## Τρίτη, 4 Απριλίου 2017

 Cincinnati.com No fooling; go get your head (and neck) examined for free Cincinnati.com Thursday, get your head examined. UC Health is offering free head and neck cancer screenings at the UC Health Barrett Cancer Center from 8:30 a.m. to 4:30 p.m.. Head and neck cancers include cancers of the mouth, nose, sinuses, salivary glands, throat ...

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### GP partnership model is “no longer fit for purpose,” says Lords inquiry

The traditional partnership model of general practice is “no longer fit for purpose” and should be phased out in favour of alternative models such as salaried employment, concludes a major...

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### IJERPH, Vol. 14, Pages 381: Epidemiology of Burns in Rural Bangladesh: An Update

Each year, approximately 265,000 deaths occur due to burns on a global scale. In Bangladesh, around 173,000 children under 18 sustain a burn injury. Since most epidemiological studies on burn injuries in low and middle-income countries are based on small-scale surveys or hospital records, this study aims to derive burn mortality and morbidity measures and risk factors at a population level in Bangladesh. A household survey was conducted in seven rural sub-districts of Bangladesh in 2013 to assess injury outcomes. Burn injuries were one of the external causes of injury. Epidemiological characteristics and risk factors were described using descriptive as well as univariate and multivariate logistic regression analyses. The overall mortality and morbidity rates were 2 deaths and 528 injuries per 100,000 populations. Females had a higher burn rate. More than 50% of injuries were seen in adults 25 to 64 years of age. Most injuries occurred in the kitchen while preparing food. 88% of all burns occurred due to flame. Children 1 to 4 years of age were four times more likely to sustain burn injuries as compared to infants. Age-targeted interventions, awareness of first aid protocols, and improvement of acute care management would be potential leads to curb death and disability due to burn injuries.

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### Laughter is the best medicine - Half Moon Bay Review

 Laughter is the best medicine Half Moon Bay Review Tate visited these dark places most notably during two nearly fatal bouts of disfiguring oral cancer and has re-emerged, committed to illuminating the way for others as they discover their own path to healing, purpose and passion. “I had cancer of the ...

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### ASTHMA: A Complex Respiratory Condition - Amandala

 Amandala ASTHMA: A Complex Respiratory Condition Amandala These conditions include bronchial asthma, bronchitis, hay fever, pneumonia, sinusitis, emphysema, and lung cancer. People who have allergic reactions to pollen are only a subgroup of a larger group of respiratory sufferers who have sensitivities ...

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### A 56-Year-Old Woman With Multiple Subcutaneous Painful Nodules in the Absence of Renal Disease.

No abstract available

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### A 56-Year-Old Woman With Multiple Subcutaneous Painful Nodules in the Absence of Renal Disease.

No abstract available

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### Primary Cutaneous Follicular Helper T-Cell Lymphoma: A Case Series and Review of the Literature.

Primary cutaneous follicular helper T-cell (Tfh) lymphoma is a recently described variant of peripheral T-cell lymphoma-not otherwise specified. This particular variant, usually presenting as a sudden onset of multiple plaques and nodules, is characterized by tumoral atypical T cells that express an array of Tfh markers, such as inducible T-cell costimulator, Bcl-6, CXCL13, PD-1, and CD10. The authors now present 3 patients whose known clinical skin findings are consistent with PTCL of Tfh origin (PTCL-Tfh). The typically protracted pattern of skin disease manifesting as scaly patches and plaques encountered in mycosis fungoides was not seen in our 3 cases, and there were distinguishing light microscopic and phenotypic features. These cases are similar to the few previous reported cases of PTCL-Tfh, although systemic involvement was not seen. The categorization of additional patients into this PTCL subtype in the medical literature would be needed to further characterize this new entity and may lead to better targeted treatments based on specific T-cell subtypes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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### A 32-Year-Old Woman With Tender Nodules That Ulcerate.

No abstract available

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### Winkelmann Granuloma.

No abstract available

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### Erythematous Bullous Patch in a Patient With Myelodysplastic Syndrome.

No abstract available

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### Effects of patient-centered communication on anxiety, negative affect, and trust in the physician in delivering a cancer diagnosis: A randomized, experimental study

#### BACKGROUND

When bad news about a cancer diagnosis is being delivered, patient-centered communication (PCC) has been considered important for patients' adjustment and well-being. However, few studies have explored how interpersonal skills might help cancer patients cope with anxiety and distress during bad-news encounters.

#### METHODS

A prospective, experimental design was used to investigate the impact of the physician communication style during a bad-news encounter. Ninety-eight cancer patients and 92 unaffected subjects of both sexes were randomly assigned to view a video of a clinician delivering a first cancer diagnosis with either an enhanced patient-centered communication (E-PCC) style or a low patient-centered communication (L-PCC) style. Participants rated state anxiety and negative affect before and immediately after the video exposure, whereas trust in the physician was rated after the video exposure only. Main and interaction effects were analyzed with generalized linear models.

#### RESULTS

Viewing the disclosure of a cancer diagnosis resulted in a substantial increase in state anxiety and negative affect among all participants. This emotional response was moderated by the physician's communication style: Participants viewing an oncologist displaying an E-PCC style were significantly less anxious than those watching an oncologist displaying an L-PCC style. They also reported significantly higher trust in the physician.

#### CONCLUSIONS

Under a threatening, anxiety-provoking disclosure of bad news, a short sequence of empathic PCC influences subjects' psychological state, insofar that they report feeling less anxious and more trustful of the oncologist. Video exposure appears to be a valuable method for investigating the impact of a physician's communication style during critical encounters. Cancer 2017. © 2017 American Cancer Society.

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### Obesity in early pregnancy may link to epilepsy in offspring, study finds

Being overweight or obese in early pregnancy is associated with increased risk for childhood epilepsy in offspring, a nationwide study in Sweden has reported.1Epilepsy is one of the most common...

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### Whooping cough booster in pregnancy is highly protective for newborns, study finds

Maternal pertussis vaccination provides more than 90% protection for babies in the first two months of life, the critical period before they can receive their first childhood jabs, research has...

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### Summary

In this prospective study, subjective sleep quality and excessive daytime sleepiness prior to, during and after deployment of German soldiers in Afghanistan were examined. Sleep quality (Pittsburgh Sleep Quality Index; PSQI) and daytime sleepiness (Epworth Sleepiness Scale; ESS) were assessed in 118 soldiers of the German army, who were deployed in Afghanistan for 6 months (deployment group: DG) and in 146 soldiers of a non-deployed control group (CG) at baseline. Results of the longitudinal analysis are reported, based on assessments conducted prior to, during the deployment and afterwards in the DG, and in the CG in parallel. Sleep quality and daytime sleepiness in the DG were already impaired during the predeployment training phase and remained at that level during the deployment phase, which clearly indicates the need for more attention on sleep in young soldiers, already at this early stage. The percentage of impaired sleepers decreased significantly after deployment. Programmes to teach techniques to improve sleep and reduce stress should be implemented prior to deployment to reduce sleep difficulties and excessive daytime sleepiness and subsequent psychiatric disorders.

