatric Diagnosis Common in Medicaid-Insured Children

FRIDAY, May 4, 2018 -- About 20 percent of Medicaid-insured children receive a psychiatric diagnosis by age 8 years, according to a study published online April 30 in JAMA Pediatrics. Dinci Pennap, M.P.H., from the University of Maryland in...

https://ift.tt/2FIoRkV

Screening Mammos Linked to Less Aggressive Tx If Diagnosed

FRIDAY, May 4, 2018 -- Breast cancer screening is associated with less aggressive treatment, including among women aged 40 to 49 years, according to a study presented at the annual meeting of the American Society of Breast Surgeons, held from May 2...

https://ift.tt/2FIoOFL

Social Media Negatively Affects Body Satisfaction in Women

FRIDAY, May 4, 2018 -- Time spent on social media sites has negative effects on female body perceptions, according to a study presented at the annual meeting of the British Psychological Society, held from May 2 to 4 in Nottingham, U.K. Martin...

https://ift.tt/2jujRaP

Obstructive Sleep Apnea Linked to Thinning of Calvaria, Skull Base

FRIDAY, May 4, 2018 -- Obstructive sleep apnea (OSA) is associated with thinning of the calvaria and skull base, according to a study published online May 3 in JAMA Otolaryngology-Head & Neck Surgery. Cyrus Rabbani, M.D., from Indiana University...

https://ift.tt/2KAGwyk

Early Intervention May Reduce Breast CA-Related Lymphedema

FRIDAY, May 4, 2018 -- For breast cancer patients undergoing treatments that are high risk for the development of breast cancer-related lymphedema (BCRL), evaluations with bioimpedance spectroscopy (BIS) allows for early detection of BCRL that is...

https://ift.tt/2FIoMO9

Study IDs Pain Descriptors for Varying Stages of Low Back Pain

FRIDAY, May 4, 2018 -- Varying pain descriptors may be useful when evaluating patients with different stages of low back pain (LBP), according to a study published online April 30 in PAIN Practice. Philipp Hüllemann, Ph.D., from University Hospital...

https://ift.tt/2jx3Rou

Novel Signal ID'd for Microalbuminuria in Europeans With T2DM

FRIDAY, May 4, 2018 -- A novel signal has been identified that is associated with microalbuminuria in Europeans with type 2 diabetes (T2D), according to a study published online April 27 in Diabetes. Natalie R. van Zuydam, Ph.D., from the University...

https://ift.tt/2FJcipj

High Incidence of Sudden and/or Arrhythmic Death in CHD

FRIDAY, May 4, 2018 -- Among patients with coronary heart disease without severe systolic dysfunction, sudden and/or arrhythmic deaths (SAD) account for a considerable proportion of deaths, according to a study published online May 2 in JAMA...

https://ift.tt/2jvGrzW

Physical Therapy Helps Recover Arm Function in Chronic CVA

FRIDAY, May 4, 2018 -- Physical therapy promotes the recovery of arm function and neuroplasticity in all chronic stroke patients, according to a study published online April 25 in the Journal of Evaluation in Clinical Practice. Raquel Carvalho,...

https://ift.tt/2FJcfd7

Punctal Plug Deemed Beneficial in Ocular Surface Disease

FRIDAY, May 4, 2018 -- For patients with ocular surface disease (OSD) using prostaglandin analogue monotherapy, a punctal plug improves OSD and reduces intraocular pressure (IOP), according to a study published online April 26 in Clinical &...

https://ift.tt/2KzBuCi

Construction of a novel multi-gene assay (42-gene classifier) for prediction of late recurrence in ER-positive breast cancer patients

Abstract

Purpose

Prediction models for late (> 5 years) recurrence in ER-positive breast cancer need to be developed for the accurate selection of patients for extended hormonal therapy. We attempted to develop such a prediction model focusing on the differences in gene expression between breast cancers with early and late recurrence.

Methods

For the training set, 779 ER-positive breast cancers treated with tamoxifen alone for 5 years were selected from the databases (GSE6532, GSE12093, GSE17705, and GSE26971). For the validation set, 221 ER-positive breast cancers treated with adjuvant hormonal therapy for 5 years with or without chemotherapy at our hospital were included. Gene expression was assayed by DNA microarray analysis (Affymetrix U133 plus 2.0).

