Resistance training status modifies inflammatory response to explosive and hypertrophic resistance exercise bouts

Abstract

The purpose of the present study was to examine the immediate and prolonged immune response in circulating cytokine and adipocytokine concentrations after two different resistance exercise bouts: hypertrophic (HYP1, 5 × 10, 80% of 1RM) and maximal explosive (POW1, 10 × 5, 60% of 1RM) resistance exercise bouts and how 12 weeks of resistance training (RT) modifies these responses (HYP2, POW2). Eight men completed the study. RE-induced interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-1 receptor antagonist (IL-1ra), monocyte-chemoattractant protein-1 (MCP-1), leptin, resistin, and adiponectin were measured before (PRE) and immediately (POST0), 24 (POST24) and 48 (POST48) hours after RE bouts before and after RT. In the untrained state, IL-6 increased immediately after RE in HYP1 (p = 0.002) and in POW1 (p = 0.003) whereas no changes were observed after RT. Similar results were observed in IL-1β, whereas conversely, IL-1ra increased only after RT in HYP2 and POW2 (p < 0.05). Resistin increased before RT in HYP1 and in POW1 (p = 0.011 and p = 0.003, respectively), but after RT, significant responses were not observed. Interestingly, in HYP2, MCP-1 increased significantly at POST24 (p = 0.009) and at POST48 (p = 0.032) only following RT. The present study shows that RT modifies RE-induced cytokine responses towards an anti-inflammatory direction.

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Effect of Time to Operative Intervention on Motility Outcomes Following Orbital Floor Fracture Repair in Children.

Purpose: To evaluate the relationship between time to surgical intervention and extraocular motility outcomes in children following repair of an orbital floor fracture with inferior rectus entrapment. Methods: After institution review board's approval, a retrospective, consecutive case series of 28 children with unilateral orbital floor fractures entrapping the inferior rectus muscle was conducted. Clinical examinations and CT images were performed on all children. The main outcomes measures were postoperative motility measurements. Results: Eleven patients underwent surgery within 24 hours of reported injury, while 17 patients underwent surgery after 24 hours. There was no statistically significant difference in average age at the time of surgery (p = 0.47) or average preoperative motility scores (p = 1.0) between the 2 groups. Patients who underwent surgery within 24 hours of reported injury had an improved likelihood of recovery (log hazard ratio = 0.469; 95% confidence interval, -0.42 to 1.36). Conclusions: Our exploratory study suggests that surgical reduction of inferior rectus entrapment in pediatric orbital floor fractures within 24 hours from the time of injury shows an improved, but nonstatistically significant, likelihood of recovery in motility deficits with earlier surgical intervention. (C) 2017 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

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Is Dexmedetomidine a Miracle Drug for Sedation in Patients With Neuroacanthocytosis With Involuntary Movements?.

No abstract available

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Psychiatric conditions and general practitioner attendance prior to HPV vaccination and the risk of referral to a specialized hospital setting because of suspected adverse events following HPV vaccination: a register-based, matched case–control study

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IJMS, Vol. 18, Pages 1958: Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

IJMS, Vol. 18, Pages 1958: Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

International Journal of Molecular Sciences doi: 10.3390/ijms18091958

Authors: Hong Li Changqing Xu Quanfeng Li Xiuxiang Gao Erkio Sugano Hiroshi Tomita Liming Yang Sa Shi

Mitochondrial oxidative stress is thought to be a key contributor towards the development of diabetic cardiomyopathy. Thioredoxin 2 (Trx2) is a mitochondrial antioxidant that, along with Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), scavenges H2O2 and offers protection against oxidative stress. Our previous study showed that TrxR inhibitors resulted in Trx2 oxidation and increased ROS emission from mitochondria. In the present study, we observed that TrxR inhibition also impaired the contractile function of isolated heart. Our studies showed a decrease in the expression of Trx2 in the high glucose-treated H9c2 cardiac cells and myocardium of streptozotocin (STZ)-induced diabetic rats. Overexpression of Trx2 could significantly diminish high glucose-induced mitochondrial oxidative damage and improved ATP production in cultured H9c2 cells. Notably, Trx2 overexpression could suppress high glucose-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. Our studies suggest that high glucose-induced mitochondrial oxidative damage can be prevented by elevating Trx2 levels, thereby providing extensive protection to the diabetic heart.

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IJMS, Vol. 18, Pages 1981: Up-Regulation of HSFA2c and HSPs by ABA Contributing to Improved Heat Tolerance in Tall Fescue and Arabidopsis

IJMS, Vol. 18, Pages 1981: Up-Regulation of HSFA2c and HSPs by ABA Contributing to Improved Heat Tolerance in Tall Fescue and Arabidopsis

International Journal of Molecular Sciences doi: 10.3390/ijms18091981

Authors: Xiuyun Wang Lili Zhuang Yi Shi Bingru Huang

Abscisic acid (ABA) is known to play roles in regulating plant tolerance to various abiotic stresses, but whether ABA's effects on heat tolerance are associated with its regulation of heat stress transcription factors (HSFs) and heat shock proteins (HSPs) is not well documented. The objective of this study was to determine whether improved heat tolerance of tall fescue (Festuca arundinacea Schreb.) by ABA was through the regulation of HSFs and HSPs. ABA-responsive transcriptional factors, ABA-responsive element binding protein 3 (FaAREB3) and dehydration-responsive element binding protein 2A (FaDREB2A) of tall fescue, were able to bind to the cis-elements in the promoter of tall fescue heat stress transcription factor A2c (FaHSFA2c). Exogenous ABA (5 μM) application enhanced heat tolerance of tall fescue, as manifested by increased leaf photochemical efficiency and membrane stability under heat stress (37/32 °C, day/night). The expression levels of FaHSFA2c, several tall fescue HSPs (FaHSPs), and ABA-responsive transcriptional factors were up-regulated in plants treated with ABA. Deficiency of Arabidopsis heat stress transcription factor A2 (AtHSFA2) suppressed ABA-induction of AtHSPs expression and ABA-improved heat tolerance in Arabidopsis. These results suggested that HSFA2 plays an important role in ABA-mediated plant heat tolerance, and FaAREB3 and FaDREB2A may function as upstream trans-acting factors and regulate transcriptional activity of FaHSFA2c and the downstream FaHSPs, leading to improved heat tolerance.