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### Summary

Sleep inertia is affected by circadian phase, with worse performance upon awakening from sleep during the biological night than biological day. Visual search/selective visual attention performance is known to be sensitive to sleep inertia and circadian phase. Individual differences exist in the circadian timing of habitual wake time, which may contribute to individual differences in sleep inertia. Because later chronotypes awaken at an earlier circadian phase, we hypothesized that later chronotypes would have worse visual search performance during sleep inertia than earlier chronotypes if awakened at habitual wake time. We analysed performance from 18 healthy participants [five females (22.1 ± 3.7 years; mean ± SD)] at ~1, 10, 20, 30, 40 and 60 min following electroencephalogram-verified awakening from an 8 h in-laboratory sleep opportunity. Cognitive throughput and reaction times of correct responses were impaired by sleep inertia and took ~10–30 min to improve after awakening. Regardless whether chronotype was defined by dim light melatonin onset or mid-sleep clock hour on free days, derived from the Munich ChronoType Questionnaire, the duration of sleep inertia for cognitive throughput and reaction times was longer for later chronotypes (= 7) compared with earlier chronotypes (= 7). Specifically, performance for earlier chronotypes showed significant improvement within ~10–20 min after awakening, whereas performance for later chronotypes took ~30 min or longer to show significant improvement (< 0.05). Findings have implications for decision making immediately upon awakening from sleep, and are consistent with circadian theory suggesting that sleep inertia contributes to longer-lasting impairments in morning performance in later chronotypes.

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### Summary

Periodic leg movements during sleep (PLMS) are sequences of ≥4 motor events with intermovement intervals (IMI) of 10–90 s. PLMS are a supportive diagnostic criterion for restless legs syndrome (RLS) and entail cardiac activation, particularly when associated with arousal. RLS patients also over-express short-interval leg movements during sleep (SILMS), which have IMI <10 s and are organized mainly in sequences of two movements (doublets). We tested whether the cardiac activation associated with SILMS doublets differs from that associated with PLMS in a sample of 25 RLS patients. We analysed time–series of R–R intervals synchronized to the onset of SILMS doublets or PLMS that entailed an arousal during non-rapid eye movement (NREM) sleep. We assessed cardiac activation based on the R–R interval decrease with respect to baseline during NREM sleep without leg movements. We found that the duration of the R–R interval decrease with SILMS doublets was significantly longer than that with PLMS, whereas the maximal decrease in R–R interval was similar. Scoring SILMS in RLS patients may therefore be relevant from a cardiac autonomic perspective.

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### Congratulations to Arnold Demain

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### Erratum to: Calcium and oxidative stress mediate perillaldehyde-induced apoptosis in Candida albicans

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### Obituary: Hans-Jürgen Rehm 1927–2017

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### Abstract

A β-1,4-mannanase, termed AoMan134A, that belongs to the GH 134 family was identified in the filamentous fungus Aspergillus oryzae. Recombinant AoMan134A was expressed in Pichia pastoris, and the purified enzyme produced mannobiose, mannotriose, mannotetraose, and mannopentaose from galactose-free β-mannan, with mannotriose being the predominant reaction product. The catalytic efficiency (k cat/K m ) of AoMan134A was 6.8-fold higher toward galactomannan from locust bean gum, than toward galactomannan from guar gum, but similar toward galactomannan from locust bean gum and glucomannan from konjac flour. After incubation at 70°C for 120 min, the activity of AoMan134A toward glucomannan decreased to 50% of the maximal activity at 30°C. AoMan134A retained 50% of its β-1,4-mannanase activity after heating at 90°C for 30 min, indicating that AoMan134A is thermostable. Furthermore, AoMan134A was stable within a neutral-to-alkaline pH range, as well as exhibiting stability in the presence of a range of organic solvents, detergents, and metal ions. These findings suggest that AoMan134A could be useful in a diverse range of industries where conversion of β-mannans is of prime importance.

http://ift.tt/2nVOAyV

### Abstract

We previously engineered Escherichia coli YL104 to efficiently produce succinate from glucose. In this study, we investigated the relationships between the NADH/NAD+ ratio, ATP level, and overall yield of succinate production by using glucose as the carbon source in YL104. First, the use of sole NADH dehydrogenases increased the overall yield of succinate by 7% and substantially decreased the NADH/NAD+ ratio. Second, the soluble fumarate reductase from Saccharomyces cerevisiae was overexpressed to manipulate the anaerobic NADH/NAD+ ratio and ATP level. Third, another strategy for reducing the ATP level was applied by introducing ATP futile cycling for improving succinate production. Finally, a combination of these methods exerted a synergistic effect on improving the overall yield of succinate, which was 39% higher than that of the previously engineered strain YL104. The study results indicated that regulation of the NADH/NAD+ ratio and ATP level is an efficient strategy for succinate production.

http://ift.tt/2ozWWzh

### Abstract

New anti-Candida albicans drugs are needed due to the emergence of resistant cases in recent years. Perillaldehyde (PAE) is a natural monoterpenoid compound derived from Perilla frutescens. The minimum inhibitory concentration of PAE against C. albicans was 0.4 μL/mL. We aimed to elucidate the antifungal mode of action of PAE against C. albicans. The antifungal activity of PAE against C. albicans was found to correlate with an elevation in intracellular Ca2+ and accumulation of ROS. Several downstream apoptosis events such as the disruption of mitochondrial membrane potential, phosphatidylserine externalization, cytochrome c release, and metacaspase activation were observed in PAE-treated cells. DNA damage and nuclear fragmentation assays also revealed apoptosis of C. albicans cells. In summary, by means of fluorescent microscopy, flow cytometer analysis, and Western blot, our data uncovered that PAE exerts its antifungal activity through Ca2+ and oxidative stress-mediated apoptosis mechanisms. This study deciphered the mode of action of PAE, which will be useful in the design of improved antifungal therapies.

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### Abstract

A 63-year-old Caucasian man presented with a 4-month history of disseminated asymptomatic reddish-brown papulonodular lesions. A skin biopsy showed dermal infiltration with CD68+ histiocytes, predominantly with eosinophilic cytoplasm, some with a ground-glass cytoplasm, and a small number of giant cells. The diagnosis of multiple cutaneous reticulohistiocytosis was made. Bone marrow immunophenotyping due to peripheral blood lymphocytosis revealed the presence of a monoclonal population of CD3+, CD8+ CD57+ large granular lymphocytes. The present case suggests the coexistence of multiple cutaneous reticulohistiocytosis with an underlying disorder.