Results

With the 42 genes differentially expressed in early and late recurrence breast cancers in the training set, a prediction model (42GC) for late recurrence was constructed. The patients classified by 42GC into the late recurrence-like group showed a significantly (P = 0.006) higher late recurrence rate as expected but a significantly (P = 1.62 × E−13) lower rate for early recurrence than non-late recurrence-like group. These observations were confirmed for the validation set, i.e., P = 0.020 for late recurrence and P = 5.70 × E−5 for early recurrence.

Conclusion

We developed a unique prediction model (42GC) for late recurrence by focusing on the biological differences between breast cancers with early and late recurrence. Interestingly, patients in the late recurrence-like group by 42GC were at low risk for early recurrence.

https://ift.tt/2HTuVJd

Double-stranded RNA Oral Delivery Methods to Induce RNA Interference in Phloem and Plant-sap-feeding Hemipteran Insects

This article demonstrates novel techniques developed for oral delivery of double-stranded RNA (dsRNA) through the vascular tissues of plants for RNA interference (RNAi) in phloem sap feeding insects.

https://ift.tt/2FHkw17

Murine Salivary Functional Assessment via Pilocarpine Stimulation Following Fractionated Radiation

We present a detailed approach to performing saliva collection, including murine tracheostomy and the isolation of three major salivary glands.

https://ift.tt/2Kz6UZs

Ambulance service shares quote from EMT killed in crash

Paramount Ambulance shared a story from fallen EMT Steve Warner about a particularly special call that reminded him why he loved his job

https://ift.tt/2HScDIl

Virtual Reality Exploration and Planning for Precision Colorectal Surgery

BACKGROUND: Medical software can build a digital clone of the patient with 3-dimensional reconstruction of Digital Imaging and Communication in Medicine images. The virtual clone can be manipulated (rotations, zooms, etc), and the various organs can be selectively displayed or hidden to facilitate a virtual reality preoperative surgical exploration and planning. OBJECTIVE: We present preliminary cases showing the potential interest of virtual reality in colorectal surgery for both cases of diverticular disease and colonic neoplasms. DESIGN: This was a single-center feasibility study. SETTINGS: The study was conducted at a tertiary care institution. PATIENTS: Two patients underwent a laparoscopic left hemicolectomy for diverticular disease, and 1 patient underwent a laparoscopic right hemicolectomy for cancer. The 3-dimensional virtual models were obtained from preoperative CT scans. The virtual model was used to perform preoperative exploration and planning. Intraoperatively, one of the surgeons was manipulating the virtual reality model, using the touch screen of a tablet, which was interactively displayed to the surgical team. MAIN OUTCOME MEASURES: The main outcome was evaluation of the precision of virtual reality in colorectal surgery planning and exploration. RESULTS: In 1 patient undergoing laparoscopic left hemicolectomy, an abnormal origin of the left colic artery beginning as an extremely short common trunk from the inferior mesenteric artery was clearly seen in the virtual reality model. This finding was missed by the radiologist on CT scan. The precise identification of this vascular variant granted a safe and adequate surgery. In the remaining cases, the virtual reality model helped to precisely estimate the vascular anatomy, providing key landmarks for a safer dissection. LIMITATIONS: A larger sample size would be necessary to definitively assess the efficacy of virtual reality in colorectal surgery. CONCLUSIONS: Virtual reality can provide an enhanced understanding of crucial anatomical details, both preoperatively and intraoperatively, which could contribute to improve safety in colorectal surgery.

https://ift.tt/2rkPJSJ

Kill the Sitz Bath and Save the Planet

No abstract available

https://ift.tt/2HQA34T

Announcements

No abstract available

https://ift.tt/2rluLTD

Health Care in Guatemala

No abstract available

https://ift.tt/2KCACgu

Procedure for Prolapse and Hemorrhoids Complication Solutions: Repair of a Completely Closed Off Rectum

No abstract available

https://ift.tt/2rlVBuT

In Memoriam: Professor Toshiaki Watanabe

No abstract available

https://ift.tt/2HQOEx2

Visceral Fat Is Associated With Mucosal Healing of Infliximab Treatment in Crohn’s Disease