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NHS in England receives 571 written complaints a day in 2016/17

Data from NHS Digital shows a 4.9% rise in the last year in complaints from patients, friends and family about GPs, dentists and hospital care. There were 208,415 written complaints received by the NHS in England during 2016/17 - the same as 4,008 a week or 571 for every single day.

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Regulatory experience of TOPS: an internet-based system to prevent healthy subjects from over-volunteering for UK clinical trials

Abstract

Purpose

The aim was to review the use of The Over-volunteering Prevention System (TOPS) since the HRA began hosting it in 2013, and the Medicines and Healthcare products Regulatory Agency (MHRA) experience of monitoring its use by UK clinical research units.

Methods

The HRA searched the TOPS database for the number, type and location of units and the number of entries. The MHRA inspectors reviewed their findings from routine inspections.

Results

Twenty-two additional UK units registered to use TOPS during 2013–2016, making a total of 84 units since TOPS was established in 2002. Use of TOPS is now a condition of research ethics committee approval of a phase 1 study and fulfils MHRA accreditation requirements for preventing over-volunteering. The total number of entries by all active units during 2013–2016 was 89,335, of which 84% were UK citizens and 16% non-UK citizens. The total number of entries during 2002–2016 was 249,612. Only 15 of 24,531 subjects (1/1600) and 18 of 18,745 subjects (1/1040) entered in 2015 and 2016, respectively, were deemed potential over-volunteers.

Conclusions

The findings continue to support the concept that TOPS not only helps to prevent over-volunteering, but also deters subjects from trying to do so. Regulation of TOPS by the HRA and MHRA has enhanced its effectiveness, benefited all users and helped to improve the safety of volunteers who participate in non-therapeutic trials in the UK. The UK is still the only country with a national database to prevent over-volunteering that has published data on its widespread use and effectiveness.

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Managing Asthma in Low-Income, Underrepresented Minority, and Other Disadvantaged Pediatric Populations: Closing the Gap

Abstract

Purpose of Review

In this article, we review current understanding of the epidemiology and etiology of disparities in asthma. We also highlight current and emerging literature on solutions to tackle disparities while underscoring gaps and pressing future directions.

Recent Findings

Tailored, multicomponent approaches including the home, school, and clinician-based interventions show great promise.

Summary

Managing asthma in disadvantaged populations can be challenging as they tend to have disproportionately worse outcomes due to a multitude of factors. However, multifaceted, innovative interventions that are sustainable and scalable are key to improving outcomes.

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Managing Asthma in Low-Income, Underrepresented Minority, and Other Disadvantaged Pediatric Populations: Closing the Gap

Abstract

Purpose of Review

In this article, we review current understanding of the epidemiology and etiology of disparities in asthma. We also highlight current and emerging literature on solutions to tackle disparities while underscoring gaps and pressing future directions.

Recent Findings

Tailored, multicomponent approaches including the home, school, and clinician-based interventions show great promise.

Summary

Managing asthma in disadvantaged populations can be challenging as they tend to have disproportionately worse outcomes due to a multitude of factors. However, multifaceted, innovative interventions that are sustainable and scalable are key to improving outcomes.

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Dampness-heat accelerates DMBA-induced mammary tumors in rats

Abstract

Objective

To investigate the impact of dampness-heat (DH) on the development of mammary tumors in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rats.

Methods

Forty rats were randomly divided into 3 groups in a randomized block design, including the control group (n=13), DMBA group (n=14), and DMBA plus DH group (n=13). Rats in the DMBA group and DMBA plus DH group were intragastrically administrated with DMBA (100 mg/kg) for twice, once per week, while rats in the control group were treated with equivalent volumes of sesame oil. After DMBA administration, rats in the DMBA plus DH group were exposed to a simulated climate chamber with ambient temperature (33.0±0.5 °C) and humidity (90%±5%) for 8 weeks, 8 h per day. The body weight, time of tumor formation, and number of tumors were measured weekly to calculate tumor incidence, average latency period, average number of tumors, and average tumor weight. At the end of the experiment, the levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in serum, and the contents of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in serum and tumor tissue were measured, respectively. Some tumor tissues were processed for hematoxylin-eosin staining to determine the histopathological changes.

Results

Compared with DMBA, DMBA plus DH significantly increased the average number of tumors, average tumor weight, levels of serum MMP-9, TIMP-1, TNF-α and IL-1β, and contents of tumor tissue TNF-α and IL-1β (P<0.05 or P<0.01).

Conclusion

DH could accelerate the development of mammary tumors through increasing the expressions of MMP-9, TIMP-1, TNF-α and IL-1β in DMBA-induced rats.

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Chinese and Indian women’s experience with alternative medications for menopause related symptoms: A qualitative analysis

Abstract

Objective

To explore women's rationalization for using alternative medications, their experience and view on safety of long-term use.

Methods

Two focus group discussions, involving 5 participants each for Chinese and Indian groups, were conducted separately. Participant's personal information was collected anonymously. The discussion covered 5 areas: determinants for taking medications; reason for choosing alternative medications rather than hormone replacement therapy (HRT); how these medications help them; their view on cost-effectiveness and concerns over long-term use. The discussions were audio-taped, transcribed and analyzed.

Results

Chinese participants took supplements for controlling symptoms while Indian participants used herbs as a preventive measure during menopause according to their tradition. Women of both groups mentioned that they did not take HRT because of fear of side effects. Chinese group mentioned that medications remarkably improved their symptoms whereas Indian participants appreciated their herbals more for improvement in general wellbeing than for specific symptoms. All members agreed that using alternative medication was cost-effective. Both Chinese and Indian participants were quite confident in saying that long-term use will not be associated with any side effects. However, Indian group emphasized that proper preparation of herbal compound using different types of leaves, is essential in order to avoid untoward effects.

Conclusions

Chinese and Indian women used alternative medicine in prevention and treatment of menopause-related problems even as they were avoiding HRT because of the fear of side effects. They believed that their supplements were effective, safe and cost-beneficial even with long-term use.