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### Unusual clinical umbilical hernia: pitfall

Description

A 75-year-old alcoholic male patient with severe malnutrition was admitted to the hospital with the diagnosis of pneumonia. The finding of a symptomatic umbilical hernia on patient examination mandated a surgical consultation with the question of an operative hernia repair.

Clinically, the abdomen was distended with spider angiomas. Palpation of the umbilical hernia was painless. The hernia content was not reducible. A suspicious murmur (Cruveilhier-Baumgarten murmur) was identified on auscultation of the umbilicus (figure 1). The abdominal CT scan showed signs of portal hypertension. A large recanalised paraumbilical vein coursing from the left side of the portal vein through the falciform ligament and draining into a large umbilical varicose vein was visible. An enlarged right inferior epigastric vein originating from the umbilical varicose vein drained into the right femoral vein. The hernial sac contained only the umbilical varicose (figure 2A,B,C). On further investigation,...

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### Biologics,Biologic Response Modifiers,Biopharmaceutical.

http://otorhinolarygology.blogspot.com/2017/04/biologicsbiologic-response.html

Major kinds of biopharmaceuticals include:

Blood factors (Factor VIII and Factor IX)
Thrombolytic agents (tissue plasminogen activator)
Hormones (insulin, glucagon, growth hormone, gonadotrophins)
Haematopoietic growth factors (Erythropoietin, colony stimulating factors)
Interferons (Interferons-α, -β, -γ)
Interleukin-based products (Interleukin-2)
Vaccines (Hepatitis B surface antigen)
Monoclonal antibodies (Various)
Additional products (tumour necrosis factor, therapeutic enzymes)
Research and development investment in new medicines by the biopharmaceutical industry stood at \$65.2 billion in 2008.[11] A few examples of biologics made with recombinant DNA technology include:

USAN/INN Trade name Indication Technology Mechanism of action
abatacept Orencia rheumatoid arthritis immunoglobin CTLA-4 fusion protein T-cell deactivation
adalimumab Humira rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Ulcerative Colitis, Crohn's disease monoclonal antibody TNF antagonist
alefacept Amevive chronic plaque psoriasis immunoglobin G1 fusion protein incompletely characterized
erythropoietin Epogen anemia arising from cancer chemotherapy, chronic renal failure, etc. recombinant protein stimulation of red blood cell production
etanercept Enbrel rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis recombinant human TNF-receptor fusion protein TNF antagonist
infliximab Remicade rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Ulcerative Colitus, Crohn's disease monoclonal antibody TNF antagonist
trastuzumab Herceptin breast cancer humanized monoclonal antibody HER2/neu (erbB2) antagonist
ustekinumab Stelara psoriasis humanized monoclonal antibody IL-12 and IL-23 antagonist
denileukin diftitox Ontak cutaneous T-cell lymphoma (CTCL) Diphtheria toxin engineered protein combining Interleukin-2 and Diphtheria toxin Interleukin-2 receptor binder
golimumab Simponi rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Ulcerative colitis monoclonal antibody TNF antagonist

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

### Abstract

A genetic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is challenging due to allelic heterogeneity, high GC-content, and homology of the PKD1 gene with six pseudogenes. Short-read next-generation sequencing (NGS) approaches, such as whole genome (WGS) and whole exome sequencing (WES), often fail at reliably characterizing complex regions such as PKD1. However, long-read single-molecule sequencing has been shown to be an alternative strategy that could overcome PKD1 complexities and discriminate between homologous regions of PKD1 and its pseudogenes. In this study, we present the increased power of resolution for complex regions using long-read sequencing to characterize a cohort of 19 patients with ADPKD. Our approach provided high sensitivity in identifying PKD1 pathogenic variants, diagnosing 94.7% of the patients. We show that reliable screening of ADPKD patients in a single test without interference of PKD1 homologous sequences, commonly introduced by residual amplification of PKD1 pseudogenes, by direct long-read sequencing is now possible. This strategy can be implemented in diagnostics and is highly suitable to sequence and resolve complex genomic regions that are of clinical relevance.

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### Seizing market shaping opportunities for vaccine cold chain equipment.

Seizing market shaping opportunities for vaccine cold chain equipment.

Vaccine. 2017 Apr 19;35(17):2260-2264

Authors: Azimi T, Franzel L, Probst N

Abstract
Gavi, the Vaccine Alliance, supports immunisation programmes in eligible countries to reach children with lifesaving vaccines. Dramatic improvement in the scale and performance of current cold chain systems is required to extend the reach of immunisation services - especially for children living in remote locations - to advance progress towards full vaccine coverage. Achieving these improvements will require a healthier market for cold chain equipment where the products meet user needs, are sustainably priced, and are available in sufficient quantities to meet demand. Yet evidence suggests that the cold chain market has suffered from several failures including limited demand visibility, fragmented procurement, and insufficient information exchange between manufacturers and buyers on needs and equipment performance. One of Gavi's strategic goals is to shape markets for vaccines and other immunisation products, including cold chain equipment and in 2015, Gavi created a new mechanism - the Cold Chain Equipment (CCE) Optimisation Platform - to strengthen country cold chain systems by offering financial support and incentives for higher performing CCE. The main objective of the CCE Platform is to get more equipment that is efficient, sustainable, and better performing deployed to every health facility where it is required at an affordable price. To achieve these objectives, Gavi is putting in place tested market shaping approaches and tools adapted for the CCE market: the development of market strategies or 'roadmaps'; improvement of product performance through the development of target product profiles (TPPs); strategic engagement with CCE manufacturers and countries to enhance information sharing; and tailoring procurement tactics to the CCE market. These approaches and tools will allow for increased demand and supply of higher-performing, cost-effective and quality products. By strengthening immunisation systems with improved cold chain equipment, Gavi countries can begin to address the underlying problems limiting vaccine availability and improve the coverage and equity of vaccines.

PMID: 28364940 [PubMed - in process]

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### Long-acting insulin allergy in a diabetic child.

Long-acting insulin allergy in a diabetic child.

Int J Immunopathol Pharmacol. 2017 Apr 01;:394632017700431

Authors: Mastrorilli C, Rizzuti L, Cangelosi AM, Iovane B, Chiari G, Caffarelli C

Abstract
Insulin allergy has been uncommon since the introduction of human recombinant insulin preparations; the prevalence is 2.4%. Insulin injection could elicit immediate reactions, which are usually induced by an IgE-mediated mechanism, within the first hour after drug administration. In the present study, we describe the case of a child who experienced immediate urticaria after long-acting insulin injection. A 9-year-old girl affected by type I diabetes mellitus referred a history of three episodes of urticaria 30 min after insulin subcutaneous injection. During the first week of insulin therapy, she developed generalized immediate urticaria twice after long-acting insulin glargine first and then once after insulin degludec administration. Symptoms resolved within a few hours after treatment with oral antihistamine. She tolerated rapid insulin lispro. Her personal allergological history was negative. Skin prick tests with degludec, glargine and detemir were performed, showing negative results. Intradermal 1:100000-diluted tests were immediately positive for both degludec and glargine but not for detemir. In light of these findings, detemir was administered without any reaction. Our results show that detemir is tolerated by patients with clinical hypersensitivity reactions to degludec and glargine. Although reactions could be attributable to additives allergy, such as zinc or metacresol, this was excluded since all three preparations contain the same components. So, insulin itself acted as offending allergen. Detemir differs from degludec and glargine in a few aminoacids. Therefore, it is possible that the conformational rather than the linear epitope may be responsible for the reaction. This result suggests integrating intradermal tests in the diagnostic flowchart for insulin allergy. Insulin allergy should always be suspected in patients with immediate symptoms after drug injection. As allergologic work-up, prick by prick test and intradermal test to insulin preparations should be performed. In case of negative results of cutaneous tests, insulin analogs may be administered.

