Fungal Keratitis: Epidemiology, Rapid Detection, and Antifungal Susceptibilities of Fusarium and Aspergillus Isolates from Corneal Scrapings

Fungal aetiology of keratitis/corneal ulcer is considered to be one of the leading causes of ocular morbidity, particularly in developing countries including India. More importantly, Fusarium and Aspergillus are reported commonly implicating corneal ulcer and against this background the present work was undertaken so as to understand the current epidemiological trend of the two fungal keratitis. During the project period, a total of 500 corneal scrapings were collected from suspected mycotic keratitis patients, of which 411 (82.2%) were culture positive for bacteria, fungi, and parasites. Among fungal aetiologies, Fusarium (216, 52.5% of 411) and Aspergillus (68, 16.5% of 411) were predominantly determined. While the study revealed a male preponderance with both the fungal keratitis , it further brought out that polyene compounds (natamycin and amphotericin B) and azoles were active, respectively, against Fusarium spp. and Aspergillus spp. Additionally, 94.1% of culture proven Fusarium keratitis and, respectively, 100% and 63.6% of A. flavus and A. fumigatus were confirmed by multiplex PCR. The sensitivity of the PCR employed in the present study was noted to be 10 fg/μl, 1 pg/μl, and 300 pg/μl of DNA, respectively, for Fusarium, A. flavus, and A. fumigatus. Alarming fact was that Fusarium and Aspergillus regionally remained to be the common cause of mycotic keratitis and the Fusarium isolates had a higher antifungal resistance than Aspergillus strains against most of the test drugs.

http://bit.ly/2T2tMV5

Transcatheter Arterial Embolization Compared With Surgery for Uncontrolled Peptic Ulcer Bleeding: A Population-based Cohort Study

Objective: To compare key outcomes after transcatheter arterial embolization (TAE) with conventional surgery for peptic ulcer bleeding when endoscopic intervention fails to achieve hemostasis. Background: Mortality in peptic ulcer bleeding remains high, especially in patients who require surgical treatment. Methods: A population-based cohort study in Stockholm, Sweden, in 2000 to 2014, assessing the main outcome all-cause mortality and the secondary outcomes re-bleeding, re-intervention, length of hospitalization, and complications, was conducted. Data were taken from well-maintained registries and medical records. Multivariable Cox-regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, ulcer history, comorbidity, and calendar period were considered. Results: Included were 282 patients, 97 in the TAE group and 185 in the surgery group. Compared with the surgery group, the overall hazard of death was 34% decreased in the TAE group (adjusted HR 0.66, 95% CI 0.46–0.96). The corresponding HRs for mortality within 30 days, 90 days, 1 year, and 5 years were 0.70 (95% CI 0.37–1.35), 0.69 (95% CI 0.38–1.26), 0.88 (95% CI 0.53–1.47), and 0.67 (95% CI 0.45–1.00), respectively. The risk of re-bleeding was higher after TAE compared with surgery (HR 2.48, 95% CI 1.33–4.62). The median length of hospital stay was shorter in the TAE group—8 versus 16 days—acceleration factor 0.59 (95% CI 0.45–0.77) and the risk of complications was lower (8.3% vs 32.2%; P

http://bit.ly/2AMl46z

Leadership in American Surgery: Women are Rising to the Top

No abstract available

http://bit.ly/2SJ12kf

No Surgical Innovation Without Evaluation: Evolution and Further Development of the IDEAL Framework and Recommendations

Objective: To update, clarify, and extend IDEAL concepts and recommendations. Background: New surgical procedures, devices, and other complex interventions need robust evaluation for safety, efficacy, and effectiveness. Unlike new medicines, there is no internationally agreed evaluation pathway for generating and analyzing data throughout the life cycle of surgical innovations. The IDEAL Framework and Recommendations were designed to provide this pathway and they have been used increasingly since their introduction in 2009. Based on a Delphi survey, expert workshop and major discussions during IDEAL conferences held in Oxford (2016) and New York (2017), this article updates and extends the IDEAL Recommendations, identifies areas for future research, and discusses the ethical problems faced by investigators at each IDEAL stage. Methods: The IDEAL Framework describes 5 stages of evolution for new surgical therapeutic interventions—Idea, Development, Exploration, Assessment, and Long-term Study. This comprehensive update proposes several modifications. First, a "Pre-IDEAL" stage describing preclinical studies has been added. Second we discuss potential adaptations to expand the scope of IDEAL (originally designed for surgical procedures) to accommodate therapeutic devices, through an IDEAL-D variant. Third, we explicitly recognise the value of comprehensive data collection through registries at all stages in the Framework and fourth, we examine the ethical issues that arise at each stage of IDEAL and underpin the recommendations. The Recommendations for each stage are reviewed, clarified and additional detail added. Conclusions: The intention of this article is to widen the practical use of IDEAL by clarifying the rationale for and practical details of the Recommendations. Additional research based on the experience of implementing these Recommendations is needed to further improve them.

http://bit.ly/2SLJuEa

Management of Reducible Ventral Hernias: Clinical Outcomes and Cost-effectiveness of Repair at Diagnosis Versus Watchful Waiting

Objective: To compare long-term clinical and economic outcomes associated with 3 management strategies for reducible ventral hernia: repair at diagnosis (open or laparoscopic) and watchful waiting. Background: There is variability in ventral hernia management. Recent data suggest watchful waiting is safe; however, long-term clinical and economic outcomes for different management strategies remain unknown. Methods: We built a state-transition microsimulation model to forecast outcomes for individuals with reducible ventral hernia, simulating a cohort of 1 million individuals for each strategy. We derived cohort characteristics (mean age 58 years, 63% female), hospital costs, and perioperative mortality from the Nationwide Inpatient Sample (2003–2011), and additional probabilities, costs, and utilities from the literature. Outcomes included prevalence of any repair, emergent repair, and recurrence; lifetime costs; quality-adjusted life years (QALYs); and incremental cost-effectiveness ratios. We performed stochastic and probabilistic sensitivity analyses to identify parameter thresholds that affect optimal management, using a willingness-to-pay threshold of $50,000/QALY. Results: With watchful waiting, 39% ultimately required repair (14% emergent) and 24% recurred. Seventy per cent recurred with repair at diagnosis. Laparoscopic repair at diagnosis was cost-effective compared with open repair at diagnosis (incremental cost-effectiveness ratio $27,700/QALY). The choice of operative strategy (open vs laparoscopic) was sensitive to cost and postoperative quality of life. When perioperative mortality exceeded 5.2% or yearly recurrence exceeded 19.2%, watchful waiting became preferred. Conclusions: Ventral hernia repair at diagnosis is very cost-effective. The choice between open and laparoscopic repair depends on surgical costs and postoperative quality of life. In patients with high risk of perioperative mortality or recurrence, watchful waiting is preferred.

http://bit.ly/2AB8bMc

Characteristics of Effective Mentorship for Academic Surgeons: A Grounded Theory Model

Objective: The authors sought to describe characteristics of effective mentoring relationships in academic surgery based upon lived experiences of mid-career and senior female academic surgeons. Background: Prior qualitative work describes characteristics of successful mentoring relationships. However, no model exists of effective mentorship that is specific to academic surgery. Methods: The authors conducted in-depth interviews with mid-career and senior female US academic surgeons about the impact of mentoring on professional development during 2014 and 2015. Purposive selection aimed to maximize institutional, specialty, years in career, and racial diversity. Grounded theory method was used to generate a conceptual model of effective mentoring relationships. Data saturation occurred following 15 interviews. Results: Interviewees described the need for multiple mentors over time with each mentor addressing a unique domain. Interviewees suggested that mentees should seek mentors who will serve as strategic advisors, who will be unselfish, and who engage with diverse mentees. Conclusions: This study identified a need for multiple mentors across time and disciplines, and identified 3 key characteristics of effective mentoring relationships in academic surgery. Future work in this area should generate an operational definition of mentorship that supports quantitative evaluation of mentor and mentoring panel performance.

http://bit.ly/2SLJunE

A Successful Case of Cholangioscope‐assisted Extraction of a radiolucent intrahepatic bile duct stent

Abstract

We report a case of a 63‐year‐old man with a history of pancreatic cancer who underwent pylorus‐pancreaticoduodenectomy and Child's reconstruction in eight years before, and a radiolucent stent (Atom Medical, Tokyo, Japan) was placed in the choledochojejunostomy then. Following surgery, the patient presented with recurrent cholangitis. Though the mild dilation of bile duct of the anterior lobe, the cause of cholangitis remained unelucidated. Eight years after surgery, several liver abscesses (S8) were diagnosed (Figure 1a). Ultrasound revealed a linear object in the bile duct of the anterior lobe, which was thought to be the radiolucent stent.

This article is protected by copyright. All rights reserved.

http://bit.ly/2DoEXlF

Cancers, Vol. 11, Pages 118: Oral Administration of Fermented Papaya (FPP®) Controls the Growth of a Murine Melanoma through the In Vivo Induction of a Natural Antioxidant Response

Cancers, Vol. 11, Pages 118: Oral Administration of Fermented Papaya (FPP®) Controls the Growth of a Murine Melanoma through the In Vivo Induction of a Natural Antioxidant Response

Cancers doi: 10.3390/cancers11010118

Authors: Mariantonia Logozzi Davide Mizzoni Rossella Di Raimo Daniele Macchia Massimo Spada Stefano Fais

Prolonged oxidative stress may play a key role in tumor development. Antioxidant molecules are contained in many foods and seem to have a potential role in future anti-tumor strategies. Among the natural antioxidants the beneficial effect of Fermented Papaya (FPP®) is well known. The aim of this study was to investigate the effects of orally administered FPP® in either the prevention or treatment of a murine model of melanoma. The tumor growth was analyzed together with the blood levels of both oxidants (ROS) and anti-oxidants (SOD-1 and GSH). The results showed that FPP® controlled tumor growth, reducing the tumor mass of about three to seven times vs. untreated mice. The most significant effect was obtained with sublingual administration of FPP® close to the inoculation of melanoma. At the time of the sacrifice none of mice treated with FPP® had metastases and the subcutaneous tumors were significantly smaller and amelanotic, compared to untreated mice. Moreover, the FPP® anti-tumor effect was consistent with the decrease of total ROS levels and the increase in the blood levels of GSH and SOD-1. This study shows that a potent anti-oxidant treatment through FPP® may contribute to both preventing and inhibiting tumors growth.

http://bit.ly/2Mjfugh

Retinal measurements predict 10‐year disability in multiple sclerosis

Abstract

Objective

Optical coherence tomography (OCT)‐derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long‐term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later.

