Colon and Rectal Surgery Regional Society Meetings

No abstract available

https://ift.tt/2PvE9y1

Biomechanical Comparison of Three Different Intramedullary Nails for Fixation of Unstable Basicervical Intertrochanteric Fractures of the Proximal Femur: Experimental Studies

Objectives. This biomechanical study was conducted to compare fixation stability of the proximal fragments and their mechanical characteristics in proximal femur models of unstable basicervical IT fractures fixed by cephalomedullary nailing using 3 different types of the femoral head fixation. Methods. A total of 36 composite femurs corresponding to osteoporotic human bone were used. These specimens were fixed with Gamma 3 (hip screw type; group 1) in 12, Gamma 3 U-blade (screw-blade hybrid type; group 2) in 12, and proximal femoral nail antirotation-II (helical blade type; group 3) in 12, respectively, and an unstable basicervical IT fracture was created by an engraving machine. After preloading and cyclic loading, the migration of the proximal fragment according to 3 axes was assessed by the stereophotogrammetric method and the migration of screw or blade tip within the femoral head was measured radiographically. Next, the vertical load was continued at a speed of 10 mm/min until the construct failure occurred. Finite element analysis was additionally performed to measure the stress and compressive strain just above the tip of screw or blade within the femoral head. Results. The rotational change of the proximal fragment according to the axis of screw or blade was much greater in group 1 than in groups 2 and 3 (p=0.016 and p=0.007, respectively). Varus collapse was greater in group 3 than in group 2 (p=0.045). Cranial and axial migration of screw or blade within the femoral head were significantly greater in group 3 than in both group 1 (p=0.001 and p=0.002, respectively) and group 2 (p=0.002 and p=0.016, respectively). On finite element analysis, group 3 showed the highest peak von-Mises stress value (13.3 MPa) and compressive strain (3.2%) just above the tip of the blade within the femoral head. Meanwhile, groups 1 and 2 showed similar results on two values. Conclusions. Screw-blade hybrid type and blade type would be more effective in minimizing rotation instability of the proximal fragment in unstable basicervical IT fractures. However, varus collapse of the proximal fragment and cranial and axial migration within the femoral head were greater with blade type than screw-blade hybrid type.

https://ift.tt/2zMlQ2P

Radioprotective Properties of Pterocarpus santalinus Chloroform Extract in Murine Splenic Lymphocytes and Possible Mechanism

Cancer Biotherapy and Radiopharmaceuticals, Volume 33, Issue 10, Page 427-437, December 2018.


https://ift.tt/2zT8GRv

Progression of Central Nervous System Metastases in Advanced Nonsmall Cell Lung Cancer Patients Effectively Treated with First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor

Cancer Biotherapy and Radiopharmaceuticals, Volume 33, Issue 10, Page 421-426, December 2018.


https://ift.tt/2zSODCF

The impact of the tumor shrinkage by initial EGFR inhibitors according to the detection of EGFR -T790M mutation in patients with non-small cell lung cancer harboring EGFR mutations

Abstract

Background

The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples.

Methods

Seventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles.

Results

Thirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p < 0.001). Moreover, there was a significant difference in the maximal tumor shrinkage rate relative to baseline in T790M-positive tumors compared with T790M-negative tumors (42.7% versus 24.0%, p = 0.001). Multivariate analysis demonstrated that the maximum tumor shrinkage rate was a significant predictive factor for the detection of the T790M mutation (p = 0.023, odds ratio 1.03, 95% confidence interval 1.00–1.05).

Conclusions

Our retrospective observations suggested that the maximum tumor shrinkage rate with initial EGFR-TKI treatment might be one of the promising predictive biomarkers for emerging refractory tumors with the EGFR-T790M mutation.

https://ift.tt/2SEpl2o

Bioinformatics Analysis Reveals Potential Candidate Genes for Different Glioma Subtypes (Astrocytoma, Ependymoma, and Oligodendroglioma)

Cancer Biotherapy and Radiopharmaceuticals, Volume 33, Issue 10, Page 478-490, December 2018.


https://ift.tt/2PwzVWW

SKA1 overexpression is associated with poor prognosis in hepatocellular carcinoma

Abstract

Background

SKA1, an important mitosis protein, has been indicated in the initiation and progression of several malignancies. However, its clinical significance in hepatocellular carcinoma (HCC) remain to be elucidated.

Methods

mRNA expression of SKA1 was examined in 126 HCC and paired non-neoplastic tissues using real-time PCR and validated in The Cancer Genome Atlas (TCGA) database. SKA1 protein expression was detected using immunohistochemistry in the 126 HCC tissues and its associations with clinicopathological parameters and prognosis were analyzed. Hierarchical cluster analysis and gene set enrichment analysis (GSEA) were performed in selected Gene Expression Omnibus data sets.

Results

SKA1 mRNA expression was significantly elevated in HCC tissues from both local hospital and TCGA database. Immunohistochemistry revealed that increased SKA1 expression was present in 65 of the 126 cases and was significantly associated with higher serum alpha-fetoprotein concentration, larger tumor size and higher TNM stage. Patients with positive SKA1 expression showed significantly worse overall and relapse-free survival. Multivariate Cox regression analysis revealed that SKA1 was an independent predictor of patient prognosis. Gene expression profiling analysis of public data showed that high-SKA1 expression HCC tissues had similar gene expression profiles with fetal liver tissues. Moreover, GSEA showed that genes up-regulated in high SKA1 HCC subgroup were significantly enriched in cell cycle pathway, while genes down-regulated were significantly enriched in apoptosis pathway.

Conclusions

Our findings indicate that the oncofetal gene SKA1 might be involved in the progression of the HCC and could serve as a prognostic marker for HCC.

https://ift.tt/2QEi5Gr

Letter to the editors regarding the paper: Prognostic factors in HIV-positive patients with non-Hodgkin lymphoma: a Peruvian experience

Abstract

Non-Hodgkin Lymphoma (NHL) is a neoplasm associated with a group of malignancies called AIDs-Defining Malignancies (ADMs) in Human-Immunodeficiency Virus (HIV) -patients. Similar to the case of NHL in Latin America, particularly in Peru, the amount of research done on others ADMs is limited, especially in the case of Kaposi's Sarcoma (KS). Prior investigations have talked about the great potential risk that represents this illness in latin american population, but topics as prognosis factors are yet to be well defined. In this letter, we address the importance of investigation in this area and include previously reported data that may enlighten the current national standpoint.

https://ift.tt/2RNeDq4

Targeted radiotherapy of pigmented melanoma with 131 I-5-IPN

Abstract

Purpose

There has been no satisfactory treatment for advanced melanoma until now. Targeted radionuclide therapy (TRNT) may be a promising option for this heretofore lethal disease. Our goal in this study was to synthesize ¹³¹I-N-(2-(diethylamino)ethyl)-5-(iodo-131I)picolinamide (¹³¹I-5-IPN) and evaluate its therapeutic ability and toxicity as a radioiodinated melanin-targeting therapeutic agent.

Methods

The trimethylstannyl precursor was synthesized and labeled with ¹³¹I to obtain ¹³¹I-5-IPN. The pharmacokinetics of ¹³¹I-5-IPN was evaluated through SPECT imaging, and its biodistribution was assessed in B16F10 tumor models and in A375 human-to-mouse xenografts. For TRNT, B16F10 melanoma-bearing mice were randomly allocated to receive one of five treatments (n = 10 per group): group A (the control group) received 0.1 mL saline; group B was treated with an equimolar dose of unlabeled precursor; group C received 18.5 MBq of [¹³¹I]NaI; group D and E received one or two dose of 18.5 MBq ¹³¹I-5-IPN, respectively. TRNT efficacy was evaluated through tumor volume measurement and biology study. The toxic effects of ¹³¹I-5-IPN on vital organs were assessed with laboratory tests and histopathological examination. The radiation absorbed dose to vital organs was estimated based on biodistribution data.

Results

¹³¹I-5-IPN was successfully prepared with a good radiochemistry yield (55% ± 5%, n = 5), and it exhibited a high uptake ratio in melanin-positive B16F10 cells which indicating high specificity. SPECT imaging and biodistribution of ¹³¹I-5-IPN showed lasting high tumor uptake in pigmented B16F10 models for 72 h. TRNT with ¹³¹I-5-IPN led to a significant anti-tumor effect and Groups D and E displayed an extended median survival compared to groups A, B, and C. The highest absorbed dose to a vital organ was 0.25 mSv/MBq to the liver; no obvious injury to the liver or kidneys was observed during treatment. ¹³¹I-5-IPN treatment was associated with reduction of expression of proliferating cell nuclear antigen (PCNA) and Ki67 and cell cycle blockage in G2/M phase in tumor tissues. Decreased vascular endothelial growth factor and CD31 expression, implying reduced tumor growth, was noted after TRNT.

Conclusion

We successfully synthesized ¹³¹I-5-IPN, which presents long-time retention in melanotic melanoma. TRNT with ¹³¹I-5-IPN has the potential to be a safe and effective strategy for management of pigmented melanoma.

https://ift.tt/2QpIqZd

Intercultural Competence of Western Teachers for Nepalese Rescuers

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2SL162D

EQ-5D-5L Valuation for the Malaysian Population

Abstract

Objectives

The aim of this study was to develop an EQ-5D-5L value set reflecting the health preferences of the Malaysian adult population.

Methods

Respondents were sampled with quotas for urbanicity, gender, age, and ethnicity to ensure representativeness of the Malaysian population. The study was conducted using a standardized protocol involving the EuroQol Valuation Technology (EQ-VT) computer-assisted interview system. Respondents were administered ten composite time trade-off (C-TTO) tasks and seven discrete choice experiment (DCE) tasks. Both linear main effects and constrained non-linear regression models of C-TTO-only data and hybrid models combining C-TTO and DCE data were explored to determine an efficient and informative model for value set prediction.