PMID: 28368217 [PubMed - as supplied by publisher]

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### Abstract

Vibrio parahaemolyticus expresses one major virulence determinant T6SS2, which is constituted into three putative operons, i.e., VPA1027-1024, VPA1043-1028, and VPA1044-1046. CalR, a LysR-type transcriptional regulator, was originally identified as a repressor of the swarming motility and T3SS1 gene expression. As shown in this study, CalR binds to the promoter-proximal region of each of the three operons to activate their transcription, and moreover, CalR activates the adhesion of V. parahaemolyticus to HeLa cells. In addition, competitive EMSAs demonstrated that CalR acts as an antagonist of H–NS in V. parahaemolyticus. Collectively, these studies confirmed a new physiological role for CalR in V. parahaemolyticus.

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### Sleep Duration Across the Adult Lifecourse and Risk of Lung Cancer Mortality: A Cohort Study in Xuanwei, China

Sufficient sleep duration is crucial for maintaining normal physiological function and has been linked to cancer risk; however, its contribution to lung cancer mortality is unclear. Therefore, we evaluated the relationship between average sleep duration in various age-periods across the adult lifecourse, and risk of lung cancer mortality in Xuanwei, China. An ambidirectional cohort study was conducted in 42,422 farmers from Xuanwei, China. Participants or their surrogates were interviewed in 1992 to assess average sleep hours in the age-periods of 21-30, 31-40, 41-50, 51-60, 61-70, and ≥71 years, which were categorized as ≤7, 8 (reference), 9, and ≥10 hours/day. Vital status was followed until 2011. Sex-specific Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer mortality in 1994-2011, adjusted for demographic, anthropometric, medical, and household characteristics. J-shaped relationships were found between average sleep duration and lung cancer mortality. The patterns were consistent across sex, age-periods, and fuel usage. Compared to sleeping 8 hours/day on average, ≤7 hours/day was associated with significantly increased HRs ranging from 1.39 to 1.58 in ages ≥41 years in men, and 1.29 to 2.47 in ages ≥51 years in women. Furthermore, sleeping ≥10 hours/day was associated with significantly increased HRs ranging from 2.44 to 3.27 in ages ≥41 year in men, and 1.31 to 2.45 in ages ≤60 years in women. Greater and less than 8 hours/day of sleep in various age-periods may be associated with elevated risk of lung cancer mortality in Xuanwei, China.

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### On this day: April 4 - KEYT

 KEYT On this day: April 4 KEYT 2013: Movie critic Roger Ebert, the first film critic to win the Pulitzer Prize for Criticism, dies at the age of 70 in Chicago, Illinois, after a recurrence of cancer. Ebert, who had lived with cancer of the thyroid and salivary glands since 2002, was ... and more »

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### Commentary on Some Recent Theses Relevant to Combating Aging: April 2017

Rejuvenation Research , Vol. 0, No. 0.

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### The p53/p21 complex regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins

The tumor suppressor p53 binds pro-survival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts pro-apoptotic or anti-invasive functions depending on stress context. Based on our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21.

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### Combination therapy targeting BCL6 and phospho-STAT3 defeats intra-tumor heterogeneity in a subset of non-small cell lung cancers

Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, K-RAS, and MYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1 and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 up-regulation and another with SMAD2/3 down-regulation. Treatment with a STAT3 inhibitor eliminated the up-regulated STAT3 subpopulation, but left a large surviving subpopulation with down-regulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes and tumor suppressors may provide a potent way to defeat intra-tumor heterogeneity.

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### Cellular prion protein PRPC and ecto-5'-nucleotidase are markers of the cellular stress response to aneuploidy

Aneuploidy is a hallmark of most human tumors, but the molecular physiology of aneuploid cells is not well characterized. In this study, we screened cell surface biomarkers of ~300 proteins by multiparameter flow cytometry using multiple aneuploid model systems such as cell lines, patient samples and mouse models. Several new biomarkers were identified with altered expression in aneuploid cells, including overexpression of the cellular prion protein CD230/PRPC and the immunosuppressive cell surface enzyme ecto-5'-nucleotidase CD73. Functional analyses associated these alterations with increased cellular stress. An increased number of CD73+ cells was observed in confluent cultures in aneuploid cells relative to their diploid counterparts. An elevated expression in CD230/PRPC was observed in serum-deprived cells in association with increased generation of reactive oxygen species. Overall, our work identified biomarkers of aneuploid karyotypes which suggest insights into the underlying molecular physiology of aneuploid cells.

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### Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma

Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild type counterparts expressing all isoforms (fs120, fs164, fs188 or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 versus fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site

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### Abstract

Chemokine and the chemokine receptor have a key role in the tumor progress. Here, we supposed that CCR7 might induce the invasion, migration, and epithelial–mesenchymal transition (EMT) process of breast cancer. In this research, human breast cancer MCF-7 and MDA-MB-231cells were treated with CCL19 and small-interfering RNA (CCR7 siRNA) for activation and inhibition of CCR7, respectively. Cell invasion and transwell assays were used to detect the effect of CCR7 on invasion and migration. The results demonstrated that CCL19 mediated cell invasion and migration by inducing the EMT, with downregulation of E-cadherin and up-regulation of N-cadherin and vimentin levels. On the other hand, knockdown of CCR7 revealed the changes compared with CCL19 group and the control group. Knockdown of CCR7 inhibits CCL19-induced breast cancer cell proliferation, the cell cycle, migration, invasion and EMT. Moreover, we demonstrated that CCL19-induced AKT phosphorylation; however, CCR7 siRNA suppressed CCL19-induced AKT phosphorylation, a key regulator of tumor metastasis. In conclusion, all findings demonstrated that CCL19/CCR7 axis regulated EMT progress in breast cancer cells and mediated the tumor cell invasion and migration process via activation of AKT signal pathway. Our results suggested that CCR7 may regard as a therapeutic target for the breast cancer treatment.

All findings demonstrated that CCL19/CCR7 axis regulated EMT progress in breast cancer cells and mediated the tumor cell invasion and migration process via activation of AKT signal pathway. Our results suggested that CCR7 may regard as a therapeutic target for the breast cancer treatment.