Methods

Between 2006 and 2008, 172 people with MS underwent Stratus time domain‐OCT imaging [160 with measurement of total macular volume (TMV)] and high and low‐contrast letter acuity (LCLA) testing (n = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10‐year follow‐up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10‐year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status.

Results

In multivariable models, lower baseline TMV was associated with higher 10‐year EDSS scores (mean increase in EDSS of 0.75 per 1 mm³ loss in TMV (mean difference = 0.75; 95% CI: 0.11–1.39; P = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23–1.48) and had over 3.5‐fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30–9.82; P _trend = 0.008). pRNFL and LCLA predicted the 10‐year EDSS scores only in univariate models.

Interpretation

Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.

http://bit.ly/2QXsdWM

After the Storm — A Responsible Path for Genome Editing

New England Journal of Medicine, Ahead of Print.


http://bit.ly/2SWQ5vl

Steering CAR T Cells into Solid Tumors

New England Journal of Medicine, Volume 380, Issue 3, Page 289-291, January 2019.


http://bit.ly/2ANXg1U

Better Words for Better Deaths

New England Journal of Medicine, Volume 380, Issue 3, Page 211-213, January 2019.


http://bit.ly/2SXz4RV

Erythema Gyratum Repens Associated with Anal Cancer

New England Journal of Medicine, Volume 380, Issue 3, January 2019.


http://bit.ly/2ARGRtl

The Future of Gene Editing — Toward Scientific and Social Consensus

New England Journal of Medicine, Ahead of Print.


http://bit.ly/2STuRi8

The Structural Violence of Hyperincarceration — A 44-Year-Old Man with Back Pain

New England Journal of Medicine, Volume 380, Issue 3, Page 205-209, January 2019.


http://bit.ly/2ANXcPI

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria

New England Journal of Medicine, Volume 380, Issue 3, Page 229-241, January 2019.


http://bit.ly/2SUbsxf

Case 2-2019: A 36-Year-Old Man with Rash, Abdominal Pain, and Lymphadenopathy

New England Journal of Medicine, Volume 380, Issue 3, Page 275-283, January 2019.


http://bit.ly/2AM5HuE

Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria

New England Journal of Medicine, Volume 380, Issue 3, Page 215-228, January 2019.


http://bit.ly/2SZYH4j

Tafenoquine — A Radical Improvement?

New England Journal of Medicine, Volume 380, Issue 3, Page 285-286, January 2019.


http://bit.ly/2AQ9Rlr

Coronary CT Angiography and Subsequent Risk of Myocardial Infarction

New England Journal of Medicine, Volume 380, Issue 3, Page 298-300, January 2019.


http://bit.ly/2AL99FJ

Climate Change — A Health Emergency

New England Journal of Medicine, Volume 380, Issue 3, Page 209-211, January 2019.


http://bit.ly/2SYUrlV

The Imperative for Climate Action to Protect Health

New England Journal of Medicine, Volume 380, Issue 3, Page 263-273, January 2019.


http://bit.ly/2SZlk94

Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation

New England Journal of Medicine, Volume 380, Issue 3, Page 302-302, January 2019.


http://bit.ly/2AJeTA3

Vasa Previa

New England Journal of Medicine, Volume 380, Issue 3, Page 274-274, January 2019.


http://bit.ly/2STZ14G

Platelet Transfusions in Neonates — Less Is More

New England Journal of Medicine, Volume 380, Issue 3, Page 287-288, January 2019.


http://bit.ly/2ANX3vE

Risk of Human T-Cell Leukemia Virus Type 1 Infection in Kidney Transplantation

New England Journal of Medicine, Volume 380, Issue 3, Page 296-298, January 2019.


http://bit.ly/2SUbsgJ

Brain Change in Addiction as Learning, Not Disease

New England Journal of Medicine, Volume 380, Issue 3, Page 301-302, January 2019.


http://bit.ly/2SYpgXP

The Spy Who Came In with a Cold

New England Journal of Medicine, Volume 380, Issue 3, Page 292-295, January 2019.


http://bit.ly/2AOJzjb

Rogues and Regulation of Germline Editing

New England Journal of Medicine, Ahead of Print.


http://bit.ly/2AZIqpp

Cancers, Vol. 11, Pages 117: A Barter Economy in Tumors: Exchanging Metabolites through Gap Junctions

Cancers, Vol. 11, Pages 117: A Barter Economy in Tumors: Exchanging Metabolites through Gap Junctions

Cancers doi: 10.3390/cancers11010117

Authors: Pawel Swietach Stefania Monterisi

To produce physiological functions, many tissues require their cells to be connected by gap junctions. Such diffusive coupling is important in establishing a cytoplasmic syncytium through which cells can exchange signals, substrates and metabolites. Often the benefits of connectivity become apparent solely at the multicellular level, leading to the notion that cells work for a common good rather than exclusively in their self-interest. In some tumors, gap junctional connectivity between cancer cells is reduced or absent, but there are notable cases where it persists or re-emerges in late-stage disease. Diffusive coupling will blur certain phenotypic differences between cells, which may seem to go against the establishment of population heterogeneity, a central pillar of cancer that stems from genetic instability. Here, building on our previous measurements of gap junctional coupling between cancer cells, we use a computational model to simulate the role of connexin-assembled channels in exchanging lactate and bicarbonate ions down their diffusion gradients. Based on the results of these simulations, we propose that an overriding benefit of gap junctional connectivity may relate to lactate/bicarbonate exchange, which would support an elevated metabolic rate in hypoxic tumors. In this example of barter, hypoxic cancer cells provide normoxic neighbors with lactate for mitochondrial oxidation; in exchange, bicarbonate ions, which are more plentiful in normoxic cells, are supplied to hypoxic neighbors to neutralize the H+ ions co-produced glycolytically. Both cells benefit, and so does the tumor.

http://bit.ly/2RCP2nN

Downregulation of SPARC Is Associated with Epithelial-Mesenchymal Transition and Low Differentiation State of Biliary Tract Cancer Cells

Background: Biliary tract cancers (BTCs) have a poor prognosis. BTCs are characterized by a prominent desmoplastic reaction which possibly contributes to the aggressive phenotype of this tumor. The desmoplastic reaction includes excessive production and deposition of extracellular matrix proteins such as periostin, secreted protein acidic and rich in cysteine (SPARC), thrombospondin-1, as well as accumulation of α-smooth muscle actin-positive cancer-associated fibroblasts and immune cells, secreting growth factors and cytokines including transforming growth factor (TGF)-β. In the present study, we investigated the expression of SPARC in BTC as well as its possible regulation by TGF-β. Methods: Expression levels of Sparc, TGF-β1 and its receptor ALK5 were evaluated by quantitative real-time PCR in 6 biliary tract cell lines as well as 1 immortalized cholangiocyte cell line (MMNK-1). RNAs from tumor samples of 7 biliary tract cancer patients were analyzed for expression of Sparc, TGF-β type II receptor (TbRII) as well as Twist and ZO-1. MMNK-1 cells were stimulated with TGF-β for 24 h, and Sparc, ZO-1 and E-Cadherin expressions were determined. The presence of SPARC protein was analyzed by immunohistochemistry in tumor specimens from 10 patients. Results: When comparing basal Sparc transcript levels in diverse BTC cell lines to MMNK-1 cells, we found that it was strongly downregulated in all cancer cell lines. The remaining expression levels were higher in highly differentiated cell lines (CCSW1, MZChA1, MZChA2 and TFK-1) than in less differentiated and undifferentiated ones (BDC, SKChA1). Expression of Sparc in BTC patient samples showed a significant positive correlation with expression of the epithelial marker ZO-1. In contrast, the mesenchymal marker Twist and the TbRII showed a trend of negative correlation with expression of Sparc in these samples. TGF-β exposure significantly downregulated Sparc expression in MMNK-1 cholangiocytes in vitro in parallel to downregulation of epithelial markers (E-Cadherin and ZO-1). Finally, SPARC immunostaining was performed in 10 patient samples, and the correlation between absence of SPARC and survival times was analyzed. Conclusions: These data imply that a decrease in SPARC expression is correlated with dedifferentiation of BTC cells resulting in enhanced EMT being possibly mediated by TGF-β. Thereby SPARC levels might be a marker for individual prognosis of a patient, and strategies aiming at inhibition of SPARC downregulation might have potential for new future therapies.
Eur Surg Res 2019;60:1–12

http://bit.ly/2szdRSL

Different Types of Maculopathy in Eyes after a High-Voltage Electrical Shock Injury

Background: We report a case of different types of maculopathy in eyes after a high-voltage electrical shock injury. Case Report: A 43-year-old male suffered high-voltage electrical injury through his left arm. He underwent cataract surgery in both eyes 3 months after the injury, but there was no vision improvement. Ocular examination, including spectral domain optical coherence tomography, revealed diffuse retinal atrophy in the left eye which did not change until the final visit. In the right eye, an impending macular hole was observed but regressed spontaneously 9 months after the injury, and the visual acuity improved to 20/32 at the final visit. Conclusion: Two different types of maculopathy can occur in each eye after high-voltage electrical shock injury, and this might be due to asymmetric pathogenesis of the eyes according to the proximity to the route of electrical current.
Case Rep Ophthalmol 2019;10:19–23

http://bit.ly/2RYYXDx

The Difficulty of Diagnosing Invasive Aspergillosis Initially Manifesting as Optic Neuropathy