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Salutary potential of ethanolic extract of avocado fruit on anomalous carbohydrate metabolic key enzymes in hepatic and renal tissues of hyperglycaemic albino rats

Abstract

Objective

To assess the beneficial potential of ethanolic extract of avocado fruit on abnormal carbohydrate metabolic key enzymes in hepatic and renal tissues in streptozotocin (STZ) induced hyperglycemic albino rats.

Methods

Twenty-four male albino rats were randomly divided into four groups with six in each group by simple random sampling method. Group 1 as control rats; Group 2 as STZ induced diabetic rats; Group 3 as diabetic rats treated with avocado fruit extract (AFE), 300 mg/kg as aqueous suspension orally for 30 days; Group 4 as diabetic rats treated with gliclazide (5 mg/kg) in aqueous solution orally for 30 days. The rats were fasted overnight and sacrificed by cervical dislocation and the blood was collected for various biochemical analysis and excision of hepatic and kidney were done for histological analysis. Levels of fasting blood glucose, plasma insulin and glycosylated hemoglobin were estimated. The activities of key enzymes in carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6- phosphatase, fructose-1, 6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase were assayed by standard methods described in the methodology.

Results

Oral administration of AFE significantly improved the altered levels of blood glucose, plasma insulin, glycosylated hemoglobin, and modulated the activities of carbohydrate metabolizing enzymes (P<0.05, respectively). The glycogen content in hepatic tissues was significantly increased in diabetic rats treated with AFE (P<0.05, respectively).

Conclusion

AFE plays a pivotal role to maintain normoglycemia in diabetes by modulating the activities of carbohydrate metabolic enzymes.

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Combination therapy of tacrolimus and Chinese herb medicated bath in children with inverse psoriasis

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Antihypercholesterolemic, antioxidant and renal protective effects of Mengkudu ( Rubiaceae ) fruit in nephropathy-induced albino rats

Abstract

Objective

To assess the modulatory impact of alcoholic extract of fruit of Mengkudu (AEFM, Morinda citrifolia L., Rubiaceae) on renal oxido-lipidemic stress in hypercholesterolemic albino rats.

Methods

Twenty-four male albino rats were randomly divided into four groups with six rats in each group: group I as control, group II fed with hypercholesterolemic diet (HCD) for 45 days (4% cholesterol and 1% cholic acid), Group III rats fed with HCD for 45 days + AEFM (300 mg/kg body weight/day orally) for last 30 days and group IV normal rats fed AEFM alone. The blood was collected using ethylenediamine tetraacetic acid (EDTA) as an anticoagulant for various biochemical analysis, and excision of kidney was done for histological analysis.

Results

The levels of total cholesterol (TC), triacylglycerol (TG), phospholipids (PLs), renal functional parameters and lipid peroxidation products were markedly mitigated in AEFM treated hypercholesterolemic rats (group III) compared to group I (P<0.01). Activities of both enzymic and non-enzymic free radical scavenging factors were significantly increased in group III compared to group I (P<0.01). In group III the mRNA levels of interstitial endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) genes were obviously up-regulated (P<0.01) and down-regulated in (P<0.05) compared with group I. Histomorphological observations also exhibited similar as in group III AEFM commendably protects the renal tissues compared with group I (P<0.01).

Conclusion

AEFM can act as nephroprotective agent by attenuating the renal oxidative stress, lipid levels as well as regulating NOS level and by this means protects the kidney in hypercholesterolemic induced nephropathy experimental rats.

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Acid–base safety during the course of a very low-calorie-ketogenic diet

Abstract

Background and Aims

Very low-calorie ketogenic (VLCK) diets have been consistently shown to be an effective obesity treatment, but the current evidence for its acid-base safety is limited. The aim of the current work was to evaluate the acid-base status of obese patients during the course of a VLCK diet.

Method

Twenty obese participants undertook a VLCK diet for 4 months. Anthropometric and biochemical parameters, and venous blood gases were obtained on four subsequent visits: visit C-1 (baseline); visit C-2, (1-2 months); maximum ketosis; visit C-3 (2-3 months), ketosis declining; and visit C-4 at 4 months, no ketosis. Results were compared with 51 patients that had an episode of diabetic ketoacidosis as well as with a group that underwent a similar VLCK diet in real life conditions of treatment.

Results

Visit C1 blood pH (7.37 ± 0.03); plasma bicarbonate (24.7 ± 2.5 mmol/l); plasma glucose (96.0 ± 11.7 mg/l) as well as anion gap or osmolarity were not statistically modified at four months after a total weight reduction of 20.7 kg in average and were within the normal range throughout the study. Even at the point of maximum ketosis all variables measured were always far from the cut-off points established to diabetic ketoacidosis.

Conclusion

During the course of a VLCK diet there were no clinically or statistically significant changes in glucose, blood pH, anion gap and plasma bicarbonate. Hence the VLCK diet can be considered as a safe nutritional intervention for the treatment of obesity in terms of acid-base equilibrium.

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Editorial.

No abstract available

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Management of Type I and Type II laryngeal clefts: controversies and evidence.

Purpose of review: To summarize the pediatric Type I and Type II laryngeal cleft literature, paying special attention to recent trends, including evolution of surgical techniques, standardization of outcome assessments, and utilization of management algorithms. Recent findings: There are a variety of options to choose from whenever considering Type I and Type II cleft repair, including endoscopic repair, transoral robotic surgery, and injection laryngoplasty. Conservative management including feeding therapy and treatment of comorbid medical conditions is recommended prior to repair. Validated outcome measures have arisen for swallow study interpretation and timing, as well as caregiver quality-of-life assessment. In addition, a series of medical algorithms have been proposed, which provide specific recommendations for diagnosis, treatment, and follow-up. Summary: For clefts that fail conservative management, endoscopic repair has become the gold standard. In addition, injection laryngoplasty appears to provide both a diagnostic and therapeutic option in the management of these patients. Transoral robotic-assisted endoscopic repair appears well tolerated and feasible, although broader implementation of this technology remains limited. The development and refinement of best practice algorithms can help standardize management and improve decision-making. Furthermore, incorporating validated outcome measures, recorded and followed over time, will improve both patient care and research efforts moving forward. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Regenerative endodontics in non-vital immature permanent teeth

This review of regenerative endodontics for non-vital immature permanent teeth included 14 studies. Although suggesting god outcomes overall they were of low quality with a high risk of bias. Larger high quality studies are needed.