Results

Data from 1125 respondents representative of the Malaysian population were included in the analysis. Logical consistency was present in all models tested. Using cross-validation, eight-parameter models for C-TTO only and C-TTO + DCE hybrid data displayed greater out-of-sample predictive accuracy than their 20-parameter, main-effect counterparts. The hybrid eight-parameter model was chosen to represent the Malaysian value set, as it displayed greater out-of-sample predictive accuracy over C-TTO data than the C-TTO-only model, and produced more precise estimates. The estimated value set ranged from − 0.442 to 1.

Conclusions

The constrained eight-parameter hybrid model demonstrated the best potential in representing the Malaysian value set. The presence of the Malaysian EQ-5D-5L value set will facilitate its application in research and health technology assessment activities.

https://ift.tt/2rxiKLC

Drak/STK17A drives neoplastic glial proliferation through modulation of MRLC signaling

Glioblastoma (GBM) and lower grade gliomas (LGG) are the most common primary malignant brain tumors and are resistant to current therapies. Genomic analyses reveal that signature genetic lesions in GBM and LGG include copy gain and amplification of chromosome 7, amplification, mutation, and overexpression of receptor tyrosine kinases (RTK) such as EGFR, and activating mutations in components of the PI-3 kinase (PI3K) pathway. In Drosophila melanogaster, constitutive co-activation of RTK and PI3K signaling in glial progenitor cells recapitulates key features of human gliomas. Here we use this Drosophila glioma model to identify death-associated protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A, as a downstream effector of EGFR and PI3K signaling pathways. Drak was necessary for glial neoplasia, but not for normal glial proliferation and development, and Drak cooperated with EGFR to promote glial cell transformation. Drak phosphorylated Sqh, the Drosophila ortholog of MRLC (non-muscle myosin regulatory light chain), which was necessary for transformation. Moreover, Anillin, which is a binding partner of phosphorylated Sqh, was upregulated in a Drak-dependent manner in mitotic cells and co-localized with phosphorylated Sqh in neoplastic cells undergoing mitosis and cytokinesis, consistent with their known roles in non-muscle myosin-dependent cytokinesis. These functional relationships were conserved in human GBM. Our results indicate that Drak/STK17A, its substrate Sqh/MRLC and the effector Anillin/ANLN regulate mitosis and cytokinesis in gliomas. This pathway may provide a new therapeutic target for gliomas.

https://ift.tt/2PwnfiT

Hepatic endothelial Notch activation protects against liver metastasis by regulating endothelial-tumor cell adhesion independent of angiocrine signaling

The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cretg/wt mice were crossed to Rosa26N1ICD IRES-GFP to enhance Notch signaling in HEC (NICDOE-HEC). In NICDOE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of WlsHEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICDOE-HEC revealed a special form of sinusoidal capillarization with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo. Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wildtype mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type- and context-specific manner.

https://ift.tt/2zRkeF2

Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer

Castration resistant prostate cancer is characterized by loss of the androgen inactivation enzyme HSD17B2, emphasizing the importance of intratumoral androgens in tumor progression. Inactive isoforms generated by alternative splicing destabilize the wild-type enzyme, adding steroidogenesis to other prostate cancer drivers that undergo oncogenic splicing, highlighting aberrant splicing as a therapeutic target.

https://ift.tt/2C1wR1y

Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

The defect in homologous recombination (HR) found in BRCA1-associated cancers can be therapeutically exploited by treatment with DNA-damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here we identify radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors that acquire drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy.

https://ift.tt/2Pt6mpf

Virus, vessel, victory: a novel approach to tumor killing

Ovarian cancer is intimately dependent on aberrant tumor vasculature. A unique therapeutic approach combining a systemic oncolytic virus with a novel vascular-normalizing agent in ovarian cancer demonstrates the potential to enhance anti-tumor efficacy through improved delivery of the virus and enhanced infiltration of immune cells into the tumors.

https://ift.tt/2L795UO

Role of the Hydrophobic Bridge in the Carbapenemase Activity of Class D {beta}-Lactamases [Mechanisms of Resistance]

Class D carbapenemases are enzymes of utmost clinical importance due to their ability to confer resistance to the last resort carbapenem antibiotics. We investigated the role of the conserved hydrophobic bridge in the carbapenemase activity of OXA-23, the major carbapenemase of the important pathogen, Acinetobacter baumannii. We show that substitution of the bridge residue Phe110 affects resistance to meropenem and doripenem and has little effect on MICs of imipenem. The opposite effect was observed upon substitution of the other bridge residue, Met221. Complete disruption of the bridge by the F110A/M221A substitution resulted in a significant loss of affinity for doripenem and meropenem, and to a lesser extent, for imipenem, which is reflected in the reduced MICs of these antibiotics. In the wild-type OXA-23, the pyrrolidine ring of the meropenem tail forms a hydrophobic interaction with Phe110 of the bridge. Similar interactions would ensue with ring-containing doripenem but not with imipenem, which lacks this ring. Our structural studies showed that this interaction with the meropenem tail is missing in the F110A/M221A mutant. These data explain why disruption of the interaction between the enzyme and the carbapenem substrate impacts the affinity and MICs of meropenem and doripenem to a larger degree than those of imipenem. Our structures also show that the bridge directs the acylated carbapenem into a specific tautomeric conformation. However, it is not this conformation, but rather the stabilizing interaction between the tail of the antibiotic and the hydrophobic bridge that contributes to the carbapenemase activity of class D β-lactamases.

https://ift.tt/2C24UqD

The direct and indirect inhibition effects of resveratrol against Toxoplasma gondii tachyzoites in vitro [Experimental Therapeutics]

Toxoplasma gondii is one of the most widespread obligatory parasitic protozoa which infect nearly all the warm-blooded animals, leading to toxoplasmosis. Current administration of the therapeutic drugs like the combination of pyrimethamine and sulfadiazine shows high rates of toxic side effects and encounters drug resistance in some cases. Resveratrol is a natural plant extracts with multiple functions, such as anti-bacterial, anti-cancer and anti-parasite activities. In this study, we evaluated the inhibitory effects of resveratrol upon the tachyzoites of Toxoplasma gondii RH strain extracellularly and intracellularly. We demonstrated that resveratrol possessed a direct anti-toxoplasma activity by reducing the population of extracellularly grown tachyzoites, probably through disturbing the redox homeostasis of the parasites. Moreover, resveratrol was also able to release the burden of cellular stress, promote the apoptosis and maintain the autophagic status of macrophages that were turned out to be regulated by intracellular parasites, thereby functioning indirectly in eliminating T. gondii. In conclusion, resveratrol has both direct and indirect anti-toxoplasma effects against the RH tachyzoites and may possess a potential to be further evaluated and employed in toxoplasmosis treatment.

https://ift.tt/2C3roas

Modeling prevention of malaria and selection of drug resistance with different dosing schedules of dihydroartemisinin-piperaquine preventive therapy during pregnancy in Uganda [Clinical Therapeutics]

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and probability of genotypes of interest using nonlinear mixed effects modeling. Increasing piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant compared to wild type infections (pfmdr1 N86: 9.6 ng/mL, 86Y: 19.6 ng/mL; pfcrt K76: 6.5 ng/mL, 76T: 19.6 ng/mL). Comparing monthly, weekly, and daily dosing, daily low dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly: 607, DHA-PQ monthly: 198, DHA-PQ daily: 1; for pfcrt 76T: SP monthly: 1564, DHA-PQ monthly: 283, DHA-PQ daily: 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with pfmdr1/pfcrt mutant compared to wild type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP.

https://ift.tt/2L7yrCd

Real-life experience with ceftolozane/tazobactam in patients with hematologic malignancy and Pseudomonas aeruginosa infection: a case-control study [Clinical Therapeutics]

Background:

We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam.

Materials/methods:

We performed a single-center case-control study including all patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) and compared them with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy.

Results:

Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 y vs 57.6 y, p=0.012) and less frequently had bacteremia (52.6% vs 86.8%, p=0.008). They also had a worse MASCC score (10.2 vs 16.1, p=0.0001), more hospital-acquired infections (78.9% vs 47.4%, p=0.013), and more XDR P. aeruginosa (47.4% vs 21.1%, p=0.015).

Cases received a median of 14 days (7-18) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16; 84.2%) because of resistance (9; 47.4%), failure (4; 21.1%), and toxicity (3; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue infection (5.3%). No toxicity was attributed to ceftolozane/tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis.

There were no significant differences in clinical cure at day 14 (89.5% vs 71.1%, p=0.183) or recurrence (15.8% vs 10.5%, p=0.675). Thirty-day mortality was lower among cases (5.3% vs 28.9%, p=0.045).