Background: Invasive aspergillosis is often fatal. Here, we report a patient with invasive aspergillosis primarily involving the optic nerve diagnosed on autopsy. Case Presentation: A 77-year-old female with underlying diabetes mellitus, hyperlipidemia, and hypertension presented with disc swelling of the left eye. Although mini-pulse steroid therapy improved visual acuity (VA) of the left eye, it abruptly decreased to no light perception within a month, followed by a decrease in VA of the right eye to 0.5. At referral, VA was 0.3 in the right eye, and there was no light perception in the left eye. Results: Fundus examination revealed optic disc swelling of both eyes. Goldmann perimetry showed irregular visual field defects, whereas magnetic resonance imaging (MRI), general, and cerebrospinal fluid (CSF) examinations revealed no distinct abnormalities. We suspected anterior ischemic optic neuropathy and invasive optic neuropathy. As with the left eye, steroid pulse therapy temporarily improved VA of the right eye and then decreased to 0.2. Additional anticoagulant therapy did not improve VA. Concurrent to therapy, the patient became febrile with depressed consciousness. Repeat MRI identified suspected midbrain infarction, and CSF examination indicated cerebral meningitis. In spite of administering transfusions and antibiotics, she died on hospital day 40. Autopsy revealed large amounts of Aspergillus hyphae mainly localized in the dura mater of the optic nerve and destruction of the cerebral artery wall, suggesting an etiology of subarachnoid hemorrhage. Conclusions: When examining refractory and persistent disc swelling, we should rule out fungal infections of the optic nerve.
Case Rep Ophthalmol 2019;10:11–18

http://bit.ly/2Hn8ksN

Metformin Use and Kidney Cancer Survival Outcomes: A Systematic Review and Meta-Analysis

Objectives: Metformin has been associated with improved survival outcomes in various malignancies. However, studies in kidney cancer are conflicting. We performed a systematic review and meta-analysis to evaluate the association between metformin and kidney cancer survival. Materials and Methods: We searched Medline and EMBASE databases from inception to June 2017 to identify studies evaluating the association between metformin use and kidney cancer survival outcomes. We evaluated risk of bias with the Newcastle-Ottawa scale. We pooled hazard ratios (HRs) for recurrence-free, progression-free, cancer-specific, and overall survival using random effects models, and explored heterogeneity with metaregression. We evaluated publication bias through Begg's and Egger's tests, and the trim and fill procedure. Results: We identified 9 studies meeting inclusion criteria, collectively involving 7426 patients. Five studies were at low risk of bias. The direction of association for metformin use was toward benefit for recurrence-free survival (HR, 0.99; 95% confidence interval [CI], 0.36-2.74), progression-free survival (pooled HR, 0.84; 95% CI, 0.66-1.07), cancer-specific (pooled HR, 0.72; 95% CI, 0.48-1.09), and overall survival (pooled HR, 0.73; 95% CI, 0.50-1.09), though none reached statistical significance. Metaregression found no study-level characteristic to be associated with the effect size, and there was no strong evidence of publication bias for any outcome. Conclusions: There is no evidence of a statistically significant association between metformin use and any survival outcome in kidney cancer. We discuss the potential for bias in chemoprevention studies and provide recommendations to reduce bias in future studies evaluating metformin in kidney cancer. The authors declare no conflicts of interest. Reprints: Robert J. Hamilton, MD, MPH, Department of Surgery Princess Margaret Cancer Centre, Division of Urology, University Health Network 610 University, Ave 3-130, Toronto, ON, Canada M5G 2M9. E-mail: rob.hamilton@uhn.ca. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2MlwZwG

Impact of Primary Care Access on Mortality of Lung Cancer Patients in an Underserved Community

Background: Lack of access to primary care physicians (PCPs) may be an important contributor to mortality differences attributed to race/ethnicity. This study examined the effects of primary care access on mortality of lung cancer patients in an underserved community. Methods: Medical records of all newly diagnosed patients with primary lung cancer from 2012 to 2016 at a National Cancer Institute (NCI)-designated center in Bronx, New York were reviewed. Demographic data, PCP status, and residence in primary care shortage areas (PCSAs) were collected. Survival data from time of first imaging to death or the end of follow-up on January 1, 2018 were recorded. Survival analysis was performed using Kaplan-Meier and Cox hazards modeling. Results: Among 1062 patients, 874 (82%) were PCSA residents, 314 (30%) were Hispanic, and 445 (42%) were African American. PCSA residents were likely Hispanics (P

http://bit.ly/2szegEL

Effect of exosomes derived from MiR-133b-modified ADSCs on the recovery of neurological function after SCI

OBJECTIVE: To investigate the recovery effect of exosomes derived from micro ribonucleic acid (miR)-133b-modified adipose-derived stem cells (ADSCs) on neurological function after spinal cord injury (SCI) and its mechanism.

MATERIALS AND METHODS: The SCI model of rats was used and divided into the following 5 groups: sham-operation group, 4 d SCI group, phosphate-buffered saline (PBS) group, miR-control group and miR-133b group. At 96 h after operation, rats were euthanatized, and spinal tissues were removed. Next, the level of miR-133b was detected via reverse transcription-polymerase chain reaction (RT-PCR), and the expression of RhoA protein was measured via Western blotting. Moreover, expressions of proteins associated with the axon regeneration pathway, including phosphorylated-cAMP-response element binding protein (p-CREB), CREB, phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) and STAT3, along with expressions of neurofilament (NF), growth associated protein 43 (GAP43), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP), were tested by Western blotting and immunofluorescence staining.

RESULTS: The miR-133b mimics significantly upregulated the expression of miR-133b in adipose-derived stem cells (ADSCs), compared to blank group (p<0.05). The expression of miR-133b was significantly decreased in 4 d SCI group compared with that in sham-operation group (p<0.001). The RhoA expression was statistically increased in 4 d SCI group compared with that in sham-operation group (p<0.001), and it was partially impaired by using miR-133b compared with that in 4 d SCI group (p<0.001). Expressions of NF, GAP43, GFAP and MBP were remarkably higher in 4 d SCI group than those in sham-operation group (p<0.01), and they were also significantly increased in miR-133b group than those in 4 d SCI group (p<0.01). Besides, our data showed a significant increase of p-CREB/CREB, p-STAT3/STAT3, NF, GAP-43, GFAP and MBP in miR-133b group compared to those in 4 d SCI group, with statistical reduction of RhoA (p<0.05).

CONCLUSIONS: We showed that exosomes derived from miR-133b-modified ADSCs can significantly promote the recovery of neurological function of SCI animals through affecting the signaling pathway related to axon regeneration and expressions of NF, GAP-43, GFAP and MBP.

L'articolo Effect of exosomes derived from MiR-133b-modified ADSCs on the recovery of neurological function after SCI sembra essere il primo su European Review.

http://bit.ly/2SPTdco

Repairing effect of Schwann cells combined with mesenchymal stem cells on optic nerve injury in rats

OBJECTIVE: To investigate the effect and the underlying mechanisms of combined transplantation of Schwann cells (Scs) and Mesenchymal stem cells (MSCs) on optic nerve injury in rats.

MATERIALS AND METHODS: A total of 160 normal healthy adult rats were randomly divided into 4 groups: optic nerve injury group, optic nerve injury + Sc transplantation group, optic nerve injury + MSC transplantation group and optic nerve injury + Sc + MSC transplantation group. The optic nerve in the left eye of each rat was damaged via clamping to establish a model of optic nerve injury, and the right eye was used as self-control. Scs + MSCs, Scs alone, MSCs alone and normal saline were injected into the vitreous space, respectively. After the treatment, the optic nerve tissues were collected and subjected to hematoxylin-eosin (HE) staining. Next, the morphologic and pathological changes of rats in each group were observed. Retrograde labeling was utilized to count the number of retinal ganglion cells (RGCs) in the optic nerve tissues. The apoptosis of RGCs was detected using flow cytometry. Western blot was carried out to measure the protein expression level of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). The expression and distribution of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) in the optic nerve of rats in each group were detected by immunohistochemistry.

RESULTS: Transplantation of Scs and MSCs could maintain the morphological structures of the retina and optic nerve of rats, increase the amount of RGCs in optic nerve tissues, reduce the apoptosis of RGCs, promote the expression of the Bcl-2 protein and decrease the expression of Bax protein. In addition, our joint transplantation strategy also showed an important role in repairing optic nerve injury by clearly promoting the secretion and expression of BDNF and GAP-43, which indicated a better curative effect than that of separate application of Scs or MSCs.

CONCLUSIONS: Therapy with combined use of Scs and MSCs has a significant therapeutic effect in repairing optic nerve injury.

L'articolo Repairing effect of Schwann cells combined with mesenchymal stem cells on optic nerve injury in rats sembra essere il primo su European Review.

http://bit.ly/2S1aWQU

Expression of T follicular helper lymphocytes with different subsets and analysis of serum IL-6, IL-17, TGF-β and MMP-3 contents in patients with rheumatoid arthritis

OBJECTIVE: To investigate the expression levels of T follicular helper (Tfh) with different subsets in patients with rheumatoid arthritis (RA) and their serum interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and matrix metalloproteinase 3 (MMP-3) contents.

PATIENTS AND METHODS: The medical records of 45 RA patients in the Department of Rheumatology and Immunology in the First Affiliated Hospital of Chengdu Medical College from January 2016 to April 2018 were retrospectively analyzed. They were divided into the RA high activity group (24 cases, group A) (DAS28 score ≥ 5.0) and RA low activity group (21 cases, group B) (3.2 < DAS28 score < 5.0). At the same time, 20 healthy subjects were selected as a control group. Flow cytometry was used to detect the expression levels of Tfh1, Tfh2 and Tfh17, enzyme-linked immunosorbent assay to detect serum IL-6, IL-17, IL-21 and MMP-3 concentrations. The correlation of Tfh cells with IL-6, IL-17, IL-21 and MMP-3 was analyzed.

RESULTS: Those of peripheral blood mononuclear cell (PBMC) Tfh2 and Tfh17 cells were significantly higher in group A than those in group B (p < 0.05). Compared with the control group, the concentrations of serum IL-6, IL-17 and MMP-3 significantly increased (p < 0.001), but that of serum TGF-β markedly decreased in group A and group B (p < 0.01). The concentrations of serum IL-6, IL-17 and MMP-3 were remarkably higher in group A than those in group B (p < 0.001), but that of serum TGF-β was significantly lower in group A than that in group B (p < 0.001). The expression level of PBMC Tfh2 cells, PBMC Tfh17 cells was positively correlated with serum IL-6, IL-17 and MMP-3. The expression levels of Tfh2 and Tfh17 cells are positively correlated with serum IL-6, IL-17 and MMP-3 concentrations, negatively correlated with serum TGF-β concentration.