The post Regenerative endodontics in non-vital immature permanent teeth appeared first on National Elf Service.

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Study of the mechanism of remediation of Cd-contaminated soil by novel biochars

Abstract

This article used novel non-magnetized and magnetized biochars prepared under a CO₂ atmosphere returned to Cd-contaminated soil and compared these to the effects of conventional biochars prepared under a N₂ atmosphere with regard to Cd-contaminated soil remediation. A pot experiment with lettuce (Lactuca sativa) was conducted to investigate the relative soil remediation effects of these biochars. The soil used for the pot experiment was spiked with 20 mg kg⁻¹ Cd and amended with 5% of a biochar before sowing. Through these research works, some important results were obtained as follows: (1) applying biochar treated by pyrolysis under a CO₂ atmosphere can obtain the best remediation effect of Cd-contaminated soil that the content of cadmium in the lettuce roots, stems, and leaves was reduced 67, 62, and 63%, respectively; (2) the magnetic biochar aggregation for the soil is weak, so the heavy metal cadmium in the soil could not be immobilized well by the magnetic biochar; (3) The remediation mechanism of novel biochars is that biochar includes a large number of organic functional groups (−C–OH, −C=O, COO−) that can act in a complexing reaction with heavy metal Cd(II) and the inorganic salt ions (Si, S, Cl, etc.) that can combine with cadmium and generate a stable combination.

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New onset of asthma and job status change among world trade center responders and workers

Background

Despite the high rates, the consequences of new onset asthma among the World Trade Center (WTC) responders in terms of the change in job status have not been studied.

Methods

This study consists of a cohort of 8132 WTC responders out of the total 25 787 responders who held a full-time job at the baseline visit, and participated in at least one follow-up visit.

Results

Overall, 34% of the study cohort changed their job status from full-time at a follow-up visit. Multivariable models showed that asthmatics were respectively 27% and 47% more likely to have any job status change and get retired, and twice as likely to become disabled as compared to non-asthmatics.

Conclusions

With asthma incidence from WTC exposure, negative job status change should be considered as a potential long-term consequence of WTC exposure.

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Experimental asbestos studies in the UK: 1912-1950

The asbestos industry originated in the UK in the 1870s. By 1898, asbestos had many applications and was reported to be one of the four leading causes of severe occupational disease. In 1912, the UK government sponsored an experimental study that reported that exposure to asbestos produced no more than a modicum of pulmonary fibrosis in guinea pigs. In the 1930s, the newly established Medical Research Council, with assistance from industry, sponsored a study of the effects of exposing animals to asbestos by injection (intratracheal and subcutaneous) and by inhalation in the factory environment. Government reports, publications, and contemporary records obtained by legal discovery have been reviewed in the context of the stage of scientific development and the history of the times. Experimenters were engaged in a learning process during the 1912–1950 period, and their reports of the effects of asbestos were inconsistent. Pathologists who studied the effects of asbestos experimentally, at whole animal, tissue and cellular levels, advanced experimental methodology and mechanistic knowledge. In the hands of public relations experts, however, research was exploited to preserve an industry and perpetuate preventable diseases, a practice that continues to this day.

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The effect of neuromuscular blockade on the efficiency of facemask ventilation in patients difficult to facemask ventilate: a prospective trial

Summary

Facemask ventilation of the lungs can be an important rescue intervention in a 'cannot intubate' scenario. We assessed the effect of neuromuscular blockade on expiratory tidal volumes in patients with expected difficulty in mask ventilation. The lungs of patients with at least three predictors of difficulty in mask ventilation were ventilated using a facemask held with two hands, with mechanical ventilation set in a pressure-controlled mode. Tidal volumes were recorded before and after the establishment of complete neuromuscular block. In 113 patients, median (IQR [range]) tidal volume increased from 350 (260–492 [80–850]) ml initially, by 48% to 517 (373–667 [100–1250]) ml 30 s after rocuronium administration, (p < 0.001). After the onset of the complete neuromuscular block, a median tidal volume of 600 (433–750 [250–1303]) ml was observed, corresponding to an increase of 71% from baseline values (p < 0.001), and 16% from values obtained 30 s after rocuronium administration, respectively; p = 0.003). No decrease in the tidal volume during the measurements was observed. We conclude that the administration of rocuronium at a dose of 0.6 mg.kg⁻¹ was able to improve facemask ventilation in all cases with a potentially clinically relevant increase in tidal volume. The early use of a neuromuscular blocking agent can be considered as a therapeutic option in case of difficulty with mask ventilation.

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Real-time continuous monitoring of injection pressure at the needle tip for peripheral nerve blocks: description of a new method

Summary

The measurement of injection pressure during the performance of peripheral nerve blocks can be pivotal to detect intraneural placement of the needle tip and thus avoid intrafascicular injection. However, injection pressure can only be measured along the injection line (tubing), which is influenced by several factors. The primary aim of this feasibility study was to describe and validate the principle of a novel nerve-block needle conceived for real-time continuous monitoring of injection pressures at the needle tip. Our secondary aim was to provide measurements and compare injection pressure values at the needle tip and in the injection line. Four porcine lower limb anatomic models were prepared and extraneural injections were performed with fractioned boluses of 2 ml saline at a controlled infusion rate of 10 ml.min⁻¹ (0.16 ml.s⁻¹). Injection pressure at the needle tip was monitored and compared with the pressure in the injection line. The system proved to be reliable. Thirty injections were successfully performed without technical failures. The mean (95%CI) difference between pressures at the needle tip and the injection line varied substantially from 14.33 (12.58–16.08) kPa at 0.5 ml injected volume to 41.56 (39.66–43.45) kPa at the end of the injection. This study demonstrates that the described system allows for real-time continuous monitoring of injection pressure at the needle tip. Moreover, this study shows that injection pressure values measured in the injection line cannot be assumed to be a reliable indicator of the injection pressure at the needle tip.