Conclusions:

Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains.

https://ift.tt/2C4ogLF

Optimal Piperacillin/Tazobactam Dosing Strategies against ESBL-producing Enterobacteriaceae [Experimental Therapeutics]

Piperacillin/tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae. However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin/tazobactam to efficacy using a modified pharmacokinetic/pharmacodynamic index. Using a clinical Klebsiella pneumoniae isolate expressing CTX-M-15, piperacillin MICs were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory E_max model. A hollow fiber infection model (HFIM) was used to evaluate the efficacy of escalating tazobactam dosing with a fixed piperacillin exposure. Simulated drug concentrations from the HFIM were incorporated in the E_max model to determine the percentage of free-time above instantaneous MIC (%fT>MICi) associated with each experimental exposure. The target %fT>MICi associated with growth suppression was prospectively validated using a SHV-12-producing isolate of Escherichia coli and 2 other CTX-M-15-producing K. pneumoniae isolates. Based on our reference isolate, piperacillin/tazobactam exposures of %fT>MICi ≥55.1% were associated with growth suppression. Despite underlying differences, these findings were consistent with prospective observations in 3 other clinical isolates. Our modeling approach can be applied relatively easily in the clinical setting and appeared to be robust in predicting the effectiveness of various piperacillin/tazobactam exposures. This modified pharmacokinetic/pharmacodynamic index could be used to characterize response to other β-lactam/β-lactamase inhibitor combinations.

https://ift.tt/2Lbs1lp

The Fungal Cyp51 Specific Inhibitor VT-1598 Demonstrates In vitro and In vivo Activity against Candida auris [Experimental Therapeutics]

Candida auris is an emerging pathogen associated with significant mortality and often multi-drug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris. Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 hours post-inoculation with vehicle control, oral VT-1598 (5, 15, and 50 mg/kg once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm, and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 μg/mL and MICs ranging from 0.03 to 8 μg/mL. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival 15 and >21 days for VT-1598 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (1.88 to 3.61 log₁₀ CFU/g reduction) compared to control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.

https://ift.tt/2C24ZKX

Endonuclease Activity Inhibition of the NS1 Protein of Parvovirus B19 as a Novel Target for Antiviral Drug Development [Antiviral Agents]

Human parvovirus B19 (B19V), a member of the genus Erythroparvovirus of the family Parvoviridae, is a small non-enveloped virus that has a single-stranded DNA (ssDNA) genome of 5.6 kilobases with two inverted terminal repeats (ITRs). B19V infection often results in severe hematological disorders and fetal death in humans. B19V replication follows a model of rolling hairpin-dependent DNA replication, in which the large non-structural protein NS1 introduces a site-specific single strand nick in the viral DNA replication origins, which locate at the ITRs. NS1 executes endonuclease activity through the N-terminal origin binding domain. Nicking of the viral replication origin is a pivotal step in rolling hairpin-dependent viral DNA replication. Here, we developed a fluorophore-based in vitro nicking assay of the replication origin using the origin binding domain of the NS1 and compared it with the radioactive in vitro nicking assay. We used both assays to screen a set of small molecule compounds (96) that have potential anti-nuclease activity. We found that the fluorophore-based in vitro nicking assay demonstrate sensitivity and specificity values as high as the radioactive assay. Among the 96 compounds, we identified 8 which have an inhibition of >80% at 10 µM in both the fluorophore-based and radioactive in vitro nicking assays. We further tested 3 compounds that have flavonoid-like structure for IC₅₀in vitro that falls in the range of 1-3 µM. Importantly, they also exhibited inhibition of B19V DNA replication in UT7/Epo-S1 cells and ex vivo expanded human erythroid progenitor cells.

https://ift.tt/2LdASTO

Spreading patterns of NDM-producing Enterobacteriaceae in clinical and environmental settings in Yangon, Myanmar [Epidemiology and Surveillance]

The spread of carbapenemase-producing Enterobacteriaceae (CPE) has become a global concern, contributing to widespread carbapenem resistance. However, the specific dissemination patterns of carbapenemase genes have not been intensively investigated in developing countries, including Myanmar, where NDM-type carbapenemases are spreading in clinical settings. In the present study, we phenotypically and genetically characterized 91 CPE isolates obtained from clinical (n = 77) and environmental (n = 14) samples in Yangon, Myanmar. We determined the dissemination of plasmids harboring genes encoding NDM-1 and its variants using whole-genome sequencing and plasmid analysis. IncFII plasmids harboring bla_NDM-5 and IncX3 plasmids harboring bla_NDM-4 or bla_NDM-7 were the most prevalent plasmid types identified among the isolates. The IncFII plasmids were predominantly carried by clinical isolates of Escherichia coli, and their clonal expansion was observed within the same ward of a hospital. By contrast, the IncX3 plasmids were found in phylogenetically divergent isolates from clinical and environmental samples classified into nine species, suggesting the widespread dissemination of plasmids via horizontal transfer. Half of the environmental isolates were found to possess IncX3 plasmids, and this type of plasmid was confirmed to transfer more effectively to recipient organisms at a relatively low temperature (25°C) compared to the IncFII plasmid. Moreover, various other plasmid types were identified harboring bla_NDM-1, including IncFIB, IncFII, IncL/M, and IncA/C₂, among clinical isolates of Klebsiella pneumoniae or Enterobacter cloacae complex. Overall, our results highlight three distinct patterns of the dissemination of bla_NDM-harboring plasmids among CPE isolates in Myanmar, contributing to gaining a better understanding of their molecular epidemiology and dissemination in an endemic setting.

https://ift.tt/2L8i347

Diverse vectors and mechanisms spread NDM beta-lactamases among carbapenem resistant Enterobacteriaceae in the Greater Boston area [Epidemiology and Surveillance]

New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM carrying strains of E. coli and E. cloacae complex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3114-bp region containing the bla_NDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed broad capacity for bla_NDM transmission by conjugation, transposition, and complex inter-plasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naïve strains to acquire multi- and extensively-drug resistance profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization, to inform clinical decisions to prevent further spread.

https://ift.tt/2C24Siv

An IncR Plasmid harbored by a hypervirulent, carbapenem resistant Klebsiella pneumoniae strain possesses five tandem repeats of the blaKPC-2::NTEKPC-Id fragment [Mechanisms of Resistance]

Completed sequences of three plasmids from a carbapenem-resistant, hypervirulent Klebsiella pneumoniae isolate, SH9, were obtained. In addition to the a pLVPK-like virulence-conferring plasmid (pVir-CR-HvKP_SH9), the two MDR plasmids (pKPC-CR-HvKP4_SH9 and pCTX-M-CR-HvKP4_SH9) were predicted to originate from a single pKPC-CR-HvKP4-like multi-replicon plasmid through homologous recombination. Interestingly, bla_KPC-2 gene was detectable in five tandem repeats exhibiting the format of a NTE_KPC-Id-like transposon (IS26-Tn3-ISKpn8-bla_KPC-2-ISKpn6-korC-orf-IS26). The data suggested the important role of DNA recombination on mediating active plasmid evolution.

https://ift.tt/2LaGVIu

Successful treatment of a bacteremia due to NDM-1-producing Morganella morganii with Aztreonam and Ceftazidime-avibactam combination in a pediatric patient with hematologic malignancy [Letters]

Worldwide spread of multiresistant bacteria, especially carbapenemase-producing Enterobacteriaceae, can lead to situations for which no antibiotic therapy option is available....

https://ift.tt/2LfXhQt

A Transgenic Flock House Virus Replicon Reveals an RNAi Independent Antiviral Mechanism Acting in Drosophila Follicular Somatic Cells

The small interfering RNA (siRNA) pathway is the main and best studied invertebrate antiviral response. Other poorly characterized protein based antiviral mechanisms also contribute to the control of viral replication in insects. In addition, it remains unclear whether tissue specific factors contribute to RNA and protein-based antiviral immunity mechanisms. In vivo screens to identify such factors are challenging and time consuming. In addition, the scored phenotype is usually limited to survival and/or viral load. Transgenic viral replicons are valuable tools to overcome these limitations and screen for novel antiviral factors. Here we describe transgenic Drosophila melanogaster lines encoding a Flock House Virus-derived replicon (FHVB2eGFP), expressing GFP as a reporter of viral replication. This replicon is efficiently controlled by the siRNA pathway in most somatic tissues, with GFP fluorescence providing a reliable marker for the activity of antiviral RNAi. Interestingly, in follicular somatic cells (FSC) of ovaries, this replicon is still partially repressed in an siRNA independent manner. We did not detect replicon derived Piwi-interacting RNAs in FSCs and identified 31 differentially expressed genes between restrictive and permissive FSCs. Altogether, our results uncovered a yet unidentified RNAi-independent mechanism controlling FHV replication in FSCs of ovaries and validate the FHVB2eGFP replicon as a tool to screen for novel tissue specific antiviral mechanisms.

https://ift.tt/2zOasU0

Comprehensive Transcriptional Profiling of the Gastrointestinal Tract of Ruminants from Birth to Adulthood Reveals Strong Developmental Stage Specific Gene Expression

One of the most significant physiological challenges to neonatal and juvenile ruminants is the development and establishment of the rumen. Using a subset of RNA-Seq data from our high-resolution atlas of gene expression in sheep (Ovis aries) we have provided the first comprehensive characterisation of transcription of the entire gastrointestinal (GI) tract during the transition from pre-ruminant to ruminant. The dataset comprises 164 tissue samples from sheep at four different time points (birth, one week, 8 weeks and adult). Using network cluster analysis we illustrate how the complexity of the GI tract is reflected in tissue- and developmental stage-specific differences in gene expression. The most significant transcriptional differences between neonatal and adult sheep were observed in the rumen complex. Comparative analysis of gene expression in three GI tract tissues from age-matched sheep and goats revealed species-specific differences in genes involved in immunity and metabolism. This study improves our understanding of the transcriptomic mechanisms involved in the transition from pre-ruminant to ruminant by identifying key genes involved in immunity, microbe recognition and metabolism. The results form a basis for future studies linking gene expression with microbial colonisation of the developing GI tract and provide a foundation to improve ruminant efficiency and productivity through identifying potential targets for novel therapeutics and gene editing.

https://ift.tt/2Pwlour

Optimizing Genomic Selection for a Sorghum Breeding Program in Haiti: A Simulation Study