CONCLUSIONS: Tfh2 and Tfh17 are expected to be new targets for immunotherapy in RA patients.

L'articolo Expression of T follicular helper lymphocytes with different subsets and analysis of serum IL-6, IL-17, TGF-β and MMP-3 contents in patients with rheumatoid arthritis sembra essere il primo su European Review.

http://bit.ly/2AMUWZ1

Adverse events need for hospitalization and systemic immunosuppression in very elderly patients (over 80 years) treated with ipilimumab for metastatic melanoma

Abstract

Background

Checkpoint inhibitors are first-line therapies in melanoma, but safety in older adults has not yet been assessed. Ipilimumab improves survival, but immunologic-related adverse events (AEs) can be threatening, and its use in elderly people raises questions.

Aim

To assess safety in a cohort of very elderly patients treated with ipilimumab.

Methods

All patients over 80 years treated with ipilimumab for melanoma were retrospectively included. AE occurrence, management, and outcome, as well as response rate at week 16 and overall survival were recorded, and compared to data for a group of younger patients treated in our institution during the same period.

Results

In the elderly group, 23 patients were included with a median age of 82 years [80–90]. AEs amounting to 23 occurred in 15 patients (65%) with 5 grade 3 (22%) and 1 grade 5 (opportunistic infection) AEs. Corticosteroids were required for five (22%) patients, additive immunosuppressive therapy for two, hospitalization for four, and definitive interruption of ipilimumab for three. Median overall survival was 14 months. In the younger group, 29 patients were included with a median age of 58 years. AEs occurred in 15/29 (52%) with 4 grade 3 (19%) and 1 grade 4 (7%). Median OS was 17 months.

Conclusion

Serious AEs occurred in 80 + adults at the same rate as observed in our younger patients and as previously reported in younger populations. Ipilimumab can be an option in elderly patients, as patients may benefit from therapy and safety seems to be manageable.

http://bit.ly/2Taeiyg

The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial

Abstract

For the treatment of metastatic renal cell cancer several strategies are used among which the mTOR inhibitor everolimus. As mTOR plays an important role in the immune system, e.g., by controlling the expression of the transcription factor FoxP3 thereby regulating regulatory T cells (Tregs), it plays a key role in the balance between tolerance and inflammation. Previous reports showed stimulatory effects of mTOR inhibition on the expansion of Tregs, an effect that can be considered detrimental in terms of cancer control. Since metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs, a phase 1 clinical trial was conducted to comprehensively investigate the immune-modulating effects of several dosages and schedules of CTX in combination with the standard dose of everolimus, with the explicit aim to achieve selective Treg depletion. Our data show that 50 mg of CTX once daily and continuously administered, in combination with the standard dose of 10 mg everolimus once daily, not only results in depletion of Tregs, but also leads to a reduction in MDSC, a sustained level of the CD8⁺ T-cell population accompanied by an increased effector to suppressor ratio, and reversal of negative effects on three peripheral blood DC subsets. These positive effects on the immune response may contribute to improved survival, and therefore this combination therapy is further evaluated in a phase II clinical trial.

http://bit.ly/2QUmxN5

Strong antigen-specific T-cell immunity induced by a recombinant human TERT measles virus vaccine and amplified by a DNA/viral vector prime boost in IFNAR/CD46 mice

Abstract

Cancer immunotherapy is seeing an increasing focus on vaccination with tumor-associated antigens (TAAs). Human telomerase (hTERT) is a TAA expressed by most tumors to overcome telomere shortening. Tolerance to hTERT can be easily broken both naturally and experimentally and hTERT DNA vaccine candidates have been introduced in clinical trials. DNA prime/boost strategies have been widely developed to immunize efficiently against infectious diseases. We explored the use of a recombinant measles virus (MV) hTERT vector to boost DNA priming as recombinant live attenuated measles virus has an impressive safety and efficacy record. Here, we show that a MV-TERT vector can rapidly and strongly boost DNA hTERT priming in MV susceptible IFNAR/CD46 mouse models. The cellular immune responses were Th1 polarized. No humoral responses were elicited. The 4 kb hTERT transgene did not impact MV replication or induction of cell-mediated responses. These findings validate the MV-TERT vector to boost cell-mediated responses following DNA priming in humans.

http://bit.ly/2RU1ezP

STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes

Abstract

Tumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163^pos TAMs is associated with poor outcome in most human cancers. Therefore, therapeutic strategies for reprogramming TAMs from a tumor-supporting (M2-like) phenotype towards a tumoricidal (M1-like) phenotype are of great interest. Activation of the transcription factor STAT3 within the tumor microenvironment is associated with worse prognosis, and STAT3 activation promotes the immunosuppressive phenotype of TAMs. Therefore, we aimed to develop a drug for inhibition of STAT3 specifically within human TAMs by targeting the endocytic CD163 scavenger receptor, which is highly expressed on TAMs. Here, we report the first data on a CD163-targeted STAT3-inhibitory drug consisting of corosolic acid (CA) packaged within long-circulating liposomes (LCLs), which are CD163-targeted by modification with monoclonal anti-CD163 antibodies (αCD163)—CA-LCL-αCD163. We show, that activation of STAT3 (by phosphorylation) was inhibited by CA-LCL-αCD163 specifically within CD163^pos cells, with minor effect on CD163^neg cells. Furthermore, CA-LCL-αCD163 inhibited STAT3-regulated gene expression of IL-10, and increased expression of TNFα, thus indicating a pro-inflammatory effect of the drug on human macrophages. This M1-like reprogramming at the mRNA level was confirmed by significantly elevated levels of pro-inflammatory cytokines (IFNγ, IL-12, TNFα, IL-2) in the culture medium. Since liposomes are attractive vehicles for novel anti-cancer drugs, and since direct TAM-targeting may decrease adverse effects of systemic inhibition of STAT3, the present results encourage future investigation of CA-LCL-αCD163 in the in vivo setting.

http://bit.ly/2RKg6ki

Melanocytes, Organogenesis, and Angiogenesis: Evidence for More than a Pigment-Producing Capability of Melanocytes

Cells Tissues Organs

http://bit.ly/2FLvjeo

Relationships Between Biochemical Markers of Hyperandrogenism and Metabolic Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

Horm Metab Res 2019; 51: 22-34
DOI: 10.1055/a-0806-8281

While several studies have documented an increased risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS), associations between androgenic and metabolic parameters in these patients are unclear. We aimed to investigate the relationships between biochemical markers of hyperandrogenism (HA) and metabolic parameters in women with PCOS. In this systematic review and meta-analysis, a literature search was performed in the PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science from 2000 to 2018 for assessing androgenic and metabolic parameters in PCOS patients. To assess the relationships between androgenic and metabolic parameters, meta-regression analysis was used. A total number of 33 studies involving 9905 patients with PCOS were included in this analysis. The associations of total testosterone (tT) with metabolic parameters were not significant; after adjustment for age and BMI, we detected associations of this androgen with low-density lipoproteins cholesterol (LDL-C) (β=0.006; 95% CI: 0.002, 0.01), high-density lipoproteins cholesterol (HDL-C) (β=–0.009; 95% CI: –0.02, –0.001), and systolic blood pressure (SBP) (β=–0.01; 95% CI: –0.03, –0.00). We observed a positive significant association between free testosterone (fT) and fasting insulin (β=0.49; 95% CI: 0.05, 0.91); this association remained significant after adjustment for confounders. We also detected a reverse association between fT and HDL-C (β=–0.41; 95% CI: –0.70, –0.12). There was a positive significant association between A4 and TG (β=0.02; 95% CI: 0.00, 0.04) after adjustment for PCOS diagnosis criteria. We also found significant negative associations between A4, TC, and LDL-C. Dehydroepiandrosterone sulfate (DHEAS) had a positive association with LDL-C (β=0.02; 95% CI: 0.001, 0.03) and a reverse significant association with HDL-C (β=–0.03; 95% CI: –0.06, –0.001). This meta-analysis confirmed the associations of some androgenic and metabolic parameters, indicating that measurement of these parameters may be useful for predicting metabolic risk in PCOS patients.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

http://bit.ly/2RSJC7D

Correction: Optical Imaging Technology: A Useful Tool to Identify Remission in Cushing Disease After Surgery

Horm Metab Res
DOI: 10.1055/a-0828-9509

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://bit.ly/2Hoq0E8

Comorbidities in elderly patients with glioblastoma: a field-practice study

Future Oncology, Ahead of Print.


http://bit.ly/2FM74N7

Comparison of different prognostic models for predicting cancer-specific survival in bladder transitional cell carcinoma

Future Oncology, Ahead of Print.


http://bit.ly/2FCJCmi

Role of osimertinib in the treatment of EGFR-mutation positive non-small-cell lung cancer

Future Oncology, Ahead of Print.


http://bit.ly/2FM7KSF

Why have microRNA biomarkers not been translated from bench to clinic?

Future Oncology, Ahead of Print.


http://bit.ly/2FD7JS6

Comparison of cardiovascular effects of crizotinib and chemotherapy in ALK-positive advanced non-small-cell lung cancer

Future Oncology, Ahead of Print.


http://bit.ly/2FL9hsd

Hypothyroidism in patients with hepatocellular carcinoma receiving cabozantinib: an unassessed issue

Future Oncology, Ahead of Print.


http://bit.ly/2FBlGjp

Role of the receptor tyrosine kinase Axl in hepatocellular carcinoma and its clinical relevance

Future Oncology, Ahead of Print.


http://bit.ly/2FQFfDJ

The inhibition effect of cold atmospheric plasma-activated media in cutaneous squamous carcinoma cells

Future Oncology, Ahead of Print.


http://bit.ly/2FDmWCz

Ramucirumab and its use in the treatment of hepatocellular carcinoma

Future Oncology, Ahead of Print.


http://bit.ly/2FMgfgG

Prognostic value of dynamic albumin-to-alkaline phosphatase ratio in limited stage small-cell lung cancer

Future Oncology, Ahead of Print.


http://bit.ly/2FCSPew

Cobimetinib in malignant melanoma: how to MEK an impact on long-term survival

Future Oncology, Ahead of Print.


http://bit.ly/2FM727X

Corrigendum

Future Oncology, Ahead of Print.


http://bit.ly/2FDI6R0

A Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer

Future Oncology, Ahead of Print.


http://bit.ly/2FLuUIU

First in Houston to Offer a New Treatment for Obtructive Sleep Apnea

UT Physicians is now offering an alternative therapy for obstructive sleep apnea (OSA) when traditional approaches fail. The first six...

http://bit.ly/2ASN74f

Head and Neck Surgical Oncology: How Do We Make the Experience Better for the Patient?