BACKGROUND: Visceral fat is the pathogenesis of Crohn's disease and is associated with disease status. OBJECTIVE: This study aimed to evaluate the effect of the visceral fat on mucosal healing in patients with Crohn's disease after infliximab induction therapy DESIGN: This was a retrospective study. SETTINGS: The study was conducted in a tertiary referral hospital. PATIENTS: Between 2011 and 2017, 97 patients with Crohn's disease with the presence of ulcers underwent infliximab therapy. MAIN OUTCOME MEASURES: We studied them retrospectively. Mucosal healing was the end point. Patients composed 2 groups: mucosal healing and no mucosal healing. Univariate, multivariate, and receiver operating characteristic curve analyses determined the predictive value of the visceral fat area. RESULTS: Univariate analysis showed a statistically significant difference in the smoking history between the groups. Mucosal healing rates after infliximab were lower among active smokers (p = 0.022). Healed patients had significantly less visceral fat area before therapy (47.76 ± 4.94 vs 75.88 ± 5.55; p = 0.000) and a lower mesenteric fat index (0.52 ± 0.04 vs 0.89 ± 0.07; p = 0.000). There was no significant difference in the subcutaneous fat area (87.39 ± 5.01 vs 93.31 ± 6.95; p = 0.500). Multivariate analysis showed that only visceral fat area (OR = 0.978 (95% CI, 0.964–0.992); p = 0.002) and smoking history (OR = 0.305 (95% CI, 0.089–0.996); p = 0.041) were independent factors for mucosal healing. Receiver operating characteristic curve analysis showed predictive cutoff values of 61.5 cm2 and 0.62 for visceral fat area and mesenteric fat index. LIMITATIONS: This was a retrospective study. CONCLUSIONS: There was an association between increased visceral fat area and attenuated mucosal healing after infliximab therapy in biologically naive patients with Crohn's disease, indicating a need for earlier increased infliximab doses among patients with increased visceral fat. See Video Abstract at https://ift.tt/2HMpWhg.

https://ift.tt/2rlVaAL

Locally Recurrent Rectal Cancer

No abstract available

https://ift.tt/2rlSu6q

Functional Outcomes After Rectal Resection for Deep Infiltrating Pelvic Endometriosis: Long-term Results

BACKGROUND: Curative management of deep infiltrating endometriosis requires complete removal of all endometriotic implants. Surgical approach to rectal involvement has become a topic of debate given potential postoperative bowel dysfunction and complications. OBJECTIVE: This study aims to assess long-term postoperative evacuation and incontinence outcomes after laparoscopic segmental rectal resection for deep infiltrating endometriosis involving the rectal wall. DESIGN: This is a retrospective study of prospectively collected data. SETTINGS: This single-center study was conducted at the University Hospital of Bern, Switzerland. PATIENTS: Patients with deep infiltrating endometriosis involving the rectum undergoing rectal resection from June 2002 to May 2011 with at least 24 months follow-up were included. MAIN OUTCOME MEASURES: Aside from endometriosis-related symptoms, detailed symptoms on evacuation (points: 0 (best) to 21 (worst)) and incontinence (0–24) were evaluated by using a standardized questionnaire before and at least 24 months after surgery. RESULTS: Of 66 women who underwent rectal resection, 51 were available for analyses with a median follow-up period of 86 months (range: 26–168). Forty-eight patients (94%) underwent laparoscopic resection (4% converted, 2% primary open), with end-to-end anastomosis in 41 patients (82%). Two patients (4%) had an anastomotic insufficiency; 1 case was complicated by rectovaginal fistula. Dysmenorrhea, nonmenstrual pain, and dyspareunia substantially improved (p

https://ift.tt/2KzkNqG

Expert Commentary on Locally Recurrent Rectal Cancer

No abstract available

https://ift.tt/2rlSraK

Endoscopic Pilonidal Sinus: How Far Have We Come?