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### Abstract

Human papillomavirus (HPV), the causal factor of cervical cancers, was closely linked to the etiology and prognosis of oropharyngeal squamous cell carcinoma (OPSCC), but its role in oral squamous cell carcinoma (OSCC) was unclear. In addition, few researches based on Chinese population were documented. Hence, we sought to investigate the relationship of HPV marker P16 protein to the clinicopathological parameters and survival of OPSCC and OSCC patients systematically to assess the influence of ethnic, regional difference on HPV susceptibility. Specimens from 93 OPSCC patients and 95 OSCC patients were recut, and P16 immunohistochemistry (IHC) was performed. Moreover, survival analysis was conducted to confirm the independent factors that influenced the prognosis. The P16 results were positive in 25.8% and 9.5% of patients with OPSCC and OSCC, respectively. The overall survival (OS) of HPV-positive OPSCC patients was significantly longer than that of HPV-negative OPSCC patients (P = 0.004). Conversely, statistical significance was not observed regarding the OS of OSCC patients (P = 0.343). Cox regression analysis indicated that T stage and P16 status were independent factors that affected the prognosis of OPSCC patients, and the smoking index influenced the prognosis of OSCC patients. Among OPSCC patients who received radiochemotherapy (RCT), HPV-positive patients had a better survival rate than their HPV-negative counterparts (P = 0.015). Conversely, no significant difference was observed between HPV-positive and HPV-negative OSCC patients who received RCT (P = 0.237). P16 is a credible surrogate by which to define HPV status. HPV expression had a favorable effect on OPSCC patients as opposed to their OSCC counterparts in this single center population-based study.

The research regarding to the relationship between HPV and clinicopathological parameters and paprognosis of oral and oropharyngeal squamous cell carcinomas is emerging as a hotspot in the world. Taking account of the difference between The East and The West, we conduct this systematic retrospective investigation including consultation of medical records, collection of specimen, statistical analysis and postoperative follow-up.

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### Abstract

The incidences of thyroid cancer keep rising worldwide over the past few decades. Although most thyroid cancers are indolent and highly curable, the treatment for advanced thyroid cancer remains challengeable in clinical practice. We performed two separate cohorts to evaluate the safety and efficiency of Escin in patients with advanced thyroid cancer . In cohort 1, 120 patients were divided into four groups equally and were administrated with placebo or different dosages of Escin. The pharmacokinetics of Escin and the side effects were evaluated. In cohort 2, 120 patients were treated with Escin. Several biomarkers related to the progression of thyroid cancer were evaluated. Kaplan–Meier (KM) analyses were performed to evaluate progression-free survival (PFS) and overall survival (OS). The serum Escin concentrations were stable during the treatment. Escin (0.6 mg/kg/day for 9 days, intravenous injection) was tolerable for patients with thyroid cancer . Escin significantly reduced the serum levels of TSH, TgAb, Tg, and calcitonin and prolonged the PFS and OS for patients with advanced thyroid cancer. This study showed Escin is efficient and well tolerated in patients with advanced thyroid cancer. Future studies are needed to investigate the mechanism of Escin on thyroid cancer and the proper dosage of Escin clinically.

This study showed Escin is efficient and well tolerated in patients with advanced thyroid cancer. Based on the safety, and pharmacokinetic and efficacy profiles of our study, it was concluded that Escin 0.6 mg/kg/day i.v. for 9 days was tolerable.

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### Abstract

Cytology-based cervical cancer screening is restricted because of a lack of cytologists. Thus, HPV-based instead of cytology-based screening may be a more suitable strategy in China. Here, we assessed the effectiveness of HPV testing (Cobas® 4800 Test, Roche) and HPV-based programs to detect high-grade cervical intraepithelial neoplasia (CIN) or cancer compared with cytology (Thinprep, Hologic) and cytology-based programs through a cross-sectional study in 11,064 Chinese women aged 21–65 years who were enrolled from Longyou County in Zhejiang Province, China. The rates of HPV positivity and cytology abnormality were 9.8% and 6.1%, respectively. The HPV positivity rate had two age peaks, 21–24 (15.4%) and 60–65 (14.4%) years. According to adjusted data, HPV testing demonstrated significantly higher sensitivity and negative predictive value (NPV) than cytology for detecting CIN2 or worse (90.0% vs. 66.7%, 99.9% vs. 99.5%), and there was an acceptable specificity (91.3%) and positive predictive value (PPV, 12.5%). Furthermore, primary HPV testing with type 16/18 genotyping showed the highest sensitivity (78.6%) and NPV (99.7%) among four screening strategies, and there was similar specificity (96.8%) and PPV (23.9%) compared with co-testing screening to detect CIN2+, while there were fewer colposcopies (4.2) and tests (106.3) performed than with co-testing and primary cytology screening to detect a case of high-grade CIN. The differences in effectiveness were approximately similar when CIN3+ was the identifying target. Our findings suggest that primary HPV testing with type 16/18 genotyping has a higher sensitivity and NPV, possesses optimal cost/effectiveness in the first round of screening and is a feasible strategy of cervical cancer screening for Chinese women.

Cytology-based cervical cancer screening is restricted in China because of a lack of cytologists. We assessed, for the first time in China, the effectiveness of Cobas® HPV testing and HPV-based programs to detect high-grade cervical intraepithelial neoplasia (CIN) or cancer through a population-based cross-sectional study, and found that primary HPV testing with type 16/18 genotyping demonstrated higher sensitivity and negative predictive value (NPV), possessed optimal cost/effectiveness in the first round of screening and could be a feasible strategy of cervical cancer screening for Chinese women.

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### Abstract

Sporadic colorectal cancer (CRC) is classified into several molecular subtypes. We previously established two groups of DNA methylation markers through genome-wide DNA methylation analysis to classify CRC into distinct subgroups: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively). HME CRC, also called CpG island methylator phenotype (CIMP)-high CRC, shows methylation of both Group 1 markers (CIMP markers) and Group 2 markers, while IME/CIMP-low CRC shows methylation of Group 2, but not of Group 1 markers, and LME CRC shows no methylation of either Group 1 or Group 2 markers. While BRAF- and KRAS-mutation(+) CRC strongly correlated with HME and IME, respectively, clinicopathological features of NRAS-mutation(+) CRC, including association with DNA methylation, remain unclear. To characterize NRAS-mutation(+) CRC, the methylation levels of 19 methylation marker genes (6 Group 1 and 13 Group 2) were analyzed in 61 NRAS-mutation(+) and 144 NRAS-mutation(−) CRC cases by pyrosequencing, and their correlation with clinicopathological features was investigated. Different from KRAS-mutation(+) CRC, NRAS-mutation(+) CRC significantly correlated with LME. NRAS-mutation(+) CRC showed significantly better prognosis than KRAS-mutation(+) CRC (= 3 × 10−4). NRAS-mutation(+) CRC preferentially occurred in elder patients (= 0.02) and at the distal colon (= 0.006), showed significantly less lymph vessel invasion (= 0.002), and correlated with LME (= 8 × 10−5). DNA methylation significantly accumulated at the proximal colon. NRAS-mutation(+) CRC may constitute a different subgroup from KRAS-mutation(+) CRC, showing significant correlation with LME, older age, distal colon, and relatively better prognosis.