By asking cancer patients what they want, physicians in the Head and Neck Surgical Oncology Program at Memorial Hermann and...

http://bit.ly/2T68Bl6

On a Mission: Dr. Yuksel Returns to Nicaragua

Pediatric otolaryngologist Sancak Yuksel, MD joined a team of otolaryngologists, nurses, audiologists, and speech pathologists supported by Oklahoma-based Mayflower Medical Outreach...

http://bit.ly/2ATqkFk

18 F-FDG PET/CT diagnostic performance in solitary and multiple pulmonary nodules detected in patients with previous cancer history: reports of 182 nodules

Abstract

Purpose

In oncological patients, ¹⁸F-FDG PET/CT performance for pulmonary nodules' characterization is not well-established. Thus, the purpose of this study was to evaluate the ¹⁸F-FDG PET/CT diagnostic performance in pulmonary nodules detected during follow-up in oncological patients and the relationship between malignancy and nodules' characteristics.

Methods

We retrospectively evaluated 182 pulmonary nodules (121 solitary, 61 multiple; mean size = 16.5 ± 8.1 mm, mean SUVmax = 5.2 ± 5.1) in 148 oncological patients (89 males; mean age = 69.5 ± 8.4 years). Final diagnosis was established by histology or radiological follow-up. Diagnostic performance of ¹⁸F-FDG visual analysis (malignancy-criterion: uptake ≥ mediastinal activity), ROC curve analysis for SUVmax and nodules' characteristics were assessed.

Results

In 182 nodules, the prevalence of malignancy was 75.8%; PET/CT provided sensitivity = 79%, specificity = 81.8%, accuracy = 79.7%, PPV = 93.1%, NPV = 55.4%; ROC analysis (SUVmax cut-off = 1.7) provided sensitivity = 85.5%, specificity = 72.7%. In 121 solitary nodules, the prevalence of malignancy was 87.6%; PET/CT provided sensitivity = 82.1%, specificity = 73.3%, accuracy = 81%, PPV = 95.6%, NPV = 36.7%; ROC analysis (SUVmax cut-off = 2) provided sensitivity = 84%, specificity = 80%. In 61 multiple nodules, the prevalence of malignancy was 52.5%; PET/CT (nodule and patient-based analysis, respectively) provided sensitivity = 68.7% and 88.9%, specificity = 86.2% and 55.6%, accuracy = 77% and 77.8%, PPV = 84.4% and 80%, NPV = 71.8% and 71.5%; ROC analysis (nodule-based, SUVmax cut-off = 1.8) provided sensitivity = 71.9%, specificity = 82.8%. Malignant nodules were prevalent in males, in solitary pattern and in upper lobes, and had significantly greater size and metabolic activity (SUVmax and TLG) than benign ones, with no differences in interval-time between previous cancer diagnosis and nodule detection, patients' age or other nodules' features (lung side, central/peripheral). When comparing solitary and multiple patterns, malignant nodules had significantly greater size and metabolic activity than benign ones in both groups.

Conclusions

In oncological patients, ¹⁸F-FDG PET/CT provides good diagnostic performance for ruling in the malignancy in pulmonary nodules detected during follow-up, even at small size and especially when solitary. In multiple patterns, PET seems useful in the perspective of a personalized management, for identifying the "reference" nodule deserving histological assessment.

http://bit.ly/2QLZYKB

A new frontier for amyloid PET imaging: multiple sclerosis

http://bit.ly/2VSo3mG

Interferon-α versus interleukin-2 in Chinese patients with malignant melanoma: a randomized, controlled, trial

The US Food and Drug Association has approved interferon-α (IFN-α) and interleukin-2 (IL-2) as adjuvant therapy in malignant melanoma. The objective of the study was to compare efficacy and safety of subcutaneous interferon-α with continuous intravenous IL-2 in Chinese patients with malignant melanoma. A total of 250 patients with unresectable malignant melanoma were subjected to randomized in 1 : 1 ratio. Patients received subcutaneous 9×106 IU/m2 IFN-α (IFN-α group, n=125) or continuous intravenous 9×106 IU/m2 IL-2 (IL-2 group, n=125) at every 21 days for 4 months. The response, progression-free survival, overall survival, adverse effects, and cost were evaluated by experts in the field. IL-2 and IFN-α were effective in improvement of malignant melanoma after 4 months of intervention. IL-2 was effective in improving brain metastasis. Patients of the IL-2 group had a higher overall survival (P

http://bit.ly/2sAbUWf

Inhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib

Summary

MCM8 and MCM9 are paralogues of the MCM2‐7 eukaryotic DNA replication helicase proteins and play a crucial role in a homologous recombination‐mediated repair process to resolve replication stress by fork stalling. Thus, deficiency of MCM8‐9 sensitizes cells to replication stress caused, for example, by platinum compounds that induce inter‐strand crosslinks. It is suggested that cancer cells undergo more replication stress than normal cells due to hyper‐stimulation of growth. Therefore, it is possible that inhibiting MCM8‐9 selectively hypersensitizes cancer cells to platinum compounds and poly(ADP‐ribose) polymerase inhibitors, both of which hamper replication fork progression. Here, we inhibited MCM8‐9 in transformed and non‐transformed cells and examined their sensitivity to cisplatin and olaparib. We found that knockout of MCM9 or knockdown of MCM8 selectively hypersensitized transformed cells to cisplatin and olaparib. In agreement with reported findings, RAS‐ and HPV16 E7‐mediated transformation of human fibroblasts increased replication stress, as indicated by induction of multiple DNA damage responses (including formation of Rad51 foci). Such replication stress induced by oncogenes was further increased by knockdown of MCM8, providing a rationale for cancer‐specific hypersensitization to cisplatin and olaparib. Finally, we showed that knocking out MCM9 increased the sensitivity of HCT116 xenograft tumors to cisplatin. Taken together, the data suggest that conceptual MCM8‐9 inhibitors will be powerful cancer‐specific chemosensitizers for platinum compounds and PARP inhibitors, thereby opening new avenues to the design of novel cancer chemotherapeutic strategies.

This article is protected by copyright. All rights reserved.

http://bit.ly/2T3xgqx

Nitric oxide inhibits autophagy and promotes apoptosis in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the second most common cause of cancer‐related mortality worldwide. The expression of nitric oxide synthase (NOS) and the inhibition of autophagy have been linked to cancer cell death. However, the involvement of serum nitric oxide (NO), the expression of NOS, and autophagy have not been investigated in HCC. In the present study, we first established that the NO level was significantly higher in HBV‐related HCC than in the liver cirrhosis control (53.60±19.74 μmol/L vs 8.09±4.17 μmol/L, t=15.13, p<0.0001). Using immunohistochemistry, we found that the source of NO was at least partially attributed to the expression of iNOS and eNOS but not nNOS in the liver tissue. Furthermore, in human liver cancer cells, NO induced apoptosis and inhibited autophagy. Pharmacological inhibition of autophagy also induced apoptosis, whereas the induction of autophagy could ameliorate NO‐induced apoptosis. We also found that NO regulates the switch between apoptosis and autophagy by disrupting the Beclin 1/Vps34 association and by increasing the Bcl‐2/Beclin 1 interaction. Overall, the present findings suggest that increased NOS/NO promotes apoptosis via the inhibition of autophagy in liver cancer cells, which may provide a novel strategy for the treatment of HCC.

This article is protected by copyright. All rights reserved.

http://bit.ly/2ANWZfx

Roles of EphA1/A2 and ephrin‐A1 in cancer

Summary

The biological functions of the Eph/ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and ephrin are up‐ or down‐regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy.

The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin‐A1 that is a membrane‐anchored ligand for EphAs was co‐localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of ephrin‐A1‐induced lung metastasis by understanding the physiological function of ephrin‐A1 in lungs. This review focuses on the function of EphA1, EphA2, and ephrin‐A1 in tumors and an establishment of pre‐metastatic microenvironment in the lungs.

This article is protected by copyright. All rights reserved.

http://bit.ly/2T3xhuB

Distinct chemotherapy‐associated anti‐cancer immunity by myeloid cells inhibition in murine pancreatic cancer models

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti‐tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr‐1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr‐1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon‐gamma (IFN‐γ) were higher in GEM‐treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell‐depleted PDAC mice treated with GEM showed biological processes related to anti‐cancer immunity, such as natural killer cell‐mediated cytotoxicity, type I IFN signaling, and co‐stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti‐cancer effect, and depletion of myeloid‐lineage cells played an important role in enhancing anti‐cancer immunity associated with GEM treatment.