No abstract available

https://ift.tt/2HPceKP

The Rectal Cancer Female Sexuality Score: Development and Validation of a Scoring System for Female Sexual Function After Rectal Cancer Surgery

BACKGROUND: Sexual dysfunction and impaired quality of life is a potential side effect to rectal cancer treatment. OBJECTIVE: The objective of this study was to develop and validate a simple scoring system intended to evaluate sexual function in women treated for rectal cancer. DESIGN: This is a population-based cross-sectional study. SETTINGS: Female patients diagnosed with rectal cancer between 2001 and 2014 were identified by using the Danish Colorectal Cancer Group's database. Participants filled in the validated Sexual Function Vaginal Changes questionnaire. Women declared to be sexually active at follow-up were randomly assigned to 2 groups: one for development and one for validation. Logistic regression analyses identified items for the score, and multivariate analysis established a weighted-score value allocated to each item, adding up to the total score. The validity of the score was tested in the validation group. PATIENTS: Female patients with rectal cancer above the age of 18 who underwent abdominoperineal resection, Hartmann procedure, or total/partial mesorectal excision were selected. MAIN OUTCOME MEASURES: The primary outcome measured was the quality of life that was negatively affected because of sexual problems. RESULTS: A total of 466 sexually active women responded. The score includes 7 items with a range of 0 to 29 points. Score ≥9 indicates sexual dysfunction. The score has a sensitivity/specificity of 76%/75% detecting patients bothered by sexual dysfunction with a negative impact on quality of life. LIMITATIONS: This study was limited by the large amount of nonresponders. CONCLUSIONS: Living up to our demands for a short and easy-to-use validated tool, we have developed the Rectal Cancer Female Sexuality score. It captures, with high sensitivity, the essential problems of female sexuality seen from the perspective of a surviving rectal cancer patient. See Video Abstract at https://ift.tt/2KDnreX.

https://ift.tt/2rmur7l

MRI Linac and How It May Potentially Lead to More Complete Response in Rectal Cancer

No abstract available

https://ift.tt/2rjXHLK

Pouch Volvulus in Patients Having Undergone Restorative Proctocolectomy for Ulcerative Colitis: A Case Series

BACKGROUND: Restorative proctocolectomy with IPAA improves quality of life in patients with medically refractory ulcerative colitis. Although bowel obstruction is common, pouch volvulus is rare and described only in case reports. Diagnosis can be challenging, resulting in delayed care and heightened morbidity. OBJECTIVE: The purpose of this study was to delineate the symptoms and successful management strategies used in patients with IPAA volvulus that result in pouch salvage. DESIGN: This study was a case series. SETTINGS: The study was conducted at a tertiary referral center for ulcerative colitis in Milwaukee, Wisconsin. PATIENTS: Patients included those with volvulus of the IPAA. MAIN OUTCOME MEASURES: Over the study period (2010–2015), 6 patients were diagnosed with IPAA volvulus. The primary outcomes were symptom manifestation, diagnostic practices, and treatment of pouch volvulus. RESULTS: Six patients with ulcerative colitis were identified with pouch volvulus. The majority (n = 4) underwent a laparoscopic pouch creation and had early symptom manifestation after surgery. Complications preceding volvulus included pouch ulceration (n = 5) and pouchitis (n = 4). The most common presenting symptoms of volvulus were abdominal pain (n = 4) and obstipation (n = 4). Multiple imaging modalities were used, but volvulus was most frequently identified by CT scan. Management was primarily operative (n = 5), composed of excision of the pouch (n = 3), pouch-pexy (n = 1), and detorsion with defect closure (n = 1). Both operative and nonoperative treatment with endoscopic detorsion resulted in low morbidity and improved patient symptoms. LIMITATIONS: This single-institution study is limited by its retrospective design and small number of patients. CONCLUSIONS: IPAA volvulus is a rare and challenging cause of bowel obstruction in ulcerative colitis. Heralding signs and symptoms, such as pouch ulceration and acute obstipation, should initiate a workup for a twisting pouch. Diagnosis, which is multimodal, must occur early to avert necrosis and allow for preservation of a well-functioning pouch. See Video Abstract at https://ift.tt/2KBVR1G.

https://ift.tt/2rlSfZ4

Antegrade Enema After Total Mesorectal Excision for Rectal Cancer: The Last Chance to Avoid Definitive Colostomy for Refractory Low Anterior Resection Syndrome and Fecal Incontinence