Genetic and epigenetic analyses of colorectal cancer (CRC) were conducted to clarify molecular and clinicopathological features of NRAS-mutation(+) CRC compared to KRAS-mutation(+) and other subgroups of CRC. NRAS-mutation(+) CRC presented a low-methylation epigenotype, occurred in elder patients and at the distal colon, and showed relatively better prognosis

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### Abstract

In order to maximize efficiency and reduce the risk of failure in operational dams, an effective and efficient method which employs the inverse analysis of a dynamic coupled hydro-mechanical problem is proposed. The numerical model is based on the extended finite element model. The proposed method is able to identify cracks which may be detrimental to structural performance and reliability. An attempt is made using both deterministic and heuristic based strategies to solve the ill-posed inverse problem and identify the location, dimension and orientation of the crack. More so, the influence of the search space and conditioning of the cost function in identifying crack parameters are investigated. The proposed method shows promising results in the identification of cracks in a fully operational dam.

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### Abstract

The initial yield envelopes of aluminum (Al) nanocomposites reinforced with carbon nanotubes (CNTs) subjected to biaxial loading are predicted in the presence of thermal residual stress (TRS) arising from the manufacturing process. Micromechanical model based on the unit cell method is presented to generate the yielding surfaces. The formation of the interphase caused by the interfacial reaction between the CNT and Al matrix is taken into account in the analysis. The effects of several important parameters, i.e. the change of temperature, CNT volume fraction, interphase thickness and Al material properties on the yielding onset of the CNT/Al nanocomposite are explored extensively. The results clearly reveal that the initial yield surfaces of nanocomposite are dependent on the TRS. Also, the interphase has a significant influence on the yielding behavior of Al nanocomposite in the presence of TRS. The results demonstrate that the size of initial yield surfaces become minimum with considering the coupled effects of TRS and interphase. With increasing the temperature variation, interphase thickness, elastic modulus and coefficient of thermal expansion of Al matrix, the size of initial yield surfaces reduces. The present study is consequential for understanding the key role of TRS on the initial damage of CNT/Al nanocomposites.

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### Abstract

Nearest neighbor search is a core process in many data mining algorithms. Finding reliable closest matches of a test instance is still a challenging task as the effectiveness of many general-purpose distance measures such as $$\ell _p$$ -norm decreases as the number of dimensions increases. Their performances vary significantly in different data distributions. This is mainly because they compute the distance between two instances solely based on their geometric positions in the feature space, and data distribution has no influence on the distance measure. This paper presents a simple data-dependent general-purpose dissimilarity measure called ' $$m_p$$ -dissimilarity'. Rather than relying on geometric distance, it measures the dissimilarity between two instances as a probability mass in a region that encloses the two instances in every dimension. It deems two instances in a sparse region to be more similar than two instances of equal inter-point geometric distance in a dense region. Our empirical results in k-NN classification and content-based multimedia information retrieval tasks show that the proposed $$m_p$$ -dissimilarity measure produces better task-specific performance than existing widely used general-purpose distance measures such as $$\ell _p$$ -norm and cosine distance across a wide range of moderate- to high-dimensional data sets with continuous only, discrete only, and mixed attributes.

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### Background

Urothelial bladder carcinoma (UBC) is one of the most prevalent cancers in men worldwide. Human epidermal growth factor receptor 2 (HER2) expression has been detected in a wide range of urothelial carcinoma. Despite many reports in the literature, the prognostic significance of this overexpression remains unclear. The aim of this study was to assess the expression of HER2 in urothelial bladder carcinomas and its association with clinical and pathological parameters.

### Methods

103 cases of UBC were diagnosed in our department between January 2014 and December 2015. The tumor specimens obtained by transurethral resection or cystectomy were evaluated by immunohistochemistry using HER2 antibody.

### Results

HER2 protein overexpression was present in 11.7% of cases and associated with tumor grade (p = 0.003) and pathological stage (p = 0.015). In multivariate analysis, HER2 overexpression was associated only with tumor grade (P = 0.04).

### Conclusion

HER2 protein overexpression is noted in patients with high grade cancer. This expression may select patients for anti HER2 targeted therapy. Future larger and prospective studies will verify the frequency of HER2 alteration and the role of HER2 in the aggressive behavior.

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### Belle Gibson mimicked countless fake healers. They aren't delusional - The Guardian

 The Guardian Belle Gibson mimicked countless fake healers. They aren't delusional The Guardian Imagine for a moment being diagnosed with cancer and being one of the 14 million people worldwide each year shattered by a diagnosis that sinks the heart like none other. If you are lucky enough to live in one of the handful of sufficiently resourced ...

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### Summary

Melanins (eumelanin and pheomelanin) are synthesised in insects for several purposes including cuticle sclerotisation and color patterning, clot formation, organogenesis and innate immunity. Traditional views of insect immunity detail the storage of pro-phenoloxidases inside specialized blood cells (hemocytes) and their release upon recognition of foreign bodies. Activated phenoloxidases convert monophenols into reactive quinones in a two-step enzymatic reaction, and until recently, the mechanism of tyrosine hydroxylation remained a mystery. Herein, we present our interpretations of these enzyme-substrate complexes. The resultant melanins are deposited onto the surface of microbes to immobilise, agglutinate and suffocate them. Phenoloxidase activity and melanin production are not limited to the blood (hemolymph) or cuticle, as recent evidence points to more diverse, sophisticated interactions in the gut and with the resident symbionts. This review offers insight into the somewhat neglected areas of insect melanogenesis research, particularly in innate immunity, its role in beneficial insects such as pollinators, the functional versatility of phenoloxidases and the limitations of common experimental approaches that may impede progress inadvertently.

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### Corrigendum to “Effectiveness and Safety of Electroacupuncture on Poststroke Urinary Incontinence: Study Protocol of a Pilot Multicentered, Randomized, Parallel, Sham-Controlled Trial”

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### Erratum to “A Model for Spheroid versus Monolayer Response of SK-N-SH Neuroblastoma Cells to Treatment with 15-Deoxy-PGJ2”

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### Shock Tube as an Impulsive Application Device

Current investigations solely focus on application of an impulse facility in diverse area of high-speed aerodynamics and structural mechanics. Shock tube, the fundamental impulse facility, is specially designed and calibrated for present objectives. Force measurement experiments are performed on a hemispherical test model integrated with the stress wave force balance. Similar test model is considered for heat transfer measurements using coaxial thermocouple. Force and heat transfer experiments demonstrated that the strain gauge and thermocouple have lag time of 11.5 and 9 microseconds, respectively. Response time of these sensors in measuring the peak load is also measured successfully using shock tube facility. As an outcome, these sensors are found to be suitable for impulse testing. Lastly, the response of aluminum plates subjected to impulsive loading is analyzed by measuring the in-plane strain produced during deformation. Thus, possibility of forming tests in shock is also confirmed.