Young breeding programs in developing countries, like the Chibas sorghum breeding program in Haiti, face the challenge of increasing genetic gain with limited resources. Implementing genomic selection (GS) could increase genetic gain, but optimization of GS is needed to account for these programs' unique challenges and advantages. Here, we used simulations to identify conditions under which genomic-assisted recurrent selection (GARS) would be more effective than phenotypic recurrent selection (PRS) in small new breeding programs. We compared genetic gain, cost per unit gain, genetic variance, and prediction accuracy of GARS (two or three cycles per year) versus PRS (one cycle per year) assuming various breeding population sizes and trait genetic architectures. For oligogenic architecture, the maximum relative genetic gain advantage of GARS over PRS was 12-88%, which was observed only during the first few cycles. For the polygenic architecture, GARS provided maximum relative genetic gain advantage of 26­-165%, and was always superior to PRS. Average prediction accuracy declines substantially after several cycles of selection, suggesting the prediction models should be updated regularly. Updating prediction models every year increased the genetic gain by up to 33-39% compared to no-update scenarios. For small populations and oligogenic traits, cost per unit gain was lower in PRS than GARS. However, with larger populations and polygenic traits cost per unit gain was up to 67% lower in GARS than PRS. Collectively, the simulations suggest that GARS could increase the genetic gain in small young breeding programs by accelerating the breeding cycles and enabling evaluation of larger populations.

https://ift.tt/2PqHL4B

GAL4 Drivers Specific for Type Ib and Type Is Motor Neurons in Drosophila

The Drosophila melanogaster larval neuromuscular system is extensively used by researchers to study neuronal cell biology, and Drosophila glutamatergic motor neurons have become a major model system. There are two main Types of glutamatergic motor neurons, Ib and Is, with different structural and physiological properties at synaptic level at the neuromuscular junction. To generate genetic tools to identify and manipulate motor neurons of each Type, we screened for GAL4 driver lines for this purpose. Here we describe GAL4 drivers specific for examples of neurons within each Type, Ib or Is. These drivers showed high expression levels and were expressed in only few motor neurons, making them amenable tools for specific studies of both axonal and synapse biology in identified Type I motor neurons.

https://ift.tt/2zSnSOV

First-Line Ibrutinib Confirmed for CLL [News in Brief]

BTK inhibitor bests chemoimmunotherapy regimens in two phase III trials.

https://ift.tt/2BayaJW

A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer

A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer

A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer, Published online: 11 December 2018; doi:10.1038/s41416-018-0343-z

A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer

https://ift.tt/2RV8Cba

Proton beam therapy in Europe: more centres need more research

Proton beam therapy in Europe: more centres need more research

Proton beam therapy in Europe: more centres need more research, Published online: 11 December 2018; doi:10.1038/s41416-018-0329-x

Proton beam therapy in Europe: more centres need more research

https://ift.tt/2QoACao

Risk Up for Later-Born Siblings of Children With ASD, ADHD

MONDAY, Dec. 10, 2018 -- Later-born siblings of children with autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) have an elevated risk of being diagnosed with the same or the other disorder, according to a study...

https://ift.tt/2zR9MgG

HIT-Related Stress Linked to Burnout Among Physicians

MONDAY, Dec. 10, 2018 -- Stress related to use of health information technology (HIT) is common and predictive of burnout among physicians, according to a study published online Dec. 5 in the Journal of the American Medical Informatics...

https://ift.tt/2zTARzU

Higher Risk for Breast Cancer After Childbirth May Last 20+ Years

MONDAY, Dec. 10, 2018 -- The increased risk for breast cancer that occurs after childbirth can last more than 20 years, according to research published online Dec. 11 in the Annals of Internal Medicine. Hazel B. Nichols, Ph.D., from University of...

https://ift.tt/2Pv9eCb

Veterans Health Administration Hospitals Outperform Non-VHAs

MONDAY, Dec. 10, 2018 -- Veterans Health Administration (VHA) hospitals outperform non-VHA hospitals for 14 of 15 outcome measures in 121 regions, according to a research letter published online Dec. 11 in the Annals of Internal Medicine. William B....

https://ift.tt/2zM1iaH

Tap Water in Neti Pot Linked to Death From Brain-Eating Amoeba

MONDAY, Dec. 10, 2018 -- The use of tap water in a nasal-flushing Neti pot likely led to a Seattle woman's death from a Balamuthia mandrillaris brain infection, doctors write in a case study. It is believed that instead of using sterile water or...

https://ift.tt/2PwDvAD

UT Physicians Sinus Surgeons Use Augmented Reality Technology During Minimally Invasive Sinus Procedures.

"Augmented reality, which uses 3-D mapping and imagery, enhances our understanding of complex anatomy so surgical procedures are more precise,"...

https://ift.tt/2GbhgRn

When It Isn’t Tonsillitis

Repeated bouts of strep throat and suspected tonsillitis led Shelby Boatwright's primary care physician to refer her to William Yao,...

https://ift.tt/2rwRywy

ENT Doctors at UT Physicians Provide Comprehensive ENT Care in Southeast Houston

The Department of Otorhinolaryngology-Head & Neck Surgery at McGovern Medical School at UTHealth now offers comprehensive care in southeast Houston....

https://ift.tt/2ruUvgQ

Cancer mortality and predictions for 2018 in selected Australasian countries and Russia

Abstract

Background

Predicted cancer mortality figures and rates are useful for public health planning.

Materials and methods

We retrieved cancer death certification data for 10 major cancer sites and total cancers from the World Health Organization (WHO) database and population data from WHO and United Nations Population Division databases. We obtained figures for Russia, Israel, Hong Kong, Japan, the Philippines, Korea, and Australia in 1970–2015. We predicted numbers of deaths by age group and age-standardized rates (world population) for 2018 by applying a linear regression to mortality data of each age group over the most recent trend segment identified by a joinpoint regression model.

Results

Russia had the highest predicted total cancer mortality rates, 158.5/100 000 men and 84.1/100 000 women. Men in the Philippines showed the lowest rates for 2018 (84.6/100 000) and Korean males the most favourable predicted fall (21% between 2012 and 2018). Women in Korea had the lowest total cancer predicted rate (52.5/100 000). Between 1993 and 2018, i.e. by applying the 1993 rates to populations in subsequent years, a substantial number of cancer deaths was avoided in Russia (1 000 000 deaths, 821 000 in men and 179 000 in women), Israel (40 000 deaths, 21 000 in men and 19 000 in women), Hong Kong (63 000 deaths, 40 000 in men and 23 000 in women), Japan (651 000 deaths, 473 000 in men and 178 000 in women), Korea (327 000 deaths, 250 000 in men and 77 000 in women), and Australia (181 000 deaths, 125 000 in men and 56 000 in women). No appreciable reduction in cancer deaths was found in the Philippines.

Conclusion

Overall, we predicted falls in cancer mortality. However, these are less marked and later compared with the European Union and United States. Substantial numbers of deaths were avoided in all countries considered except the Philippines. Lung cancer mortality remains exceedingly high in Russian men, despite recent falls.

https://ift.tt/2rxucH3

Multiple Linear Regression Analysis of lncRNA–Disease Association Prediction Based on Clinical Prognosis Data

Long noncoding RNAs (lncRNAs) have an important role in various life processes of the body, especially cancer. The analysis of disease prognosis is ignored in current prediction on lncRNA–disease associations. In this study, a multiple linear regression model was constructed for lncRNA–disease association prediction based on clinical prognosis data (MlrLDAcp), which integrated the cancer data of clinical prognosis and the expression quantity of lncRNA transcript. MlrLDAcp could realize not only cancer survival prediction but also lncRNA–disease association prediction. Ultimately, 60 lncRNAs most closely related to prostate cancer survival were selected from 481 alternative lncRNAs. Then, the multiple linear regression relationship between the prognosis survival of 176 patients with prostate cancer and 60 lncRNAs was also given. Compared with previous studies, MlrLDAcp had a predominant survival predictive ability and could effectively predict lncRNA–disease associations. MlrLDAcp had an area under the curve (AUC) value of 0.875 for survival prediction and an AUC value of 0.872 for lncRNA–disease association prediction. It could be an effective biological method for biomedical research.

https://ift.tt/2zQKPBY

HMGB1+ microparticles present in urine are hallmarks of nephritis in patients with systemic lupus erythematosus

Non‐classical monocytes infiltrate the kidney parenchyma and participate in tissue damage in patients with lupus nephritis (LN). Circulating microparticles (MPs) seem to play critical roles in the activation of monocytes in systemic lupus erythematosus (SLE) patients. This study aims to characterize the phenotypes of MPs and monocyte subsets in LN patients and to determine their potential to discriminate between SLE patients with and without LN. Blood and urine samples from SLE patients were collected. In monocyte subsets from whole blood samples several phenotypic markers were evaluated. MPs were isolated from platelet‐poor plasma and urine by centrifugation. This phenotypic marker characterization was performed using multiparametric flow cytometry. We observed that patients with active LN have lower counts of non‐classical monocytes than do those without renal involvement. All monocyte subsets exhibited lower expression of CX3CR1 and ICAM‐1 in LN than in patients without LN. High frequencies of MP‐HMGB1+ and MP‐HLA‐DR+ were detected in circulation and urine of LN patients. Although MP‐HMGB1+, MP‐HLA‐DR+, and MP‐CX3CR1+ from urine were able to discriminate between patients with and without LN, only urinary MP‐HMGB1+ were different between patients with active and inactive LN. Therefore, these vesicles may be useful as biomarkers of LN.