BACKGROUND: Total mesorectal excision and preoperative radiotherapy in mid and low rectal cancer allow us to achieve very good oncological results. However, major and refractory low anterior resection syndrome and fecal incontinence alter the quality of life of patients with a long expected life span. OBJECTIVE: We assessed the functional results of patients treated by antegrade enema for refractory low anterior resection syndrome and fecal incontinence after total mesorectal excision. DESIGN: This is a prospective monocentric study from 2012 to 2016. PATIENTS: Patients who underwent percutaneous endoscopic cecostomy for refractory low anterior resection syndrome and fecal incontinence after total mesorectal excision were prospectively analyzed. MAIN OUTCOME MEASURES: We assessed the morbidity of the procedure and compared low anterior resection syndrome score, Wexner score, and Gastrointestinal Quality of Life Index before and after the use of antegrade enema. RESULTS: Of 25 patients treated by antegrade enema over the study period, 6 (24%) had a low anterior resection, 18 (72%) had a coloanal anastomosis, and 1 (4%) had a perineal colostomy. Postoperatively, the rate of local abscess was 8%, all treated by antibiotics. Low anterior resection syndrome score (33 vs 4, p

https://ift.tt/2KBWlow

Characteristics and Prognostic Factors of Bone Metastasis in Patients With Colorectal Cancer

BACKGROUND: Because bone metastasis from colorectal cancer is rare, there are little available data regarding such cases. OBJECTIVE: The study aim was to identify the prognostic factors and characteristics associated with survival in colorectal cancer patients with bone metastasis. DESIGN: This was a retrospective study from a prospectively collected database. SETTINGS: The study took place in a multidisciplinary, high-volume tertiary cancer center in Japan. PATIENTS: Examined were records from 104 consecutive patients treated between 2004 and 2015 for bone metastasis from colorectal cancer. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival. RESULTS: The spine was the most common site of bone metastasis from colorectal cancer. Right colon cancer correlated significantly with long bone metastasis (p = 0.046), whereas left colon cancer correlated significantly with spinal bone metastasis (p = 0.034). Liver metastasis was also significantly correlated with spinal bone metastasis (p = 0.036). The median interval between the primary therapy for colorectal cancer and the metachronous diagnosis of bone metastasis was 20.0 months (quartile 1 to quartile 3, 9.0–46.5 mo). The median survival time from diagnosis of bone metastasis from colorectal cancer was 5.0 months (95% CI, 4.0–9.0 mo), and the 1-year survival rate was 30.0% (95% CI, 21.1%–39.4%). Multivariate analysis revealed that ≥2 extra-bone metastatic organs, hypercalcemia, and pathologic fractures were independent poor prognostic factors (p

https://ift.tt/2rlKrXj

Randomized Controlled Trial of Extended Perioperative Counseling in Enhanced Recovery After Colorectal Surgery

BACKGROUND: Enhanced recovery after surgery programs reduce the length of hospital stay in patients who undergo elective colorectal resection, but the reasons for this reduction are not well understood. OBJECTIVE: The aim of this randomized controlled trial was to assess the impact of extended perioperative counseling in treatment groups that were otherwise the same with respect to enhanced recovery after surgery criteria. DESIGN: Patients eligible for open or laparoscopic colorectal resection were randomly assigned to extended counseling (repeated information and guidance by a dedicated nurse) or standard counseling. SETTINGS: This study was conducted at a single institution. PATIENTS: Patients (n = 164) were randomly assigned to enhanced recovery after surgery plus extended counseling (n = 80) or enhanced recovery after surgery with standard counseling (n = 84). MAIN OUTCOME MEASURES: The primary end point was the total length of hospital stay. Discharge criteria were defined. Secondary end points were postoperative complications, postoperative length of hospital stay, readmission rate, and mortality. RESULTS: Total hospital stay was significantly shorter among patients randomly assigned to enhanced recovery after surgery plus extended counseling (median 5 (range 2–29) days vs 7 (range 2–39) days, p