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### Cardioprotective Effects of HuoxueAnshen Recipe against Myocardial Injuries Induced by Sleep Deprivation in Rats

Background. Traditional Chinese Medicine is extensively used in China and HuoxueAnshen Recipe (HAR) was formulated according to its method in treating CHD accompanied with insomnia in clinic. However, there are few studies related to the effect of HAR on myocardial injury and sleep disorders. Purpose. To investigate the effects of HAR on sleep deprivation- (SD-) induced myocardial I/R injury. Methods. Male Wistar rats receiving a daily gavage of HAR or vehicle were exposed to SD intervention while control rats had normal sleep. Then all rats were exposed to myocardial I/R. Hormone, vascular endothelial, and inflammatory related factors were detected before and after I/R, while cardiac injury, cardiac function, myocardial infarct size, and apoptosis were detected after I/R. Results. Levels of neuropeptide Y, vascular endothelial and inflammatory related factors were significantly increased while melatonin was decreased in vehicle-treated SD rats but not in HAR-treated SD rats after SD. In addition, cardiac injury, cardiac dysfunction, myocardial infarct size, and myocardial apoptosis were deteriorated in vehicle-treated SD rats but were ameliorated in HAR-treated SD rats after I/R. Conclusion. HAR not only improved SD-induced hormone disorders, inflammation, and endothelial dysfunction, but also alleviated I/R injury, which supports protective usage in CHD and psychocardiology.

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### Normalizing Item-Based Collaborative Filter Using Context-Aware Scaled Baseline Predictor

Item-based collaborative filter algorithms play an important role in modern commercial recommendation systems (RSs). To improve the recommendation performance, normalization is always used as a basic component for the predictor models. Among a lot of normalizing methods, subtracting the baseline predictor (BLP) is the most popular one. However, the BLP uses a statistical constant without considering the context. We found that slightly scaling the different components of the BLP separately could dramatically improve the performance. This paper proposed some normalization methods based on the scaled baseline predictors according to different context information. The experimental results show that using context-aware scaled baseline predictor for normalization indeed gets better recommendation performance, including RMSE, MAE, precision, recall, and nDCG.

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### Self-Medication in University Students from the City of Mansoura, Egypt

Background. Self-medication is a common practice in developed and developing countries. Objectives. To explore the prevalence of self-medication practices among university students, probable reasons, symptoms requiring self-medication, and sources of advice. Methods. A descriptive cross-sectional study was carried out in Mansoura University, Egypt, and included 1st and last year students of both medical and nonmedical faculties. Results. Prevalence of self-medication was 62.9%. Younger age, female, medical, and ever-married students and those having home pharmacy tended to self-medicate more than their peers with significant difference between them. Being medical student, being from urban area, having good current health condition, being careless about health, and having drugs stored at home pharmacy were independently associated with the likelihood of self-medicating. Conclusion. Prevalence of self-medication among university students is high which constitutes a health problem that needs intervention.

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### Progress in EEG-Based Brain Robot Interaction Systems

The most popular noninvasive Brain Robot Interaction (BRI) technology uses the electroencephalogram- (EEG-) based Brain Computer Interface (BCI), to serve as an additional communication channel, for robot control via brainwaves. This technology is promising for elderly or disabled patient assistance with daily life. The key issue of a BRI system is to identify human mental activities, by decoding brainwaves, acquired with an EEG device. Compared with other BCI applications, such as word speller, the development of these applications may be more challenging since control of robot systems via brainwaves must consider surrounding environment feedback in real-time, robot mechanical kinematics, and dynamics, as well as robot control architecture and behavior. This article reviews the major techniques needed for developing BRI systems. In this review article, we first briefly introduce the background and development of mind-controlled robot technologies. Second, we discuss the EEG-based brain signal models with respect to generating principles, evoking mechanisms, and experimental paradigms. Subsequently, we review in detail commonly used methods for decoding brain signals, namely, preprocessing, feature extraction, and feature classification, and summarize several typical application examples. Next, we describe a few BRI applications, including wheelchairs, manipulators, drones, and humanoid robots with respect to synchronous and asynchronous BCI-based techniques. Finally, we address some existing problems and challenges with future BRI techniques.

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### Online Adaptive Optimal Control of Vehicle Active Suspension Systems Using Single-Network Approximate Dynamic Programming

In view of the performance requirements (e.g., ride comfort, road holding, and suspension space limitation) for vehicle suspension systems, this paper proposes an adaptive optimal control method for quarter-car active suspension system by using the approximate dynamic programming approach (ADP). Online optimal control law is obtained by using a single adaptive critic NN to approximate the solution of the Hamilton-Jacobi-Bellman (HJB) equation. Stability of the closed-loop system is proved by Lyapunov theory. Compared with the classic linear quadratic regulator (LQR) approach, the proposed ADP-based adaptive optimal control method demonstrates improved performance in the presence of parametric uncertainties (e.g., sprung mass) and unknown road displacement. Numerical simulation results of a sedan suspension system are presented to verify the effectiveness of the proposed control strategy.

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### Economic Evaluation of Three Available Solutions for Promotion of Wind Power Integration

The limited operational flexibility of combined heat and power (CHP) units is the main cause of wind power curtailment in the thermal-electrical power system of Northern China. Pumped hydrostorage (PHS), heat storage (HS), and electric boiler (EB) are investigated as three alternative options for the promotion of wind power integration. On the basis of two linear models that determine the capacities of these three facilities required for integrating the curtailed wind power, economic evaluation in terms of investment costs and environmental benefits is presented. Analysis results show that HS requires the least investment and has a good performance of coal saving when accommodating the same amount of curtailed wind power. And EB has the greatest potential for wind power integration with the huge growth of installed capacity of wind power in the future.

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### Synthesis of Gold Nanoparticles Dispersed in Palm Oil Using Laser Ablation Technique

Gold nanoparticles have more applications in biology, medicine, and industry. In this study, gold nanoparticles were synthesized in pure palm oil using laser ablation technique. Gold nanoparticles were fabricated in different temperature, and the effect of the temperature on the particle size was investigated. Consequently, the tail of the carbonyl band of fatty acids was capped gold nanoparticles, and spherically shaped gold nanoparticles with size range of 8.92 to 19.73 nm were formed in palm oil. The temperature caused the agglomeration of nanoparticles while the particle size increased with an increase in the temperature.