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Validation of the American Joint Commission on Cancer (8th edition) changes for patients with stage III gastric cancer: survival analysis of a large series from a Specialized Eastern Center

Abstract

The 8th edition of the TNM was released in 2016 and included major revisions, especially for stage III. We aimed to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Clinical data from 1557 patients operated on for stage III gastric cancer according to the 7th edition between 2007 and 2014 were analyzed and compared using the 7th and 8th TNM classifications. A proposed staging system was established, and the three systems were compared in terms of prognostic performance. The stage shifted for 669 (42.96%) patients. It shifted from IIIA to IIIB (one patient, 0.06%), IIIB to IIIA (230 patients, 14.8%), IIIB to IIIC (94 patients, 6.0%), and IIIC to IIIB (344 patients, 22.1%). However, the new AJCC subgroupings did not prove distinctive for survival levels between T3N3aM0 (stage IIIB) and T3N3bM0 (stage IIIC) or between T4aN3aM0 (stage IIIB) and T4aN3bM0 (stage IIIC) when <30 lymph nodes (LNs) were resected. The performance of the 8th edition (c-index, 0.614; 95% confidence interval [CI], 0.596–0.633) revealed no relevant improvement compared to the 7th edition (c-index, 0.624; 95% CI, 0.605–0.643). The proposed staging system generated the best prognostic stratification. The 8th TNM edition may not provide better accuracy in predicting the prognosis of stage III gastric cancer. The proposed staging system, comprised of a combination of the number of LNs harvested and the 7th and 8th AJCC classifications, may improve predictive capacities for stage III gastric cancer.

The aim of this study was to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Furthermore, a proposed staging system was established, and the three systems were compared in terms of prognostic performance.

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Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection.

Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMA) and whole-tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, qPCR was performed on 57 cases of MCC from 52 patients.

Results: RNA-ISH demonstrated the presence of MCPyV in 37 of 75 cases (49.3%). Notably, tumors from younger patients (<73 years) had a significantly higher virus positivity than those from elderly patients (≥73 years; 64.9% vs. 34.2%, P = 0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P = 0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman correlation coefficient R² = 0.932, P < 0.0001).

Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. Clin Cancer Res; 23(18); 5622–30. ©2017 AACR.

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Detection of Driver and Resistance Mutations in Leptomeningeal Metastases of NSCLC by Next-Generation Sequencing of Cerebrospinal Fluid Circulating Tumor Cells

Purpose: Leptomeningeal metastases are more common in non–small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of leptomeningeal metastases.

Experimental Design: We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients.

Results: Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as MET amplification and ERBB2 mutation, were also identified in CSFCTCs.

Conclusions: CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases. Clin Cancer Res; 23(18); 5480–8. ©2017 AACR.

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Anti-CD137 and PD-1/PD-L1 Antibodies En Route toward Clinical Synergy

T-cell costimulation and coinhibition can be respectively exploited by blocking and agonist mAbs. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti–PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy. Clin Cancer Res; 23(18); 5326–8. ©2017 AACR.

See related article by Tolcher et al., p. 5349

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ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors across Tumor Types

Purpose: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in acute myelogenous leukemia, non–small cell lung cancer, and estrogen receptor–positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.

Experimental Design: Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.

Results: We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-X_L (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-X_L, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.

Conclusions: These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types. Clin Cancer Res; 23(18); 5573–84. ©2017 AACR.

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Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma

Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.

Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50–700 mg) or twice-daily (75–150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.

Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E–mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar–plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4–not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9–3.7).

Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339–48. ©2017 AACR.

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In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model

Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade.

Experimental Design: We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery.

Results: Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8⁺ T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4⁺ T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.

Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. Clin Cancer Res; 23(18); 5502–13. ©2017 AACR.

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Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.

Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.

Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8⁺ T cells was observed in responders versus nonresponders.

Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR.

See related commentary by Pérez-Ruiz et al., p. 5326

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Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer

Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).

Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m²/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.

Results: There were neither G4–5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.

Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358–65. ©2017 AACR.

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Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.

Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.

Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P < 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P = 0.002), lymph node metastasis (P = 0.004), and advanced clinical stage (P = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion, and proliferation in vitro. Further study found that RCC2 induced epithelial–mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9.

Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK–JNK signaling. Clin Cancer Res; 23(18); 5598–610. ©2017 AACR.

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Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma.

Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, C_t, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, ¹²³I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between C_t and progression-free survival (PFS).

Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their C_t values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow C_t was 7.9 ± 0.5 C_t stronger than blood C_t. When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood C_t values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood C_t values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055).

Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374–83. ©2017 AACR.

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Prognostic Impact of Circulating Tumor Cells for Breast Cancer Patients Treated in the Neoadjuvant "Geparquattro" Trial

Purpose: This study aimed to evaluate the prognostic impact of circulating tumor cells (CTC) detected in patients with operable or locally advanced breast cancer before and after neoadjuvant therapy (NT) within the clinical trial GeparQuattro.

Experimental Design: Data on CTCs enumerated with the CellSearch system were available for 213 and 207 patients before and after NT, respectively. Associations of CTCs with disease-free survival (DFS) and overall survival (OS) were analyzed by nonparametric Kaplan–Meier estimates and parametric Cox regression.

Results: After a median follow-up of 67.1 months, the detection of ≥1 CTC/7.5 mL and ≥2 CTCs/7.5 mL before NT was associated with reduced DFS (P = 0.031 and P < 0.0001, respectively) and OS (P = 0.0057 and P < 0.0001, respectively), whereas CTCs detected after NT did not correlate with DFS or OS. In parametric univariate and multivariate Cox models, ≥1 CTC/7.5 mL, ≥2 CTCs/7.5 mL, and absolute CTC numbers before NT revealed to be independent prognostic parameters of DFS and OS. CTC-negative patients with pathologic complete response (pCR) exhibited the best prognosis, whereas those with CTCs and less tumor response were at high risk of tumor relapse. In HER2 (ERBB2)-positive and triple-negative patients, ≥2 CTCs/7.5 mL detected before NT also were significantly associated with worse DFS and OS.

Conclusions: Detection of CTCs before NT is an independent prognostic factor of impaired clinical outcome, and combined with pCR, it could be helpful to stratify breast cancer patients for therapeutic interventions. Clin Cancer Res; 23(18); 5384–93. ©2017 AACR.