https://ift.tt/2HOCqFb

Characteristics of Adrenal Masses in Familial Adenomatous Polyposis

BACKGROUND: Adrenal masses are a known extraintestinal manifestation of familial adenomatous polyposis. However, the literature on this association is largely confined to case reports. OBJECTIVE: This study aimed to determine the characteristics of adrenal masses in familial adenomatous polyposis and their clinical significance, as well as to estimate their prevalence. Mutational analysis was conducted to determine if any potential genotype-phenotype correlations exist. DESIGN: This is a retrospective cohort study. SETTING: Analysis included all patients meeting the criteria of classic familial adenomatous polyposis who were registered with the Familial Gastrointestinal Cancer Registry, a national Canadian database. PATIENTS: Appropriate imaging or autopsy reports were available in 311 registry patients. Patients with adrenal metastases were excluded. OUTCOME MEASURES: Data collection included demographic data, mutation genotype, adrenal mass characteristics, surgical interventions and mortality. RESULTS: The prevalence of adrenal masses was 16% (n = 48/311). The median age at diagnosis of adrenal mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range, 1.4–3.0) with a median maximal diameter of 2.5 cm (interquartile range, 1.7–4.1) with median imaging follow-up of 48 months. The majority of adrenal masses were benign (97%, n = 61/63). Surgery was performed on 7 patients because of concerns for size, malignancy, or hormonal secretion. One adrenal-related death was due to an adrenocortical carcinoma. Mutation analysis did not identify any specific genotype-phenotype correlations. LIMITATIONS: There were incomplete or insufficient endocrinology data available in the registry to allow for the analysis of hormone secretion patterns. CONCLUSIONS: Adrenal masses are approximately twice as prevalent in the familial adenomatous polyposis population as in previous studies of the general population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at increased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or surveillance strategy with imaging screening is likely unwarranted. See Video Abstract at https://ift.tt/2HQOvtu.

https://ift.tt/2rkMgUk

Using Endoscopic Submucosal Dissection as a Routine Component of the Standard Treatment Strategy for Large and Complex Colorectal Lesions in a Western Tertiary Referral Unit

BACKGROUND: Colorectal endoscopic submucosal dissection results in high rates of en bloc resection, few recurrences, and accurate diagnosis, and it is useful in lesions with significant fibrosis. However, endoscopic submucosal dissection has not been widely adopted by Western endoscopists and the published experience from Western centers is very limited. OBJECTIVES: This study aims to report the outcomes from a UK tertiary center using colorectal endoscopic submucosal dissection as part of a standard lesion specific treatment approach. DESIGN: This was a retrospective study. SETTING: The study was conducted in a tertiary referral unit for interventional endoscopy in the United Kingdom. PATIENTS: A total of 116 colorectal lesions were resected using endoscopic submucosal dissection or hybrid endoscopic submucosal dissection in 107 patients. MAIN OUTCOME MEASURES: Outcomes included complications, recurrence, requirement for surgery, en bloc and R0 resection. RESULTS: One hundred sixteen lesions (mean size 58.8mm) were resected using endoscopic submucosal dissection (n = 58) and hybrid endoscopic submucosal dissection (n = 58). Eighty-two (70.7%) had failed attempts at resection (n = 58) or extensive sampling before referral. Twelve contained invasive adenocarcinoma; endoscopic resection was curative in 6. Only 2 of 6 patients with noncurative endoscopic resection agreed to surgery, and none had lymph node metastases. Six of 7 perforations were successfully treated with endoscopic clips. Where endoscopic submucosal dissection was used alone, en bloc resection was achieved in 93% and R0 resection was achieved in 91%. Two patients experienced recurrence; both were managed with endoscopic resection. LIMITATIONS: This was a retrospective study. Procedures were planned as endoscopic submucosal dissection, but some may have been converted to hybrid endoscopic submucosal dissection and not recorded. CONCLUSION: Colorectal endoscopic submucosal dissection can be used in a Western center as part of a standard lesion-specific approach to deliver effective organ-conserving treatment to patients with large challenging lesions. Lesion assessment in Western practice should be improved to reduce the incidence of prior heavy manipulation and to guide appropriate referral. See Video Abstract at https://ift.tt/2HRSqGJ.

https://ift.tt/2rmun7B