This article is protected by copyright. All rights reserved

https://ift.tt/2SzeIxu

Disseminated Histoplasmosis with Miliary Histoplasmosis, Neurohistoplasmosis, and Histoplasma capsulatum Bacteremia in Probable Neurosarcoidosis

Introduction. Neurosarcoidosis, either isolated or as part of systemic sarcoidosis, is an uncommon entity and has diagnostic uncertainty. Treatment for neurosarcoidosis can increase the risk of infections, including fungal infections such as disseminated histoplasmosis. Neurosarcoidosis may further predispose patients to infections of the central nervous system. Case Presentation. A 54-year-old male with a history of probable neurosarcoidosis on methotrexate and infliximab presented with encephalopathy, hypoxia, and reported fevers. The patient was found to have disseminated histoplasmosis involving the lungs (miliary histoplasmosis), central nervous system (neurohistoplasmosis), and bloodstream. The Histoplasma capsulatum infection was treated with amphotericin and then voriconazole. Discussion. Patients with neurosarcoidosis are suspected to have blood-brain barrier dysfunction. Lumbar puncture should be considered as part of initial investigative studies for infection. Empiric antimicrobial therapy for a patient with neurosarcoidosis on immunosuppressive agents may need to include antifungal agents.

https://ift.tt/2QIOATF

Diagnostic yield of upper endoscopy according to appropriateness: a systematic review

Despite some official guidelines are available, a substantial rate of inappropriateness for upper gastrointestinal (UGI) endoscopies has been reported. This study aimed to estimateen the inappropriate rate of UGI in different countries, also including the diagnostic yield.

https://ift.tt/2Pw7BnI

A study of the association between UGT1A1*28 variant allele of UGT1A1 gene and colonic phenotype of sporadic colorectal cancer

The transcriptional activity of the UGT1A1 gene is modulated by a variable number of repetitions of the dinucleotide (TA) within its promoter region. By comparison to the most common allele (TA)6 (UGT1A1*1), decreased activity is observed with increasing TA repetitions. The aim of this study was to determine whether the presence of the variant allele UGT1A1*28, harbouring seven TA repetitions, (TA)7, in the homozygous state, is associated with precancerous colonic lesions and/or with specific colorectal cancer characteristics.

https://ift.tt/2zSLhQ9

Adherence to European Society of Gastrointestinal Endoscopy recommendations of endoscopists performing small bowel capsule endoscopy in Italy

The European Society of Gastrointestinal Endoscopy (ESGE) has recently issued a technical review focused on small bowel capsule endoscopy (SBCE).

https://ift.tt/2PsHheg

Risk of advanced lesions in patients with branch-duct IPMN and relative indications for surgery according to European evidence-based guidelines

European evidence-based guidelines proposed surgery for branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) based on the presence of 1–2 relative indications, depending on the comorbidity burden.

https://ift.tt/2zU4alR

Successful outcome of the transitional process of inflammatory bowel disease from pediatric to adult age: A five years experience

The transitional process of young patients affected by inflammatory bowel disease from pediatric to adult care is a crucial step. Our study aimed to investigate the 1-year success outcome of this transitional process.

https://ift.tt/2PtXsb7

Polaris Launches Industry-Leading Work Utility Vehicle: PRO XD™

All-new diesel UTV line-up engineered for durability, serviceability and safety with industry-leading payload and towing for any jobsite MINNEAPOLIS – Polaris® Commercial has designed a breakthrough line of utility task vehicles (UTVs) purpose-built for work: the all-new PRO XD. The PRO XD line from Polaris offers three diesel-powered models built to withstand the tough duty cycles and...

https://ift.tt/2PxouOW

Colorectal cancer is increasing in rural Kenya: challenges and perspectives

https://ift.tt/2L9JhaT

Characterization and Identification of Colorectal Cancer in Persons younger than 50 Years

https://ift.tt/2rv0iDp

A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer

https://ift.tt/2Uxo4M9

Proton beam therapy in Europe: more centres need more research

https://ift.tt/2Baeje3

Learning From Temporal Relationships: Childbirth and Breast Cancer Risk

In their article, Nichols and colleagues report the results of a large and sophisticated analysis of the relationship between childbirth and breast cancer risk. The editorial discusses the insight the study provides into this complex relationship. Although the clinical implications of these findings are limited, the temporal relationship between childbirth and breast cancer risk offers an important clue for the ongoing effort to identify the mechanisms linking reproductive history and breast cancer risk.

https://ift.tt/2rup0nb

Biosimilars for Management of Crohn Disease

In this issue, Meyer and colleagues report a large and well-conducted cohort study that demonstrates that the effectiveness of the biosimilar CT-P13 is equivalent to that of infliximab in infliximab-naive patients with Crohn disease. The editorialists discuss the results and the assurance they provide about the effectiveness and safety of biosimilars.

https://ift.tt/2GkaoRs

Breast Cancer Risk After Childbirth

https://ift.tt/2G8ObpB

Breast Cancer Risk After Recent Childbirth A Pooled Analysis of 15 Prospective Studies

Background:

Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.

Objective:

To characterize breast cancer risk in relation to recent childbirth.

Design:

Pooled analysis of individual-level data from 15 prospective cohort studies.

Setting:

The international Premenopausal Breast Cancer Collaborative Group.

Participants:

Women younger than 55 years.

Measurements:

During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.

Results:

Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)–positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.

Limitations:

Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.

Conclusion:

Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.

Primary Funding Source:

The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

https://ift.tt/2rxky73

Effectiveness and Safety of Reference Infliximab and Biosimilar in Crohn Disease: A French Equivalence Study

Background:

CT-P13 is a biosimilar of the reference product (RP) infliximab, with demonstrated efficacy and safety for some inflammatory arthritides. It was approved for the treatment of Crohn disease (CD) on that basis, without specific studies examining its effects in CD.

Objective:

To compare the effectiveness and safety of CT-P13 and RP in infliximab-naive patients with CD.

Design:

Comparative equivalence cohort study.

Setting:

Système National des Données de Santé (SNDS), a French nationwide health administrative database (1 March 2015 to 30 June 2017).

Patients:

5050 infliximab-naive patients with CD who were older than 15 years, had started treatment with RP (n = 2551) or CT-P13 (n = 2499), and had no other indications for infliximab.

Measurements:

The primary outcome was a composite end point of death, CD-related surgery, all-cause hospitalization, and reimbursement of another biologic therapy. Equivalence was defined as a 95% CI of the hazard ratio (HR) of CT-P13 versus RP in a multivariable marginal Cox model situated within prespecified margins (0.80 to 1.25).

Results:

Overall, 1147 patients in the RP group and 952 patients in the CT-P13 group met the composite end point (including 838 and 719 hospitalizations, respectively). In multivariable analysis of the primary outcome, CT-P13 was equivalent to RP (HR, 0.92 [95% CI, 0.85 to 0.99]). No differences in safety outcomes were observed between the 2 groups: serious infections (HR, 0.82 [CI, 0.61 to 1.11]), tuberculosis (HR, 1.10 [CI, 0.36 to 3.34]), and solid or hematologic cancer (HR, 0.66 [CI, 0.33 to 1.32]).

Limitation:

The SNDS does not contain all relevant clinical data (for example, disease activity).

Conclusion:

This analysis of real-world data indicates that the effectiveness of CT-P13 is equivalent to that of RP for infliximab-naive patients with CD. No difference was observed for safety outcomes.

Primary Funding Source:

Caisse Nationale de l'Assurance Maladie.

https://ift.tt/2Gkajx8

Veterans Health Administration Hospitals Outperform Non–Veterans Health Administration Hospitals in Most Health Care Markets

https://ift.tt/2rtIcBF

The U.S. Medicine Chest: Implications of Increased Reliance on China

Public concern about the safety of medicines has been heightened with the recent recall of more than half of all valsartan products on the market in the United States after the U.S. Food and Drug Administration identified a probable cancer-causing chemical in the active pharmaceutical ingredient, which was made in China. This commentary discusses the increased reliance of the United States on China as a supplier of generic drugs, active pharmaceutical ingredients and the chemical building blocks and raw materials to make them.

https://ift.tt/2Gkaf0m

Sub-castrate testosterone nadir and clinical outcomes in intermediate or high-risk localized prostate cancer

Serum testosterone suppression below 20 ng/dL compared to 20-49 ng/dL was associated with improved PSA responses and lower rates of biochemical recurrence and metastasis in a cohort of intermediate- or high-risk prostate cancer patients treated with androgen deprivation and radiotherapy. This points to the potential need for closer monitoring of testosterone levels during androgen deprivation therapy for localized prostate cancer and could implicate the use of newer ADT agents among patients with inadequate testosterone suppression.

https://ift.tt/2QFLG2b

Longitudinal Trends in the Diagnosis of Attention-Deficit/Hyperactivity Disorder and Stimulant Use in Preschool Children on Medicaid

To describe trends in the diagnosis of attention-deficit/hyperactivity disorder (ADHD) and prescribing of stimulants in preschool-age children receiving Medicaid and to identify factors associated with the receipt of psychosocial care.

https://ift.tt/2EmwK3h

Residential Greenspace Association with Childhood Behavioral Outcomes

To assess the relationship between greenspace exposure and childhood internalizing and externalizing behaviors.

https://ift.tt/2Eexl6c

Metabolic Syndrome in Very Low Birth Weight Young Adults and Controls: The New Zealand 1986 VLBW Study

To assess the physical well-being and components of the metabolic syndrome in a national cohort of very low birth weight (VLBW) young adults and same age controls.

https://ift.tt/2EnWFHG

Sex Disparities in ESRD-Related Mortality: A Call to Action

Research considering the impact of sex and gender is good for patients and good for science.1 Sex differences in physiology and pathogenesis may influence both diagnoses and health outcomes. Gender differences in management may also lead to disparities in outcomes. The first step to improving outcomes for both sexes is the identification of sex disparities.

https://ift.tt/2Gdfi2L

The Donut or the Hole? Prioritizing Patient and Caregiver Values in the Delivery of High-Quality Medical Management Without Dialysis

"The optimist sees the donut, the pessimist sees the hole."― Oscar Wilde

https://ift.tt/2rwJxYe

Exploring Barriers and Potential Solutions in Home Dialysis: An NKF-KDOQI Conference Outcomes Report

Home dialysis therapy, including home hemodialysis and peritoneal dialysis, is underused as a modality for the treatment of chronic kidney failure. The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative sponsored a home dialysis conference in late 2017 that was designed to identify the barriers to starting and maintaining patients on home dialysis therapy. Clinical, operational, policy, and societal barriers were identified that need to be overcome to ensure that dialysis patients have the freedom to choose their treatment modality.