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Population-specific genetic variation in large sequencing data sets: why more data is still better

Population-specific genetic variation in large sequencing data sets: why more data is still better

European Journal of Human Genetics 25, 1173 (October 2017). doi:10.1038/ejhg.2017.110

Authors: Jeroen G J van Rooij, Mila Jhamai, Pascal P Arp, Stephan C A Nouwens, Marijn Verkerk, Albert Hofman, M Arfan Ikram, Annemieke J Verkerk, Joyce B J van Meurs, Fernando Rivadeneira, André G Uitterlinden & Robert Kraaij

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Identification of ASAH1 as a susceptibility gene for familial keloids

Identification of ASAH1 as a susceptibility gene for familial keloids

European Journal of Human Genetics 25, 1155 (October 2017). doi:10.1038/ejhg.2017.121

Authors: Regie Lyn P Santos-Cortez, Ying Hu, Fanyue Sun, Fairouz Benahmed-Miniuk, Jian Tao, Jitendra K Kanaujiya, Samuel Ademola, Solomon Fadiora, Victoria Odesina, Deborah A Nickerson, Michael J Bamshad, Peter B Olaitan, Odunayo M Oluwatosin, Suzanne M Leal & Ernst J Reichenberger

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Recontacting in clinical practice: the views and expectations of patients in the United Kingdom

Recontacting in clinical practice: the views and expectations of patients in the United Kingdom

European Journal of Human Genetics 25, 1106 (October 2017). doi:10.1038/ejhg.2017.122

Authors: Daniele Carrieri, Sandi Dheensa, Shane Doheny, Angus J Clarke, Peter D Turnpenny, Anneke M Lucassen & Susan E Kelly

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Decreased male reproductive success in association with mitochondrial dysfunction

Decreased male reproductive success in association with mitochondrial dysfunction

European Journal of Human Genetics 25, 1162 (October 2017). doi:10.1038/ejhg.2017.114

Authors: Mika H Martikainen, John P Grady, Yi Shiau Ng, Charlotte L Alston, Grainne S Gorman, Robert W Taylor, Robert McFarland & Doug M Turnbull

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Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia

Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia

European Journal of Human Genetics 25, 1126 (October 2017). doi:10.1038/ejhg.2017.107

Authors: Jacqueline A C Goos, Sigrid M A Swagemakers, Stephen R F Twigg, Marieke F van Dooren, A Jeannette M Hoogeboom, Christian Beetz, Sven Günther, Frank J Magielsen, Charlotte W Ockeloen, Maria A Ramos-Arroyo, Rolph Pfundt, Helger G Yntema, Peter J van der Spek, Philip Stanier, Dagmar Wieczorek, Andrew O M Wilkie, Ans M W van den Ouweland, Irene M J Mathijssen & Jane A Hurst

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Deep intronic hotspot variant explaining rhabdoid tumor predisposition syndrome in two patients with atypical teratoid and rhabdoid tumor

Deep intronic hotspot variant explaining rhabdoid tumor predisposition syndrome in two patients with atypical teratoid and rhabdoid tumor

European Journal of Human Genetics 25, 1170 (October 2017). doi:10.1038/ejhg.2017.115

Authors: Arnault Tauziède-Espariat, Julien Masliah-Planchon, Laurence Brugières, Stéphanie Puget, Christelle Dufour, Pascale Schneider, Annie Laquerrière, Thierry Frebourg, Damien Bodet, Emmanuèle Lechapt-Zalcman, Gaëlle Pierron, Olivier Delattre, Pascale Varlet & Franck Bourdeaut

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Clinical Utility Gene Card for hereditary angioedema with normal C1 inhibitor (HAEnC1)

Clinical Utility Gene Card for hereditary angioedema with normal C1 inhibitor (HAEnC1)

European Journal of Human Genetics 25, e1 (October 2017). doi:10.1038/ejhg.2017.104

Authors: Christiane Stieber, Sven Cichon, Markus Magerl & Markus M Nöthen

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Methods of Academic Course Planning for Cancer Biology PhD Students to Enhance Knowledge of Clinical Oncology

Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. Cancer Res; 77(18); 4741–4. ©2017 AACR.

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Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745–54. ©2017 AACR.

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HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types. Cancer Res; 77(18); 5039–53. ©2017 AACR.

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Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.

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Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1–expressing CAFs that share phenotypic and functional characteristics with bone marrow–derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1–positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced in vitro neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs in vitro and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. Cancer Res; 77(18); 5142–57. ©2017 AACR.

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The Damaging Effect of Passenger Mutations on Cancer Progression

Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution; most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (∼3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predict the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and an elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The antitumor effects of chemotherapies can in part be due to the induction of genomic instability and increased passenger load. Cancer Res; 77(18); 4763–72. ©2017 AACR.

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Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade

Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1-null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer. Cancer Res; 77(18); 4773–84. ©2017 AACR.

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Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR–PARG axis as an opportunity to enhance PARPi-based therapies. Cancer Res; 77(18); 5011–25. ©2017 AACR.

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Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells

Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome declustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in noncancer-derived cells disturbs neither spindle formation nor mitotic progression. Hence, the Nek6–Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes. Cancer Res; 77(18); 4785–96. ©2017 AACR.

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Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma

Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1–induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068–76. ©2017 AACR.

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Nrf2 Mutagenic Activation Drives Hepatocarcinogenesis

Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797–808. ©2017 AACR.

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CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity

CTL–associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4–Tyk2–STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118–28. ©2017 AACR.

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Spi-B-Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors

Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage–restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B–expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program. Cancer Res; 77(18); 4809–22. ©2017 AACR.

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Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression

A cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer–derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer. Cancer Res; 77(18); 5169–82. ©2017 AACR.

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CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1

Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res; 77(18); 4823–34. ©2017 AACR.