This article is protected by copyright. All rights reserved.

http://bit.ly/2AWm6N9

REV7 confers radioresistance of esophagus squamous cell carcinoma by recruiting PRDX2

Abstract

Radiotherapy has been widely used for the clinical management of esophageal squamous cell carcinoma. However, radioresistance remains a serious concern that prevents the efficacy of ESCC radiotherapy. REV7, the structural subunit of eukaryotic DNA polymerase ζ, has multiple functions in bypassing DNA damage and modulating mitotic arrest in human cell lines. However, the expression and molecular function of REV7 in ESCC progression remains unclear. In this study, we first examined the expression of REV7 in clinical ESCC samples, and we found higher expression of REV7 in ESCC tissues compared to matched adjacent or normal tissues. Knockdown of REV7 resulted in decreased colony formation and increased apoptosis in irradiated Eca‐109 and TE‐1 cells coupled with decreased tumor weight in a xenograft nude mouse model post‐irradiation. Conversely, overexpression of REV7 resulted in the radioresistance in vitro and in vivo. Moreover, silencing of REV7 induced increased reactive oxygen species (ROS) levels post irradiation. To elucidate the underlying mechanism, proteomic analysis of REV7‐interacting proteins revealed that REV7 interacted with peroxiredoxin 2 (PRDX2), a well‐known antioxidant protein. Existence of REV7‐PRDX2 complex and its augmentation post irradiation were further validated by immunoprecipitation and immunofluorescence assays. REV7 knockdown significantly disrupted the presence of nuclear PRDX2 post irradiation, which resulted in oxidative stress. REV7‐PRDX2 complex also assembled onto DNA double strand breaks (DSBs), whereas REV7 knockdown evidently increased DSBs that were unmerged by PRDX2. Taken together, this study sheds light on REV7‐modulated radiosensitivity through interacting with PRDX2, which provides a novel target for ESCC radiotherapy.

This article is protected by copyright. All rights reserved.

http://bit.ly/2T49VVN

Phase II trial of aflibercept with FOLFIRI as a 2nd‐line treatment for Japanese patients with metastatic colorectal cancer

Summary

Aflibercept targets vascular endothelial growth factor. This study involved assessing the efficacy, safety, and pharmacokinetics of aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity, or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression‐free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan, and 5‐fluorouracil. Sixty patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval: 1.3%–15.3%), and the disease control rate (DCR) was 80.0% (69.9%–90.1%). The median progression‐free survival was 5.42 months (4.14–6.70 months), and the median overall survival was 15.59 months (11.20–19.81 months). No treatment‐related deaths were observed, and no significant drug‐drug interactions were found. The most common treatment‐emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/day (22%), and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/day (9%) (N=62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5‐fluorouracil: The clearance was 11.1 L/h/m² (28%) for irinotecan and, at steady state, 72.6 L/h/m² (56%) for 5‐fluorouracil (N=10). Adding aflibercept to FOLFIRI was shown to be beneficial and well‐tolerated in Japanese patients with mCRC.

This article is protected by copyright. All rights reserved.

http://bit.ly/2AVSMGv

Bazedoxifene exhibits growth suppressive activity by Targeting IL‐6/GP130/STAT3 Signaling in Hepatocellular Carcinoma

Summary

The IL‐6/GP130/STAT3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL‐6 binds to IL‐6R, forming a binary complex, which further combines with glycoprotein GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL‐6 and GP130 might inhibit the IL‐6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that Bazedoxifene acetate (BAZ), a selective estrogen receptor modulator (SERM) approved by Food and Drug Administration (FDA), could inhibit IL‐6/GP130 protein‐protein interactions (PPI). Western blot, immunofluorescence staining, wound healing, and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V‐FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P‐STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P‐STAT3 induced by IL‐6, but not by Leukemia Inhibitory Factor (LIF). BAZ inhibited P‐STAT1 and P‐STAT6 less significantly as elicited by interferon‐α, interferon‐γ, and IL‐4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL‐6. BAZ inhibited cell viability, wound healing, and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that Bazedoxifene inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.

This article is protected by copyright. All rights reserved.

http://bit.ly/2B4Awer

Differential regulation of CpG island‐methylation within divergent and unidirectional promoters in colorectal cancer

Summary

The silencing of tumor suppressor genes by promoter CpG island (CGI) methylation is an important cause of oncogenesis. Silencing of MLH1 and BRCA1, two examples of oncogenic events, results from promoter CGI methylation. Interestingly, both MLH1 and BRCA1 have a divergent promoter, from which another gene on the opposite strand is also transcribed. Although studies have shown that divergent transcription is an important factor in transcriptional regulation, little is known about its implication in aberrant promoter methylation in cancer. In this study, we analyzed the methylation status of CGIs in divergent promoters using recently enriched transcriptome database. We measured the extent of CGI methylation in 119 colorectal cancer (CRC) clinical samples (65 microsatellite instability high (MSI‐H) CRCs with CGI methylator phenotype, 28 MSI‐H CRC without CGI methylator phenotype and 26 microsatellite stable CRCs) and 21 normal colorectal tissues using Infinium MethylationEPIC BeadChip. We found that CGIs within divergent promoters are less frequently methylated than CGIs within unidirectional promoters in normal cells. In the genome of CRC cells, CGIs within unidirectional promoters are more vulnerable to aberrant methylation than CGIs within divergent promoters. In addition, we identified three DNA sequence motifs that correlate with methylated CGIs. We also showed that methylated CGIs are associated with genes whose expression is low in normal cells. Thus, we here provide fundamental observations regarding the methylation of divergent promoters that are essential for the understanding of carcinogenesis and development of cancer prevention strategies.

This article is protected by copyright. All rights reserved.

http://bit.ly/2T3xcHj

Shortcuts to Intestinal Carcinogenesis by Genetic Engineering in Organoids

Abstract

Inactivation of the Adenomatous Polyposis Coli (APC) gene is an initiating and the most relevant event in the majority of sporadic cases with colorectal cancer, providing a rationale for using Apc‐mutant mice as the disease model. Whereas carcinogenesis has been observed only at the organism level, the recent development of organoid culture technique has enabled long‐term propagation of intestinal stem cells in a physiological setting, raising the possibility that organoids could serve as an alternative platform for modeling colon carcinogenesis. Indeed, we demonstrated that lentivirus‐based RNAi‐mediated knockdown of Apc in intestinal organoids gave rise to subcutaneous tumors upon inoculation in immmunodeficient mice. Reconstitution of common genetic aberrations in organoids resulted in development of various lesions ranging from aberrant crypt foci to full‐blown cancer, recapitulating multi‐step colorectal tumorigenesis. Due to its simplicity and utility, similar organoid‐based approaches have been applied to both murine and human cells in many investigations, to gain mechanistic insights into tumorigenesis, validate putative tumor suppressor genes or oncogenes, and establish preclinical models for drug discovery. In this review article, we provide a multifaceted overview of these types of approaches that will likely accelerate and advance research on colon cancer.

This article is protected by copyright. All rights reserved.

http://bit.ly/2AU3Ns5

Nodal FDG-PET/CT uptake influences outcome and relapse location among esophageal cancer patients submitted to chemotherapy or radiochemotherapy

Abstract

Purpose

Our aim was investigate whether lymph node uptake is associated with survival and regional relapses, and relapse patterns with respect to the radiotherapy fields in esophageal cancer (EC).

Materials and methods

The FDG-PET/CT image datasets of 56 patients were analyzed. All patients underwent definitive or neoadjuvant radio/chemotherapy (RCT). All patients suffering from persistent or recurrent local/regional-only disease after RCT were considered for salvage resection. Patients with adenocarcinoma without metastatic disease were considered for planned resection (usually within 3 months of treatment).

Results

Patients with PET-positive lymph nodes before treatment had a worse overall survival and a shorter disease-free survival than those without PET-positive nodes. They also had worse node and metastatic relapse-free survival. N2 patients had statistically significant poorer outcomes than N1–N0 patients and a better survival if the involved nodes were closer to the esophageal tumor. Involved node location by PET/CT also affected global, nodal and metastatic relapses. In addition, an increment of SUVmax value increased relative risk of death and increased relative risk of node and metastatic relapses. The first site of relapse was metastatic recurrence and, second, local recurrence. The most frequent were "in-field" loco/regional recurrence. We observed a relationship between patients classified-N1 and out-field nodal recurrence (p = 0.024), and between patients-N2 and in-field nodal recurrence. The number of PET-positive nodes was an independent significant prognostic predictor for relapse (p < 0.001).

Conclusion

Our study shows that only FDG-PET/CT can provide prognostic information in EC. Nodal PET/CT uptake influences outcome and relapse location among EC patients.

http://bit.ly/2Mk6Kqe

Neoadjuvant isolated limb perfusion in newly diagnosed untreated patients with locally advanced soft tissue sarcomas of the extremities: the Gustave Roussy experience

Abstract

Background

Limb-sparing surgery in locally advanced soft tissue sarcomas (LA STS) is challenging. The aim of this study is to evaluate upfront isolated limb perfusion (ILP) in untreated patients with LA STS.

Methods

All consecutive patients with LA STS of the limbs deemed borderline or unresectable and treated with upfront ILP as induction treatment between 2003 and 2016 were included. Demographic, clinical and long-term characteristics were obtained and retrospectively analyzed.

Results

41 patients (pts), with a median age of 51 years [range 21–76], were identified (lower limb 68%, upper limb 32%). Liposarcoma and undifferentiated pleomorphic sarcoma were the most common subtypes (27% and 22%, respectively). Acute toxicities, using Wieberdink classification, were grade II (35 pts, 85%), grade III (2 pts, 5%) and no grade IV–V. Local control rate was 98%. 32 pts had limb-sparing surgery (78%). 1 pt had an early amputation due to progressive disease after ILP. 8 pts were not operated (four had RT alone, one had distant metastases, two had a complete response and one died 3 months after ILP of a pulmonary embolism). 36 pts (84%) received postoperative RT. After a median follow-up of 43 months, 18 pts (47%) relapsed. Median disease-free survival (DFS) was 6.7 years. The median overall survival (OS) was not reached. The 1-year, 5-year and 10-year DFS and OS rates were, respectively, 75%, 50% and 45%, and 90%, 63% and 55%.

Conclusion

Upfront ILP is an efficient and well-tolerated limb-sparing procedure in borderline or unresectable LA STS without hampering OS.

http://bit.ly/2sAQJ68

The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

Abstract

Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

http://bit.ly/2Mkrs9z

The incidence proportion of erectile dysfunction in patients treated with cryotherapy for prostate cancer: a meta-analysis

Abstract

Objectives

With the maturity of cryotherapy for prostate cancer, the complications after operation are also decreasing, which can improve the prognosis of patients. However, erectile dysfunction (ED) is still one of the main complications after cryotherapy. Therefore, we performed a meta-analysis to evaluate the incidence of erectile dysfunction in patients after cryotherapy.