https://ift.tt/2GmlRQT

Use of Measures of Inflammation and Kidney Function for Prediction of Atherosclerotic Vascular Disease Events and Death in Patients With CKD: Findings From the CRIC Study

Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD.

https://ift.tt/2rqMERE

Development and Modification of an Outcome Measure to Follow Symptoms of Children with Sinusitis

To develop a parent-reported Pediatric Rhinosinusitis Symptom Scale (PRSS) that could be used to monitor symptoms of young children with acute sinusitis in response to therapy.

https://ift.tt/2EgMKCK

https://ift.tt/2UwTcLP

Tox and Hound – Enter Clonidine

by Sarah Shafer As promised in my last post, where I discussed the utility of naloxone in clonidine overdose, we're going to spend some time today talking about clonidine in opioid withdrawal. Is it a useful therapy for treating opioid withdrawal, or like Claudius in Hamlet, a gaslighting distractor? Before we dive in, let me […]

EMCrit Project by Tox & Hound.

https://ift.tt/2EeHZJV

The Story of the Science and Entertainment Exchange, a Program of the National Academy of Sciences

Abstract

Mainstream film and television play a critical role in inspiring public interest in science. It can provide an enticing platform to share scientific information through storytelling. This requires collaboration between storytellers and scientists. However, such opportunities often lie outside the awareness or perceived interest of both filmmakers and scientists. The National Academy of Sciences therefore created The Science & Entertainment Exchange (The Exchange) to serve as a credible conduit to facilitate scientific input on film and television projects. In this paper, we combine Hollywood storytelling with academic research to describe the history, mission, and activity of The Exchange as a model for science engagement with the public. By connecting entertainment professionals to great science communicators, The Exchange aims to improve the science that appears in narrative mainstream media and generate positive portrayals of STEM professionals. Since its launch in 2008, The Exchange has completed more than 2300 consultations on films such as Avengers: Infinity War, A Wrinkle in Time, and Black Panther. Additionally, the program has produced more than 250 live events, primarily in New York and Los Angeles. Over the course of the program's 8 years, it has built a guest list of 6000 entertainment professionals and scientists and created a database of more than 2700 science communicators. The Exchange's ongoing work, as well as those of scientists, engineers, and medical professionals who take additional time to work as film and media consultants, improves STEM depictions and brings more science to the public through engaging stories. We discuss the future potential impact of popular media on science literacy and perception, and encourage scientists to embrace opportunities to use popular media to engage the public with science.

https://ift.tt/2G9Tnto

2012 to 2016 Saw Increase in Syphilis Among Pregnant Women

MONDAY, Dec. 10, 2018 -- From 2012 to 2016, there was a 61 percent increase in syphilis cases among pregnant women, with no traditional behavioral risk factors reported among half of these women, according to a study published online Dec. 4 in...

https://ift.tt/2L6si98

AHA Scientific Statement: Low Risk of Side Effects for Statins

MONDAY, Dec. 10, 2018 -- Statins are associated with a low risk for side effects, according to a scientific statement from the American Heart Association (AHA) published online Dec. 10 in Arteriosclerosis, Thrombosis and Vascular Biology. Connie B....

https://ift.tt/2LaLaE3

Survival Similar With Donor Hearts From Hepatitis C+ Donors

MONDAY, Dec. 10, 2018 -- Transplant patients with hearts from donors with hepatitis C virus (HCV) infection and obese donors have similar survival rates as patients with other donor hearts, according to two studies published in the December issue...

https://ift.tt/2C1mScC

Smoking Linked to Cognitive Dysfunction in Fibromyalgia

MONDAY, Dec. 10, 2018 -- Smoking tobacco is a risk factor for cognitive dysfunction in patients with fibromyalgia (FM), according to a study presented at the 17th Annual Pain Medicine Meeting, a meeting of the American Society of Regional Anesthesia...

https://ift.tt/2L6sgy2

PM2.5 Exposure Linked to Asthma Rescue Medication Use

MONDAY, Dec. 10, 2018 -- For individuals with asthma, increased fine particulate matter (PM2.5) exposure is associated with increased weekly rescue inhaler use, according to a study published online Nov. 26 in the Proceedings of the National Academy...

https://ift.tt/2C2Lq5i

Women Face Less Kidney Disease Morbidity and Mortality Than Men

MONDAY, Dec. 10, 2018 -- Women may have a lower risk for chronic kidney disease (CKD) progression and death compared with men, according to a study published online Dec. 3 in the Journal of the American Society of Nephrology. Ana C. Ricardo, M.D.,...

https://ift.tt/2C0TkvQ

Smaller Heads Related to Opioid-Related Neonatal Abstinence Syndrome

MONDAY, Dec. 10, 2018 -- Chronic opioid use during pregnancy that causes neonatal abstinence syndrome (NAS) is associated with smaller neonatal head circumference (HC), according to a study published online Dec. 10 in Pediatrics. Craig V. Towers,...

https://ift.tt/2C2LsKs

EMS Times Longer for Patients From Poorest Neighborhoods

MONDAY, Dec. 10, 2018 -- Patients with cardiac arrest from the poorest neighborhoods have longer emergency medical service (EMS) times, according to a study published online Nov. 30 in JAMA Network Open. Renee Y. Hsia, M.D., from the University of...

https://ift.tt/2C1E9Ct

Less Than One Hour of Resistance Training Weekly Tied to Lower CVD Risk

MONDAY, Dec. 10, 2018 -- Less than an hour a week of resistance exercise (RE) is associated with decreased risks for cardiovascular disease (CVD)-related events and all-cause mortality, independent of aerobic exercise, according to a study recently...

https://ift.tt/2LaoRhQ

Cemented Metal-on-Polyethylene Implants Best for Seniors

MONDAY, Dec. 10, 2018 -- For older patients, small-head cemented metal-on-polyethylene implants are the cost-effective choice for total hip replacements, according to a study recently published in Value in Health. Christopher G. Fawsitt, Ph.D., from...

https://ift.tt/2L7AJkv

Iowa flight paramedic marks 500th flight

LifeGuard Air Ambulance flight paramedic Terri Staner, 55, was a stay-at-home mom before she decided to get EMS training "for fun"

https://ift.tt/2L8UZ5o

Studying Protein Import into Chloroplasts Using Protoplasts

Here we describe a protocol to express proteins into protoplasts by using PEG-mediated transformation method. The method provides easy expression of proteins of interest, and efficient investigation of protein localization and the import process for various experimental conditions in vivo.

https://ift.tt/2G8RNYB

Responding to the growing number of hate crimes

Anticipating potential targets, and preplanning a coordination and communication plan are keys to an organized response

https://ift.tt/2zQEqXC

https://ift.tt/2UzqGZO

Performance of colorectal cancer screening in the European Union Member States: data from the second European screening report

Objective

To present comparative data about the performance of colorectal cancer (CRC) screening programmes in the European Union Member States (EU MSs).

Design

Cross-sectional study. We analysed key performance indicators—participation rate, positivity rate (PR), detection rate (DR) and positive predictive value for adenomas and CRC—based on the aggregated quantitative data collected for the second EU screening report. We derived crude and pooled (through a random effects model) estimates to describe and compare trends across different MSs/regions and screening protocols.

Results

Participation rate was higher in countries adopting faecal immunochemical test (FIT) (range: 22.8%–71.3%) than in those using guaiac faecal occult blood test (gFOBT) (range 4.5%–66.6%), and it showed a positive correlation (=0.842, p<0.001) with participation in breast cancer screening in the same areas. Screening performance showed a large variability. Compliance with referral for colonoscopy (total colonoscopy (TC)) assessment ranged between 64% and 92%; TC completion rate ranged between 92% and 99%. PR and DR of advanced adenomas and CRC were higher in FIT, as compared with gFOBT programmes, and independent of the protocol among men, older subjects and those performing their first screening.

Conclusions

The variability in the results of quality indicators across population-based screening programmes highlights the importance of continuous monitoring, as well as the need to promote quality improvement efforts, as recommended in the EU guidelines. The implementation of monitoring systems, ensuring availability of data for the entire process, together with initiatives aimed to enhance reproducibility of histology and quality of endoscopy, represent a priority in screening programmes management.

https://ift.tt/2PvZpnB

Quality of Life in a Randomized Breast Cancer Prevention Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women

Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 x 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.

https://ift.tt/2Enbkmw

Comparison of Effects of Diet on Mammary Cancer: Efficacy of Various Preventive Agents and Metabolomic Changes of Different Diets and Agents

To determine the effects of diet, rats were placed on a standard diet (4% fat) or on a modified Western (high-fat diet, HFD) diet (21% fat) at 43 days of age (DOA) and administered methylnitrosourea (MNU) at 50 DOA. Rats were administered effective (tamoxifen, vorozole, and Targretin) or ineffective (metformin and Lipitor) chemopreventive agents either by daily gavage or in the diet beginning at 57 DOA and continuing until sacrifice (190 DOA). Latency period of the tumors was determined by palpation, and multiplicity and cancer weights per rat were determined at final sacrifice. Rats on the HFD versus standard diet had: (i) a 6% increase in final body weights; (ii) significant decreases in tumor latency; and (iii) significant increases in final tumor multiplicity and average tumor weight. Tamoxifen, vorozole, and Targretin were highly effective preventive agents, whereas Lipitor and metformin were ineffective in rats on either diet. Serum was collected at 78 DOA and at sacrifice (190 DOA), and metabolomics were determined to identify the metabolite changes due to diets and effective agents. Rats given the HFD had increased levels of saturated free fatty acids (including myristate) and decreased levels of 2-aminooctanoate. Furthermore, rats on the HFD diet had increased levels of 2-aminobutyrate and decreases in glycine markers previously identified as indicators of prediabetes. Targretin increased long-chain glycophospholipids (e.g., oleyl-linoleoyl-glycerophosphocholine) and decreased primary bile acids (e.g., taurocholate). Tamoxifen increased palmitoyl-linoleoyl-glycophosphocholine and decreased stearoyl-arachidonyl glycophosphocholine. Finally, increased levels of methylated nucleotides (5-methylcytidine) and decreased levels of urea cycle metabolites (N-acetylcitrulline) were associated with the presence of mammary cancers.