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An Essential Role of Maspin in Embryogenesis and Tumor Suppression—Response

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Identify a shared neural circuit linking multiple neuropsychiatric symptoms with Alzheimer’s pathology

Abstract

Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD)-associated neurodegeneration. However, NPS lack a consistent relationship with AD pathology. It is unknown whether any common neural circuits can link these clinically disparate while mechanistically similar features with AD pathology. Here, we explored the neural circuits of NPS in AD-associated neurodegeneration using multivariate pattern analysis (MVPA) of resting-state functional MRI data. Data from 98 subjects (70 amnestic mild cognitive impairment and 28 AD subjects) were obtained. The top 10 regions differentiating symptom presence across NPS were identified, which were mostly the fronto-limbic regions (medial prefrontal cortex, caudate, etc.). These 10 regions' functional connectivity classified symptomatic subjects across individual NPS at 69.46–81.27%, and predicted multiple NPS (indexed by Neuropsychiatric Symptom Questionnaire-Inventory) and AD pathology (indexed by baseline and change of beta-amyloid/pTau ratio) all above 70%. Our findings suggest a fronto-limbic dominated neural circuit that links multiple NPS and AD pathology. With further examination of the structural and pathological changes within the circuit, the circuit may shed light on linking behavioral disturbances with AD-associated neurodegeneration.

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Developmental trajectory of the prefrontal cortex: a systematic review of diffusion tensor imaging studies

Abstract

Fluctuations in gray and white matter volumes in addition to the fibers' reorganization and refinement of synaptic connectivity apparently happen in a particular temporo-spatial sequence during the dynamic and prolonged process of cerebral maturation. These developmental events are associated with regional modifications of brain tissues and neural circuits, contributing to networks' specialization and enhanced cognitive processing. According to several studies, improvements in cognitive processes are possibly myelin-dependent and associated to white matter maturation. Of particular interest is the developmental pattern of the prefrontal cortex (PFC), more specifically the PFC white matter, due to its role in high-level executive processes such as attention, working memory and inhibitory control. A systematic review of the literature was conducted using the Web of Science, PubMed and Embase databases to analyze the development of PFC white matter using Diffusion Tensor Imaging (DTI), a widely used non-invasive technique to assess white matter maturation. Both the research and reporting of results were based on Cochrane's recommendations and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Information extracted from 27 published studies revealed an increased myelination, organization and integrity of frontal white matter with age, as revealed by DTI indexes (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD] and axial diffusivity [AD]). These patterns highlight the extended developmental course of the frontal structural connectivity, which parallels the improvements in higher-level cognitive functions observed between adolescence and early adulthood.

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Feasibility and Efficacy of Mat Pilates on People with Mild-to-Moderate Parkinson's Disease: A Preliminary Study

Rejuvenation Research , Vol. 0, No. 0.


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Psoriasis

Psoriasis: A reddish, scaly rash often located over the surfaces of the elbows, knees, scalp, and around or in the ears, navel, genitals or buttocks. Psoriasis is an autoimmune disease that is mediated by T lymphocytes. It is also a very common disease, Chronic plaque psoriasis affects approximately 2% of people around the world. About 10% to 15% of patients with psoriasis develop joint inflammation (inflammatory arthritis). Treatment options include topical steroid creams, topical vitamin D derivatives, other medications, injections of biologic agents, and exposure to ultraviolet light.

See also: Erythrodermic psoriasis; Flexural psoriasis; Guttate psoriasis; Inverse psoriasis; Plaque psoriasis ; Psoriatic arthritis.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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The effect of diet or exercise on ectopic adiposity in children and adolescents with obesity: a systematic review and meta-analysis

Summary

Objective

Ectopic fat depostion in youth with obesity is associated with an increased cardiovascular disease risk. The aim of this meta-analysis was to summarize the evidence for the use of diet and/or exercise on ectopic adiposity in this population.

Methods

A systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Clinical trials that assessed ectopic fat deposition and included study arms with diet and/or exercise were searched in PubMed, PEDro and the Cochrane database.

Results

Hepatic fat content and intramyocellular lipid content were described in nine studies and three studies, respectively. Most studies included teenagers, and study duration ranged between 3 and 12 months without follow-up. Using random-effects weights, the standardized mean difference of the change in hepatic adiposity (totalling 320 subjects) was −0.54 Hedges' g (95% confidence interval: −0.69 to −0.38 with p < 0.0001). By re-expressing this effect size, it is seen that diet and/or exercise results in an absolute reduction of intrahepatic lipid with 2%, which accords with a relative reduction up to 70%. Although there were significant ameliorations of insulin sensitivity, no significant changes in intramyocellular lipid were observed.

Conclusions

This meta-analysis showed that diet and/or exercise is effective to reduce hepatic adiposity in youth with obesity.

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Newborn Thyroid Screening: Influence of Pre-Analytic Variables on Dried Blood Spot Thyrotropin Measurement

Thyroid Sep 2017, Vol. 27, No. 9: 1128-1134.


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Disease Severity at Presentation in Patients with Disease-Related Mortality from Differentiated Thyroid Cancer: Implications for the 2015 ATA Guidelines

Thyroid Sep 2017, Vol. 27, No. 9: 1171-1176.


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Future Meetings

Thyroid Sep 2017, Vol. 27, No. 9: 1211-1211.


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Idiopathic Low Ovarian Reserve Is Associated with More Frequent Positive Thyroid Peroxidase Antibodies

Thyroid Sep 2017, Vol. 27, No. 9: 1194-1200.


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Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports

Thyroid Sep 2017, Vol. 27, No. 9: 1201-1205.


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Clinical Implications of Immunoglobulin G4 to Graves' Ophthalmopathy

Thyroid Sep 2017, Vol. 27, No. 9: 1185-1193.


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Mammary phyllodes tumor with six episodes of a relapse: a case report

Phyllodes tumor is a rare breast mass. Most phyllodes tumors are benign, but occasionally some show malignancy. Even if the tumors are benign, they can easily show recurrence.

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Inner mechanism of protection of mitochondrial electron-transfer proteins against oxidative damage. Focus on hydrogen peroxide decomposition

Publication date: Available online 14 September 2017
Source:Biochimie
Author(s): Erik Sedlak, Andrej Musatov
It is generally recognized that the mitochondria are the major source of reactive oxygen species including hydrogen peroxide (H2O2). Although the local concentration of H2O2 near the electron-transfer chain is potentially quite high, the chain's components are rarely found to be significantly damaged by H2O2. Our experimental data, as well as the data published by others, suggest that mitochondrial electron-transfer proteins, which are in the first line to be harmed by ROS, are well prepared to defend themselves. One of such protection mechanism involves peroxidase/catalase-like activity of all major mitochondrial respiration chain players, which catalyze the decomposition of H2O2. Understanding the molecular mechanisms, by which mitochondrial electron-transfer proteins might defend themselves against an oxidative stress and therefore being a part of the mitochondrial antioxidant system, can help to clarify many controversial experimental data.