Materials and methods

A comprehensive literature search was performed in August 2018. PUBMED and EMBASE databases were searched to collect studies reporting the incidence rate of ED after cryotherapy from 2002 to 2018. Two reviewers independently screened the literatures, extracted data and assessed the risk of bias of included studies. Pooled ratio and its 95% confidence intervals (95% CIs) were performed by Stata 12.1.

Results

Of the 157 articles identified on August 1st 2018, 23 studies which reported ED after cold ablative therapy were identified, however, only 12 used validated outcome measures and met inclusion criteria. A total of 12 studies were included in this meta-analysis. Overall, the results of this meta-analysis showed that the pooled incidence rate of ED was 0.27 (95% CI 0.26–0.28) which means that the incidence rate of ED after cryotherapy for prostate cancer was not high, but we still found that there are great heterogeneity between the 12 articles. By subgroup analysis, we found a statistically significant incidence rate of ED in primarily localized PCa which was 0.49 (95% CI 0.30–0.68), which is clearly lower than the incidence of recurrent prostate cancer after failed primary radiotherapy 0.61 (95% CI 0.43–0.79).

Conclusion

ED is one of the major complications after cryotherapy for PCa. Furthermore, subgroup analysis revealed a higher incidence rate in PCa undergoing radiotherapy. Significantly, with the development of cryotherapy technology, the incidence of ED after cryotherapy for prostate cancer is decreasing. While we still need further researches to advance knowledge in this field.

http://bit.ly/2sz8OSj

Time for radioimmunotherapy: an overview to bring improvements in clinical practice

Abstract

Harnessing the patient's own immune system against an established cancer has proven to be a successful strategy. Within the last years, several antibodies blocking critical "checkpoints" that control the activation of T cells, the immune cells able to kill cancer cells, have been approved for the use in patients with different tumours. Unfortunately, these cases remain a minority. Over the last years, radiotherapy has been reported as a means to turn a patient's own tumour into an in situ vaccine and generate anti-tumour T cells in patients who lack sufficient anti-tumour immunity. Indeed, review data show that the strategy of blocking multiple selected immune inhibitory targets in combination with radiotherapy has the potential to unleash powerful anti-tumour responses and improve the outcome of metastatic solid tumours. Here, we review the principal tumours where research in this field has led to new knowledge and where radioimmunotherapy becomes a reality.

http://bit.ly/2Mkro9P

Evidence for Clonally Associated Increasing Rates of Azithromycin Resistant Neisseria gonorrhoeae in Rio de Janeiro, Brazil

Azithromycin is one of the drugs used in the combined therapy for syndromic treatment of gonorrhoea in many countries, including Brazil. Our research group, which receives isolates from clinical laboratories since 2006, has detected, after 2016, a tendency of rising rates of azithromycin resistance, with isolates showing higher minimal inhibitory concentrations (MICs) than those previously reported in this country. In this study, we report the susceptibility to azithromycin of 93 N. gonorrhoeae isolates obtained between 2014 and 2017. Strains with MIC ≥2 μg/mL were characterized according to azithromycin resistance mechanisms and strain typing. Results indicate that azithromycin resistance has emerged in all these years in unrelated MLST-STs, but after 2016 a clonal complex connected with ST1901 has been more frequently detected, grouping isolates with MIC varying from 2 to 64 μg/mL, with DelA mutations at the mtrR promoter region associated or not with mutations at rrl alleles. High rates of azithromycin resistance may compromise the use of this drug in the combined therapy with ceftriaxone. Inclusion of Rio de Janeiro in the Brazilian gonococcal surveillance program is important to evaluate if this data indicates an epidemiological phenomenon in the country.

http://bit.ly/2Dm2cNj

An Approach to Enhance Dissolution Rate of Tamoxifen Citrate

We tested the solubility and dissolution of tamoxifen citrate to ascertain the optimal conditions for faster dissolution. Using the solvent evaporation method and hydrophilic carriers, we formulated tamoxifen citrate (TC) that contained solid dispersions (SDs). We increased the solubility and dissolution rate of TC with a solid dispersion system that consisted of polyethylene glycol (PEG-6000), beta-cyclodextrin (β-CD), and a combination of carriers. Physicochemical characteristics of solubility (mg/ml) were found to be 0.987±0.04 (water), 1.324±0.05 (6.8pH PBS), and 1.156±0.03 (7.4 pH PBS) for F5 formulation, percentage yield was between 98.74 ± 1.11% and 99.06 ± 0.58%, drug content was between 98.06±0.58 and 99.06±1.10, and dissolution studies binary complex showed a faster release of TC as compared to a single polymer and pure drug. Furthermore, thermal properties, physicochemical drug and polymer interaction, crystal properties, and morphology were determined using differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), X-ray differential studies, and scanning electron microscopy. We used the same proportion of carrier concentrations of the formulations to calculate the solubility of TC. Our results demonstrated that increased concentrations of β-C yielded an improved solubility of TC, which was two times higher than pure TC. The uniformity in drug content was 97.99 %. A quicker drug release occurred from the binary complex formulation as seen in the dissolution profile. FTIR demonstrated an absence in the physicochemical interaction between the drug and carriers. The drug was also found to be dispersed in the amorphous state as revealed by DSC and XRD. The drug concentration did not vary during various storage conditions. Our in vivo studies demonstrated that SD displayed significantly higher values of (p

http://bit.ly/2TWkBFM

Triclosan‐containing fluoride toothpaste on clinical parameters and osteo‐inflammatory mediators when applied in a stent during experimental peri‐implant mucositis in smokers

Abstract

Objectives

To determine the effect of triclosan‐containing fluoride toothpaste on the clinical parameters and the osteo‐immunoinflammatory mediators in the peri‐implant fluid when applied in a stent during experimental peri‐implant mucositis in smokers.

Materials and Methods

Twenty‐six smokers with an implant‐supported crown were enrolled in this double‐blind, randomized, crossover study. During the two 3‐week periods without mechanical toothbrushing (wash‐out period:30 days), patients were randomly assigned to: Triclosan/fluoride (n:13) or fluoride toothpaste (n:13), three times/day. Clinical and immunoenzymatic assays were performed at baseline, 3, 7, 14 and 21 days.

Results

Both groups showed increase in the plaque index throughout the study (p=0.001), without inter‐group differences at 21 days (p>0.05). No intra‐ or inter‐group differences were observed for IFN‐γ, IL10, IL‐1β, IL8, IL‐17, IL‐6, TNF‐α, MMP‐2, MMP‐9, TGF‐β, OC, OPN, ICTP, OPG and RANKL (p>0.05). However, the RANKL/OPG ratio was significantly higher in fluoride toothpaste‐treated sites when compared to triclosan/fluoride‐treated sites at the end of period without mechanical toothbrushing, on the 21^st day (p=0.041).

Conclusion

Triclosan‐containing toothpaste favorably modulated osteo‐immunoinflammatory mediators during the experimental peri‐implant mucositis in smokers, decreasing the ratio of RANKL/OPG.

This article is protected by copyright. All rights reserved.

http://bit.ly/2RTXM8y

Diagnostic Criteria, Differential Diagnosis, and Treatment of Minor Motor Activity and Less Well-Known Movement Disorders of Sleep

Abstract

Purpose of review

Sleep-related movement disorders (SRMD) include several different motor activities during sleep. Few of them are well known and well classified, whereas others are minor motor disorders of sleep which are neither thoroughly characterized and classified nor have been extensively investigated to clarify their pathogenesis and clinical relevance. This review will focus on those minor sleep-related movement disorders.

Recent findings

Before diagnosing periodic limb movement (PLM) disorder in patients with PLM during polysomnography, other disorders associated with PLM need to be excluded, namely restless legs syndrome (RLS), narcolepsy, REM sleep behavior disorder (RBD), and sleep-related breathing disorder. For the diagnosis of propriospinal myoclonus at sleep-onset, multi-channel surface electromyography recording during polysomnography is required and a possible psychogenic origin of the movement disorder has to be considered. Excessive fragmentary myoclonus (EFM) does not require symptomatic treatment, but further evaluation is suggested as electrophysiological abnormalities are present in 50% of cases. Nine percent of healthy sleepers meet the criteria for EFM, raising the question if current, arbitrarily defined, cutoffs are valid. Hypnagogic foot tremor, rhythmic feet movements, alternating leg muscle activation, and high-frequency leg movements are somewhat overlapping minor motor activities during sleep which may exist on their own or represent stereotyped movements to relieve RLS-like symptoms. Neck myoclonus is probably a physiological phenomenon related to REM twitching. RBD is formally a parasomnia but a relevant differential diagnosis when evaluating sleep-related movement disorders. In particular, prodromal RBD is characterized by electromyographic and behavioral findings on video-polysomnography which needs to be differentiated by minor sleep-related movement disorders.

Summary

Minor SRMD beyond the well-known main motor disorders of sleep should be correctly diagnosed, distinguished from differential diagnosis, and understood in their potential clinical relevance, in order also to start an appropriate treatment if needed.

http://bit.ly/2T2bzqP

Reply

Abstract

Measurements of serum enzymes are among the 20 most frequently ordered tests in clinical laboratories. Current participation reports for external quality assessment schemes (EQAS) show that the assays (Roche Diagnostics) used for our study are widely used in Germany and account for approximately 50% of EQAS participants for AST, ALT and GGT. For our study, these assays were implemented on only one platform (cobas^® analyzer), and no other assays or manufacturers were used. AST and ALT assays included the addition of pyridoxal‐5‐phosphate, as required for standardization by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC).

This article is protected by copyright. All rights reserved.

http://bit.ly/2R2fnGC

Are Children Allowed?: A Survey of Childcare and Family Policies at Academic Medical Conferences

Abstract

Conference attendance and networking have long been a staple of career advancement in medicine. Presenting one's own research or chairing a conference panel provides academic physicians with the visibility necessary for career advancement and promotion.

Unfortunately, this pathway to career advancement may be obstructed for some physicians. Women physicians bear a larger proportion of domestic responsibilities (including childcare)² which may constitute a limitation to their participation in conferences. This in turn may ultimately be a barrier to their career development and promotion.