https://ift.tt/2SFukzU

Evidence for Chemopreventive and Resilience Activity of Licorice: Glycyrrhiza Glabra and G. Inflata Extracts Modulate Estrogen Metabolism in ACI Rats

Women are increasingly using botanical dietary supplements (BDS) to reduce menopausal hot flashes. Although licorice (Glycyrrhiza sp.) is one of the frequently used ingredients in BDS, the exact plant species is often not identified. We previously showed that in breast epithelial cells (MCF-10A), Glycyrrhiza glabra (GG) and G. inflata (GI), and their compounds differentially modulated P450 1A1 and P450 1B1 gene expression, which are responsible for estrogen detoxification and genotoxicity, respectively. GG and isoliquiritigenin (LigC) increased CYP1A1, whereas GI and its marker compound, licochalcone A (LicA), decreased CYP1A1 and CYP1B1. The objective of this study was to determine the distribution of the bioactive licorice compounds, the metabolism of LicA, and whether GG, GI, and/or pure LicA modulate NAD(P)H quinone oxidoreductase (NQO1) in an ACI rat model. In addition, the effect of licorice extracts and compounds on biomarkers of estrogen chemoprevention (CYP1A1) as well as carcinogenesis (CYP1B1) was studied. LicA was extensively glucuronidated and formed GSH adducts; however, free LicA as well as LigC were bioavailable in target tissues after oral intake of licorice extracts. GG, GI, and LicA caused induction of NQO1 activity in the liver. In mammary tissue, GI increased CYP1A1 and decreased CYP1B1, whereas GG only increased CYP1A1. LigC may have contributed to the upregulation of CYP1A1 after GG and GI administration. In contrast, LicA was responsible for GI-mediated downregulation of CYP1B1. These studies highlight the polypharmacologic nature of botanicals and the importance of standardization of licorice BDS to specific Glycyrrhiza species and to multiple constituents.

https://ift.tt/2Eob7zC

Longer-term Lipid-lowering Drug Use and Risk of Incident and Fatal Prostate Cancer in Black and White Men in the ARIC Study

Lipid-lowering medications, particularly statins, may protect against aggressive prostate cancer. Fatal prostate cancer, the most clinically relevant outcome, remains understudied for this association. We prospectively studied lipid-lowering medication use and both incident and fatal prostate cancer in black and white men in the Atherosclerosis Risk in Communities (ARIC) study. A total of 6,518 men without cancer at visit 2 (1990–1992), the start of the statin era, were followed for prostate cancer incidence and death through 2012. Medication use was collected during study visits and telephone calls at up to nine time points during follow-up. Cox regression was used to estimate HR and 95% confidence intervals (CI) of total (white N = 541, black N = 259) and fatal (white N = 56, black N = 34) prostate cancer overall and by race. Lipid-lowering medication use was modeled as time-dependent current use or duration (never, <10, and ≥10 years). By visit 4 (1996–1998), 21% of white and 11% of black men had used a lipid-lowering medication, mostly statins. There was a suggestion that current users were less likely to die from prostate cancer than nonusers (HR = 0.67, 95% CI = 0.42–1.07) after multivariable adjustment. We observed no statistically significant differences between black and white men. Current use was not associated with incident prostate cancer, although long-term use was statistically significantly inversely associated with incidence (HR = 0.68; 95% CI = 0.50–0.92). Long-term lipid-lowering medication use was associated with lower risk of prostate cancer. Current use was possibly associated with fatal prostate cancer.

https://ift.tt/2SGe8yd

AACR White Paper: Shaping the Future of Cancer Prevention - A Roadmap for Advancing Science and Public Health

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling—from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative.

https://ift.tt/2Emwgdn

Circulating Receptor Activator of Nuclear Factor-{kappa}B (RANK), RANK ligand (RANKL), and Mammographic Density in Premenopausal Women

The receptor activator of nuclear factor-B (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (P_trend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (P_trend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (P_trend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.

https://ift.tt/2SFufw6

Dietary Tomato Powder Inhibits High-Fat Diet-Promoted Hepatocellular Carcinoma with Alteration of Gut Microbiota in Mice Lacking Carotenoid Cleavage Enzymes

Both incidence and death rate due to liver cancer have increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. β-Carotene-15, 15'-oxygenase (BCO1), and β-carotene-9', 10'-oxygenase (BCO2) cleave lycopene to produce bioactive apo-lycopenoids. Although BCO1/BCO2 polymorphisms affect human and animal lycopene levels, whether dietary tomato consumption can inhibit high-fat diet (HFD)–promoted hepatocellular carcinoma (HCC) development and affect gut microbiota in the absence of BCO1/BCO2 is unclear. BCO1/BCO2 double knockout mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to an HFD (60% of energy as fat) with or without tomato powder (TP) feeding for 24 weeks. Results showed that TP feeding significantly decreased HCC development (67%, 83%, and 95% reduction in incidence, multiplicity, and tumor volume, respectively, P < 0.05). Protective effects of TP feeding were associated with (1) decreased hepatic inflammatory foci development and mRNA expression of proinflammatory biomarkers (IL1β, IL6, IL12α, monocyte chemoattractant protein-1, and inducible NO synthase); (2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD⁺ production; and (3) increased hepatic circadian clock genes (circadian locomotor output cycles kaput, period 2, and cryptochrome-2, Wee1). Furthermore, TP feeding increased gut microbial richness and diversity, and significantly decreased the relative abundance of the genus Clostridium and Mucispirillum, respectively. The present study demonstrates that dietary tomato feeding independent of carotenoid cleavage enzymes prevents HFD-induced inflammation with potential modulating gut microbiota and inhibits HFD-promoted HCC development.

https://ift.tt/2SFudnY

Comparison of Performance Between a Short Categorized Lifestyle Exposure-based Colon Cancer Risk Prediction Tool and a Model Using Continuous Measures

Risk prediction models that estimate an individual's risk of developing colon cancer could be used for a variety of clinical and public health interventions, including offering high-risk individuals enhanced screening or lifestyle interventions. However, if risk prediction models are to be translated into actual clinical and public health practice, they must not only be valid and reliable, but also be easy to use. One way of accomplishing this might be to simplify the information that users of risk prediction tools have to enter, but it is critical to ensure no resulting detrimental effects on model performance. We compared the performance of a simplified, largely categorized exposure-based colon cancer risk model against a more complex, largely continuous exposure-based risk model using two prospective cohorts. Using data from the Nurses' Health Study and the Health Professionals Follow-up Study we included 816 incident colon cancer cases in women and 412 in men. The discrimination of models was not significantly different comparing a categorized risk prediction model with a continuous prediction model in women (c-statistic 0.600 vs. 0.609, P_diff = 0.07) and men (c-statistic 0.622 vs. 0.618, P_diff = 0.60). Both models had good calibration in men [observed case count/expected case count (O/E) = 1.05, P > 0.05] but not in women (O/E = 1.19, P < 0.01). Risk reclassification was slightly improved using categorized predictors in men [net reclassification index (NRI) = 0.041] and slightly worsened in women (NRI = –0.065). Categorical assessment of predictor variables may facilitate use of risk assessment tools in the general population without significant loss of performance.

https://ift.tt/2EnzPjq

Which nasopharyngeal cancer patients need adaptive radiotherapy?

Abstract

Background

Adaptive radiotherapy (ART) has potential benefits in patients with nasopharyngeal cancer (NPC). This retrospective study aimed to identify the factors favoring ART.

Materials and methods

Forty NPC patients were retrospectively included in this study. All patients received two-phase, volumetric modulated arc radiotherapy (VMAT) and underwent a second computed tomography (CT) for the phase II ART. We generated phantom, non-ART plans by a hybrid method for comparison with ART plans. A paired t-test was used to evaluate the dose differences between these two plans. A subgroup analysis through a paired t-test was used to evaluate the factors favoring ART.

Results

The second CT images were captured at the median 22 fractions. The median total dose of the planning target volume-one (PTV-1) was 72 Gy, and the phase II dose was 16 Gy. The volumes of the ipsilateral parotid gland (23.2 vs. 19.2 ml, p <  0.000), contralateral parotid gland (23.0 vs. 18.4 ml, p <  0.000), clinical target volume-1 (CTV-1, 32.2 vs. 20.9 ml, p <  0.000), and PTV-1 (125.8 vs. 107.3 ml, p <  0.000) all shrunk significantly between these two CT simulation procedures. Among the nearby critical organs, only the ipsilateral parotid gland displayed significant dose reduction by the ART plan (5.3 vs. 6.0 Gy, p = 0.004). Compared to the phantom plan, the ART could significantly improve the PTV-1 target volume coverage of D₉₈ (15.4 vs. 12.3 Gy, p < 0.000). Based on the D₉₈ of PTV-1, the factors of a large initial weight (> 60 kg, p < 0.000), large body mass index (BMI) (> 21.5, p < 0.000), obvious weight loss (> 2.8 kg, p < 0.000), concurrent chemoradiotherapy (p < 0.000), and stages III–IV (p < 0.000) favored the use of ART.

Conclusions

ART could significantly reduce the mean dose to the ipsilateral parotid gland. ART has dosimetrical benefit for patients with a heavy initial weight, large BMI, obvious weight loss, concurrent chemoradiotherapy, and cancer in stages III–IV.

https://ift.tt/2LbN0oo

Activation of LXRɑ/β by cholesterol in malignant ascites promotes chemoresistance in ovarian cancer

Abstract

Background

The purpose of this study was to investigate the role of malignant ascites tumor microenvironment in ovarian cancer progression and chemoresistance.