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Selectin-independent adhesion during ovarian cancer metastasis

Publication date: Available online 14 September 2017
Source:Biochimie
Author(s): Nadezhda A. Khaustova, Diana V. Maltseva, Leticia Oliveira-Ferrer, Christine Stürken, Karin Milde-Langosch, Julia A. Makarova, Sergey Rodin, Udo Schumacher, Alexander G. Tonevitsky
PurposeOvarian cancer (OvCa) progression mainly takes place by intraperitoneal spread. Adhesion of tumor cells to the mesothelial cells which form the inner surface of the peritoneum is a crucial step in this process. Cancer cells use in principle different molecules of the leukocyte adhesion cascade to facilitate adhesion. This cascade is initiated by selectin-ligand interactions followed by integrin - extracellular matrix protein interactions. Here we address the question whether all tumor cells predominantly employ selectin-dependent leukocyte-like adhesion cascade (SDAC) or whether they use integrin mediated adhesion for OvCa progression as well.MethodsA comparative transcriptomic analysis of the human OvCa cell lines OVCAR8 and SKOV3 was performed. Intraperitoneal xenograft model of OVCAR8 cells was used to determine whether there is a correlation between SDAC gene expression and the metastatic potential of the control cells and the cells overexpressing c-Fos. Transcriptomic analysis of OVCAR8 and SKOV3 samples was performed using microarrays.ResultsOne-third of the protein-coding genes involved in SDAC exhibited lower expression levels in OVCAR8 than in SKOV3 cells. In contrast to SKOV3 cells, c-Fos overexpression in OVCAR8 cells did not significantly influence the expression of SDAC genes. Intraperitoneal xenograft model of OVCAR8 cells unexpectedly demonstrated that the aggressiveness of OVCAR8 tumors was not depended on the c-Fos expression level and was comparable to that of SKOV3 control tumors. Gene expression analysis of tumors suggests that SKOV3-derived tumor progression was mainly depended on SDAC. Progression of OVCAR8 tumors relied on other cell adhesion molecules that do not interact with selectins.ConclusionsHigh expression of c-Fos in ovarian cancer cells is not always associated with reduced metastatic potential. Low expression level of SDAC genes may not ensure low OvCa metastatic potential. In addition to the classical selectin-dependent adhesion pathway alternative adhesion mechanisms involving laminin-integrin interactions might exist.



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The more you test, the more you find: The smallest P-values become increasingly enriched with real findings as more tests are conducted

ABSTRACT

The increasing accessibility of data to researchers makes it possible to conduct massive amounts of statistical testing. Rather than follow specific scientific hypotheses with statistical analysis, researchers can now test many possible relationships and let statistics generate hypotheses for them. The field of genetic epidemiology is an illustrative case, where testing of candidate genetic variants for association with an outcome has been replaced by agnostic screening of the entire genome. Poor replication rates of candidate gene studies have improved dramatically with the increase in genomic coverage, due to factors such as adoption of better statistical practices and availability of larger sample sizes. Here, we suggest that another important factor behind the improved replicability of genome-wide scans is an increase in the amount of statistical testing itself. We show that an increase in the number of tested hypotheses increases the proportion of true associations among the variants with the smallest P-values. We develop statistical theory to quantify how the expected proportion of genuine signals (EPGS) among top hits depends on the number of tests. This enrichment of top hits by real findings holds regardless of whether genome-wide statistical significance has been reached in a study. Moreover, if we consider only those "failed" studies that produce no statistically significant results, the same enrichment phenomenon takes place: the proportion of true associations among top hits grows with the number of tests. The enrichment occurs even if the true signals are encountered at the logarithmically decreasing rate with the additional testing.

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Analysis of cancer gene expression data with an assisted robust marker identification approach

ABSTRACT

Gene expression (GE) studies have been playing a critical role in cancer research. Despite tremendous effort, the analysis results are still often unsatisfactory, because of the weak signals and high data dimensionality. Analysis is often further challenged by the long-tailed distributions of the outcome variables. In recent multidimensional studies, data have been collected on GEs as well as their regulators (e.g., copy number alterations (CNAs), methylation, and microRNAs), which can provide additional information on the associations between GEs and cancer outcomes. In this study, we develop an ARMI (assisted robust marker identification) approach for analyzing cancer studies with measurements on GEs as well as regulators. The proposed approach borrows information from regulators and can be more effective than analyzing GE data alone. A robust objective function is adopted to accommodate long-tailed distributions. Marker identification is effectively realized using penalization. The proposed approach has an intuitive formulation and is computationally much affordable. Simulation shows its satisfactory performance under a variety of settings. TCGA (The Cancer Genome Atlas) data on melanoma and lung cancer are analyzed, which leads to biologically plausible marker identification and superior prediction.

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Salvage brachytherapy for radiorecurrent prostate cancer: Searching for safety and success

Publication date: Available online 14 September 2017
Source:Brachytherapy
Author(s): Max Peters, Marinus A. Moerland, Jochem R.N. van der Voort van Zyp




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Analysis of cancer gene expression data with an assisted robust marker identification approach

ABSTRACT

Gene expression (GE) studies have been playing a critical role in cancer research. Despite tremendous effort, the analysis results are still often unsatisfactory, because of the weak signals and high data dimensionality. Analysis is often further challenged by the long-tailed distributions of the outcome variables. In recent multidimensional studies, data have been collected on GEs as well as their regulators (e.g., copy number alterations (CNAs), methylation, and microRNAs), which can provide additional information on the associations between GEs and cancer outcomes. In this study, we develop an ARMI (assisted robust marker identification) approach for analyzing cancer studies with measurements on GEs as well as regulators. The proposed approach borrows information from regulators and can be more effective than analyzing GE data alone. A robust objective function is adopted to accommodate long-tailed distributions. Marker identification is effectively realized using penalization. The proposed approach has an intuitive formulation and is computationally much affordable. Simulation shows its satisfactory performance under a variety of settings. TCGA (The Cancer Genome Atlas) data on melanoma and lung cancer are analyzed, which leads to biologically plausible marker identification and superior prediction.

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