This article is protected by copyright. All rights reserved.

http://bit.ly/2R0cdmF

The Calm After the Storm

Abstract

A child gets rushed into the resuscitation room ‐ chest compressions in progress, pale and mottled, emesis and blood streaking his matted hair and ashen face. Everyone springs into action, instinctively assuming the roles we were trained to do. The respiratory therapist seamlessly takes over ventilations, the nurses simultaneously obtain access, prime lines, and connect monitors, and I stand at the foot of the bed acting as the conductor amongst the cacophony of sound and motion.

This article is protected by copyright. All rights reserved.

http://bit.ly/2W3E2hP

Feasibility of emergency department initiated, mobile health, blood pressure intervention: an exploratory, randomized clinical trial

Abstract

Study Objective

We aimed to assess the feasibility of a text messaging intervention by determining the proportion of emergency department (ED) patients who responded to prompted home blood pressure (BP) self‐monitoring and had persistent hypertension. We also explored the effect of the intervention on systolic blood pressure (SBP) over time.

Methods

We conducted a randomized, controlled trial of ED patients with expected discharge to home with elevated BP. Participants were identified by automated alerts from the electronic health record. Those who consented received a BP cuff to take home and enrolled in the 3‐week screening phase. Text responders with persistent hypertension were randomized to control or weekly prompted BP self‐monitoring and healthy behavior text messages.

Results

Among the 104 patients enrolled in the ED, 73 reported at least one home BP over the 3‐week run‐in (screening) period. 55/73 reported a home BP>=140/90, and were randomized to SMS Intervention (n=28) or Control (n=27). The intervention group had significant SBP reduction over time with a mean drop of 9.1 mm Hg (95% CI 1.1 to 17.6).

Conclusions

The identification of ED patients with persistent hypertension using home BP self‐monitoring and text messaging was feasible. The intervention was associated with a decrease in SBP likely to be clinically meaningful. Future studies are needed to further refine this approach and determine its efficacy.

This article is protected by copyright. All rights reserved.

http://bit.ly/2R11d8T

Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the golgi apparatus

Abstract

It is well recognized that the world population is aging rapidly. Therefore, it is important to understand aging processes at the cellular and molecular levels to predict the onset of age‐related diseases and prevent them. Recent research has focused on the identification of aging biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi‐mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro‐inflammatory cytokines and extracellular matrix degrading enzymes, is modified during aging, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi‐related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non‐senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and aging.

This article is protected by copyright. All rights reserved.

http://bit.ly/2SYHUyQ

Monitoring Neuronal Survival via Longitudinal Fluorescence Microscopy

Here, we present a protocol to monitor survival on a single-cell basis and identify variables that significantly predict cell death.

http://bit.ly/2CztjCM

Conducting Hyperscanning Experiments with Functional Near-Infrared Spectroscopy

The present protocol describes how to conduct fNIRS hyperscanning experiments and analyze brain-to-brain synchrony. Further, we discuss challenges and possible solutions.

http://bit.ly/2RAJbPQ

Gene-therapy Inspired Polycation Coating for Protection of DNA Origami Nanostructures

Here, a protocol for the protection of DNA origami nanostructures in Mg-depleted and nuclease-rich media using natural cationic polysaccharide chitosan and synthetic linear polyethyleneimine (LPEI) coatings is presented.

http://bit.ly/2CutUpq

The HoneyComb Paradigm for Research on Collective Human Behavior

Here, we present the computer-based, multi-agent game HoneyComb, which enables experimental investigations of collective human movement behavior via black-dot-avatars on a virtual 2D hexagonal playfield. Different experimental conditions, like variable incentives on goal fields or vision radius, can be set, and their effects on human movement behavior can be investigated.

http://bit.ly/2MkNI33

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation

This protocol describes how to assess synergism between an anticancer antibody and antineoplastic drugs in preclinical models by using the combination index equation of Chou and Talalay.

http://bit.ly/2syTxAO

Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer

Objective

Our previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure.

Design

Flow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer.

Results

Increased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8⁺ T cells infiltration and Ki67⁺ CD8⁺ T cells proportion. Moreover, CXCL8 also inhibits CD8⁺ T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1⁺) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8⁺ macrophages are positively correlated with poor prognosis in patients with gastric cancer.

Conclusions

CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1⁺ macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.

http://bit.ly/2U4vmWO

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Objective

Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.

Design

Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.

Results

We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10^–10 and 0.002 (OR_allelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).

Conclusion

In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

http://bit.ly/2DnhxgJ

Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression

Here we describe a minimally invasive syngeneic orthotopic transplantation model of mouse lung adenocarcinoma cells as a time- and cost-reducing model to study non-small cell lung cancer.

http://bit.ly/2FB46vL

Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue

Acute seizure models are important for studying the mechanisms underlying epileptiform events. Furthermore, the ability to generate epileptiform events on-demand provides a highly efficient method to study the exact sequence of events underlying their initiation. Here, we describe the acute 4-aminopyridine cortical seizure models established in mouse and human tissue.

http://bit.ly/2FN1ryb

Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia

Abstract

Purpose

The combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib (CombiDT) has improved outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAF V600E/K melanoma. However, CombiDT causes a high incidence of pyrexia and treatment interruptions. Pharmacokinetic analysis may provide an explanation for the pyrexia.

Methods

34 patients with Stage 3 BRAF V600 melanoma were treated with CombiDT on a clinical trial between August 2014 and June 2017. Plasma concentrations of drugs and metabolites were determined using validated LC–MS assays, in addition to analysis of a panel of cytokines.

Results

Pyrexia was experienced by 71% of the patients, with an additional 17% requiring dose interruption related to a pyrexia-like prodrome. Dabrafenib concentrations ranged from 4.0 to 4628 ng/ml and trametinib from 1.0 to 45 ng/ml in 34 patients. N-desmethyl-dabrafenib was the most prevalent metabolite, followed by carboxy- and hydroxy-dabrafenib. No definitive association between pyrexia and AUC or C_min of the drugs, or metabolites could be observed. The level of IL-1B at the early during treatment (EDT) (as a % of pre-treatment) was higher in the pyrexia group (median 109% (range 32–681%) than in the no-incidence group [56% (26–79%)] (p = 0.029). Similarly, the level of IL-6 at EDT was higher in the pyrexia group [181% (34-3156%) vs 73% (57–101%)] (p = 0.028).

Conclusions

No apparent associations between pyrexia and exposure to the drugs or metabolites could be observed. Greater elevations in IL-1B and IL-6 were observed in patients with pyrexia during the first week of treatment compared to those without pyrexia.

http://bit.ly/2Hmll5T

Infratentorial immature teratoma of congenital origin can be associated with a 20-year survival outcome: a case report and review of literature

Abstract

Background

Congenital intracranial tumors are very rare and account for less than 2% of all childhood brain tumors. Teratomas constitute about one third to one half of these, predominantly located midline in the supratentorial region. Posterior fossa location rarely occurs and, based on the cases reported in the literature, commonly has a poor prognosis.

Case presentation

A newborn female, diagnosed prenatally with hydrocephalus, is presented at birth with increasing head circumference and Parinaud's syndrome. Magnetic resonance imaging scans demonstrated a huge posterior fossa tumor with obstructive hydrocephalus. At surgery, through a suboccipital craniotomy, complete excision was achieved of a histological-proven immature teratoma. The infant received adjuvant chemotherapy for 1 year. She had normal neurological development and remained tumor-free through her 20-year follow-up.

Conclusion

The authors report this rare case of congenital posterior fossa teratoma with long-term outcome, and the literature is reviewed.

http://bit.ly/2FALCLR

Energy-efficient multi-cell resource allocation in cognitive radio-enabled 5G systems

In this paper, we propose an energy-efficient resource allocation (RA) algorithm in cognitive radio-enabled 5th generation (5G) systems, where the scenario including one primary system and multiple secondary c...

http://bit.ly/2CtcObr

Distributed stochastic gradient descent for link prediction in signed social networks

This paper considers the link prediction problem defined over a signed social network, where the relationship between any two network users can be either positive (friends) or negative (foes). Given a portion ...

http://bit.ly/2RyKlLP

Cancers, Vol. 11, Pages 116: Vonoprazan-Based Third-Line Therapy Has a Higher Eradication Rate against Sitafloxacin-Resistant Helicobacter pylori

Cancers, Vol. 11, Pages 116: Vonoprazan-Based Third-Line Therapy Has a Higher Eradication Rate against Sitafloxacin-Resistant Helicobacter pylori

Cancers doi: 10.3390/cancers11010116

Authors: Saito Konno Sato Nakano Kato Saito Serizawa

Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of H. pylori. Here, we evaluated the success rate of eradication therapy with vonoprazan (VPZ), a new potassium-competitive acid blocker, against drug-resistant H. pylori. In total, 793 patients who received H. pylori eradication therapy were investigated retrospectively. All underwent esomeprazole (EPZ)-based triple therapy (n = 386) or VPZ-based triple therapy (n = 407) for first-, second- and third-line H. pylori eradication for 7 days. The overall success rates of first- and third-line H. pylori eradication were significantly higher for VPZ-based triple therapy (88.4% and 93.0%, respectively, per protocol (PP)) than for EPZ-based triple therapy (69.5% and 56.5%, respectively, PP). Moreover, the success rates of first- and third-line eradication of clarithromycin (CLR)- and sitafloxacin (STFX)-resistant H. pylori were significantly higher for VPZ-based triple therapy (72.0% and 91.7%, PP) than for EPZ-based triple therapy (38.5% and 20.0%, PP). In addition, patient age did not affect the eradication rate of VPZ-based first-line therapy, whereas the success rate of EPZ-based therapy was lower in patients under 65 years of age. Our results clearly demonstrated that VPZ-based therapy achieved a higher eradication rate even against CLR- and STFX-resistant H. pylori, and that patient age did not affect the eradication rate of VPZ-based therapy. These findings suggest that dual therapy using VPZ and amoxicillin may be sufficient for standard H. pylori eradication, and may thus also be beneficial for avoiding antibiotic misuse.

http://bit.ly/2Mimqu5