Methods

A total of 45 patients with ovarian cancer and three benign ascites were collected at the time of clinical intervention. Ascites cholesterol levels were quantitated using cholesterol quantitation kit and recurrence free survival (RFS) of ovarian cancer patients were collected. The sensitivity of ovarian cancer cells to cisplatin (CDDP) and paclitaxel (PAC) were assessed by viability assay, flow cytometry and protein expression. Receiver operating characteristics (ROC) curve and Youden index analysis were applied to calculate the optimal cut-off values for ascites cholesterol. Kaplan-Meier curve were applied to compare RFS between high and low ascites cholesterol levels in ovarian cancer patients.

Results

Here we show that cholesterol is elevated in malignant ascites and modulates the sensitivity of ovarian cancer cells to CDDP and PAC by upregulating the expression of drug efflux pump proteins, ABCG2 and MDR1, together with upregulation of LXRɑ/β, the cholesterol receptor. Transfection of LXRɑ/β siRNA inhibited cholesterol-induced chemoresistance and upregulation of MDR1. In addition, the cholesterol level in malignant ascites was negatively correlated with number of CDDP-induced apoptotic cell death, but not with that of PAC-induced apoptotic cell death. Cholesterol depletion by methyl beta cyclodextrin (MβCD) inhibited malignant ascites-induced chemoresistance to CDDP and upregulation of MDR1 and LXRɑ/β. For patients with ovarian cancer, high cholesterol level in malignant ascites correlated with short RFS.

Conclusions

High cholesterol in malignant ascites contributes to poor prognosis in ovarian cancer patients, partly by contributing to multidrug resistance through upregulation of MDR1 via activation of LXRɑ/β.

https://ift.tt/2C1v3WD

Liquid biopsy using the supernatant of a pleural effusion for EGFR genotyping in pulmonary adenocarcinoma patients: a comparison between cell-free DNA and extracellular vesicle-derived DNA

Abstract

Background

EGFR genotyping in pulmonary adenocarcinoma patients who develop pleural effusions is mostly performed using cytology or cell block slides with low sensitivity. Liquid biopsy using the supernatant of pleural effusions may be more effective because they contain many components released by cancer cells. Extracellular vesicles (EVs) are known to carry oncogenic double-stranded DNA that is considered a notable biomarker. Here, we investigate the efficiency of liquid biopsy using cell-free DNA (cfDNA) and extracellular vesicle-derived DNA (EV-derived DNA) from the supernatant of pleural effusions for EGFR genotyping in patients with pulmonary adenocarcinoma.

Methods

Fifty pleural effusion samples from patients with pulmonary adenocarcinoma were evaluated. The supernatant, after removing the cell pellet by centrifugation, was used for liquid biopsy, and EVs were isolated from the pleural effusion by ultracentrifugation. EV-derived DNA and cfDNA were extracted separately, and EGFR genotyping was performed by the PNA clamping method.

Results

Among 32 patients who were EGFR-tyrosine kinase inhibitor (TKI) naïve with a known tissue EGFR genotype, liquid biopsy using EV-derived DNA from the pleural effusion supernatant showed 100% matching results with tissue EGFR genotyping in 19 EGFR mutant cases and detected three additional EGFR mutations in patients with wild-type (WT) tissue. Liquid biopsy using cfDNA from pleural effusion supernatants missed two cases of tissue-based EGFR mutations and found two additional EGFR mutation cases. In 18 patients who acquired resistance to EGFR-TKI, EGFR genotyping using EV-derived DNA from the pleural effusion supernatant detected the T790 M mutation in 13 of 18 (72.2%) patients, and this mutation was detected in 11 (61.1%) patients using cfDNA. By contrast, only three patients were found to present the T790 M mutation when using cell block or cytology slides.

Conclusions

Liquid biopsy using the supernatant of pleural effusions showed significantly improved results for EGFR genotyping compared to those using conventional cell block or cytology samples. Liquid biopsy using EV-derived DNA is promising for EGFR genotyping, including T790 M detection in pulmonary adenocarcinoma patients who develop pleural effusions.

https://ift.tt/2C2psPC

Deletion of the murine ortholog of the 8q24 gene desert has anti-cancer effects in transgenic mammary cancer models

Abstract

Background

The gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer. The locus, including the gene desert and its flanking genes, MYC, PVT1 and FAM84B, is also frequently amplified in human breast cancer. We generated a megadeletion (MD) mouse model lacking 430-Kb of sequence orthologous to the breast cancer-associated region in the gene desert. The goals were to examine the effect of the deletion on mammary cancer development and on transcript level regulation of the candidate genes within the locus.

Methods

The MD allele was engineered using the MICER system in embryonic stem cells and bred onto 3 well-characterized transgenic models for breast cancer, namely MMTV-PyVT, MMTV-neu and C3(1)-TAg. Mammary tumor growth, latency, multiplicity and metastasis were compared between homozygous MD and wild type mice carrying the transgenes. A reciprocal mammary gland transplantation assay was conducted to distinguish mammary cell-autonomous from non-mammary cell-autonomous anti-cancer effects. Gene expression analysis was done using quantitative real-time PCR. Chromatin interactions were evaluated by 3C. Gene-specific patient outcome data were analysed using the METABRIC and TCGA data sets through the cBioPortal website.

Results

Mice homozygous for the MD allele are viable, fertile, lactate sufficiently to nourish their pups, but maintain a 10% lower body weight mainly due to decreased adiposity. The deletion interferes with mammary tumorigenesis in mouse models for luminal and basal breast cancer. In the MMTV-PyVT model the mammary cancer-reducing effects of the allele are mammary cell-autonomous. We found organ-specific effects on transcript level regulation, with Myc and Fam84b being downregulated in mammary gland, prostate and mammary tumor samples. Through analysis using the METABRIC and TCGA datasets, we provide evidence that MYC and FAM84B are frequently co-amplified in breast cancer, but in contrast with MYC, FAM84B is frequently overexpressed in the luminal subtype, whereas MYC activity affect basal breast cancer outcomes.

Conclusion

Deletion of a breast cancer-associated non-protein coding region affects mammary cancer development in 3 transgenic mouse models. We propose Myc as a candidate susceptibility gene, regulated by the gene desert locus, and a potential role for Fam84b in modifying breast cancer development.

https://ift.tt/2L8oKTP

Using PARP Inhibitors in the Treatment of Patients With Ovarian Cancer

Opinion statement

Use of poly(ADP-ribose) polymerase (PARP) inhibitors has greatly increased over the past 5 years. With several new Food and Drug Administration (FDA) approvals, three PARP inhibitors have entered into standard of care treatment for epithelial ovarian cancer (including ovarian, fallopian tube, and primary peritoneal cancer). Olaparib and rucaparib currently have indications for treatment of recurrent BRCA mutant ovarian cancer. Olaparib, rucaparib, and niraparib all have indications for maintenance therapy in recurrent platinum-sensitive ovarian cancer after response to platinum-based therapy. In our practice, we use both olaparib and rucaparib in the recurrent setting, and all three PARP inhibitors in the maintenance setting. Choice of which PARP inhibitor to use in either setting is largely based upon baseline laboratory values, number of prior therapies, and presence of a BRCA mutation and/or homologous recombination deficiency (HRD). As (HRD) and other biomarker assessments continue to improve, we anticipate being able to better identify which patients might most benefit from PARP inhibitor therapy in the future. The clinically available PARP inhibitors are currently undergoing extensive investigations in clinical trials. Other newer agents such as talazoparib, veliparib, 2X-121, and CEP-9722 are in earlier stages of development. As more FDA-approved indications for PARP inhibitor therapy in ovarian cancer become available, we anticipate the decision of which PARP inhibitor to use will become increasingly complex.

https://ift.tt/2SHmCoR

Down-regulation of A-FABP predicts non-muscle invasive bladder cancer progression: investigation with a long term clinical follow-up

Abstract

Background

Non-muscle invasive bladder cancers (NMIBC: pTa, pT1) are characterised by a high risk of recurrence and/or progression. Identification of prognostic markers is needed to improve both diagnosis and management of the disease. The aim of this study was to analyse the expression of A-FABP (adipocyte-fatty acid binding protein) and to evaluate its prognostic value in bladder cancer with a long term clinical follow-up.

Methods

A-FABP expression was investigated by immunohistochemistry in 236 tumours (114 pTa, 61 pT1, 61 pT2–4). Immunostaining was classified as negative (absent or weak immunostaining and moderate or strong staining on ≤10% of cells) or positive (moderate or strong staining on > 10% of cells). Event-free survival (EFS) and overall survival (OS) were determined with a 87.3 months median follow-up in the overall cohort. Recurrence-free survival (RFS) and progression-free survival (PFS) were established in NMIBC.

Results

Loss of A-FABP was associated with higher mean age, high stage/grade, and the presence of metastatic lymph nodes. It was correlated with shorter median EFS (17.5 vs 62.5 months; p = 0.001) and mean OS (76.7 vs 154.2 months; p = 0.009) and with higher risk of progression in the pTa/pT1 subgroup (HR, 0.36; 95% CI, 0.13–0.96; p = 0.041) and importantly in the pTa tumours (HR, 0.34; 95% CI, 0.10–0.97; p = 0.045).

Conclusion

These results demonstrated that loss of A-FABP expression following a long follow-up was predictive of pTa and pTa/pT1 progression. Immunohistochemistry on diagnostic biopsy is easy to use and could be of value to help clinicians to propose appropriate treatment for these tumours.

https://ift.tt/2LaAeGk

PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD)

Abstract

Background

COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC).

Methods

Using a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a ≥ 2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue.

Results

The expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p < 0.05).

Conclusion

PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and patient mortality may be mediated through the induction of specific macrophage phenotypes.

https://ift.tt/2C2puXK