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### Comment on “Unilateral Global Bifurcation from Intervals for Fourth-Order Problems and Its Applications”

In the recent paper W. Shen and T. He and G. Dai and X. Han established unilateral global bifurcation result for a class of nonlinear fourth-order eigenvalue problems. They show the existence of two families of unbounded continua of nontrivial solutions of these problems bifurcating from the points and intervals of the line trivial solutions, corresponding to the positive or negative eigenvalues of the linear problem. As applications of this result, these authors study the existence of nodal solutions for a class of nonlinear fourth-order eigenvalue problems with sign-changing weight. Moreover, they also establish the Sturm type comparison theorem for fourth-order problems with sign-changing weight. In the present comment, we show that these papers of above authors contain serious errors and, therefore, unfortunately, the results of these works are not true. Note also that the authors used the results of the recent work by G. Dai which also contain gaps.

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### Topical Drug Therapies for Chronic Rhinosinusitis

Chronic rhinosinusitis is recognized as an inflammatory syndrome involving the nose and paranasal sinuses of multifactorial etiology. Research has demonstrated a complex interplay between host factors, microbiota, environmental exposures, and epigenetics resulting in chronic mucosal inflammation. The mainstay of medical therapy addresses this inflammation. In previously operated sinuses this includes topical saline and corticosteroids, reserving antibiotics for culture-directed acute exacerbations. Topical antiinflammatory therapies allow increased local concentration of drugs while minimizing side effects. Topical therapies have advanced the surgical field by improving and maintaining postoperative outcomes. The topical therapies include saline, corticosteroids, antibiotics, and antifungals.

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### Evolution in Visualization for Sinus and Skull Base Surgery

Rhinoscopy became a formal field of study in the mid-nineteenth century as improvements in nasal specula were made and the potent vasoconstrictive effects of cocaine on the intranasal tissues were discovered. Since then, a multitude of advances in visualization and illumination have been made. The advent of the Storz-Hopkins endoscope in the mid-twentieth century represents a culmination of efforts spanning nearly 2 centuries, and illumination has evolved concomitantly. The future of endoscopic sinus surgery may integrate developing technologies, such as 3-dimensional endoscopy, augmented reality navigation systems, and robotic endoscope holders.

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### iRECIST: A clarification of tumour response assessment in the immunotherapy era

The advent of immuno-oncology (IO) drugs profoundly changes our understanding of cancer biology as well as the management of patients at bedside. This is especially true for melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin's lymphoma or bladder cancer, for which these drugs already demonstrated substantial improvements in the patients' outcome. Beyond these indications, objective tumour responses have been reported in more than 20 different cancer types in early phase trials.

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### Abstract

#### Background

Prostaglandin D2 (PGD2) is primarily produced by mast cells and is contributing to the nasal symptoms including nasal obstruction and rhinorrhea.

#### Objective

This study aimed to evaluate the efficacy and safety of a novel PGD2 receptor 1 (DP1) antagonist, ONO-4053, in patients with seasonal allergic rhinitis (SAR).

#### Methods

This study was a multicenter, randomized, double-blind, parallel-group study of patients with SAR. Following a one-week period of placebo run-in, patients who met the study criteria were randomized to either the ONO-4053, leukotriene receptor antagonist pranlukast, or placebo group for a two-week treatment period. 200 patients were planned to be randomly assigned to receive ONO-4053, pranlukast, or placebo in a 2:2:1 ratio. Nasal and eye symptoms were evaluated.

#### Results

Both ONO-4053 and pranlukast had higher efficacy than placebo on all nasal and eye symptoms. ONO-4053 outperformed pranlukast in a total of three nasal symptom scores (T3NSS) as well as in individual scores for sneezing, rhinorrhea, and nasal itching. For T3NSS, the Bayesian posterior probabilities that pranlukast was better than placebo and ONO-4053 was better than pranlukast were 70.0% and 81.6%, respectively, suggesting that ONO-4053 has a higher efficacy compared with pranlukast. There was no safety-related issue in this study.

#### Conclusions

We demonstrated that the efficacy of ONO-4053 was greater than that of pranlukast with a similar safety profile. This study indicates the potential of ONO-4053 for use as a treatment for SAR (JapicCTI-142706).

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### Abstract

#### Background

The antimicrobial peptide (AMP) RNase 7 is constitutively expressed in the epidermis of healthy human skin and has been found to be upregulated in chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Activated T-cells in lesional skin of patients with atopic dermatitis (AD) and psoriasis (PSO) might be directly exposed to RNase 7. In addition to their antimicrobial activity immunoregulatory functions have been published for several AMPs. In this study we investigated immunoregulatory effects of the antimicrobial peptide RNase 7 on activated T-cells.

#### Methods

Isolated human CD3+ T-cells were stimulated with RNase 7 and screened for possible effects by mRNA microarray analysis. The results of the mRNA microarray were confirmed in isolated CD4+T-cells and in polarised TH2 cells using skin derived native RNase 7 and a recombinant ribonuclease-inactive RNase 7 mutant. Activation of GATA3 was analysed by electrophoretic mobility shift assay.

#### Results

Treatment of activated human CD4+ T-cells and TH2 cells with RNase 7 selectively reduced the expression of TH2 cytokines (IL-13, IL-4 and IL-5). Experiments with a ribonuclease-inactive recombinant RNase 7 mutant showed that RNase 7 ribonuclease activity is dispensable for the observed regulatory effect. We further demonstrate that CD4+T-cells from AD patients revealed a significantly less pronounced downregulation of IL-13 in response to RNase 7 compared to healthy control. Finally, we show that GATA3 activation was diminished upon cultivation of T-cells with RNase7.

#### Conclusion

Our data indicate that RNase 7 has immunomodulatory functions on TH2-cells and decreases the production of TH2 cytokines in the skin

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### IJMS, Vol. 18, Pages 750: Delphinidin Reduces Glucose Uptake in Mice Jejunal Tissue and Human Intestinal Cells Lines through FFA1/GPR40

Anthocyanins are pigments with antihyperglycemic properties, and they are potential candidates for developing functional foods for the therapy or prevention of Diabetes mellitus type 2 (DM2). The mechanism of these beneficial effects of anthocyanins are, however, hard to explain, given their very low bioavailability due to poor intestinal absorption. We propose that free fatty acid receptor 1 (FFA1, also named GPR40), is involved in an inhibitory effect of the anthocyanidin delphinidin over intestinal glucose absorption. We show the direct effects of delphinidin on the intestine using jejunum samples from RF/J mice, and the human intestinal cell lines HT-29, Caco-2, and NCM460. By the use of specific pharmacological antagonists, we determined that delphinidin inhibits glucose absorption in both mouse jejunum and a human enterocytic cell line in a FFA1-dependent manner. Delphinidin also affects the function of sodium-glucose cotransporter 1 (SGLT1). Intracellular signaling after FFA1 activation involved cAMP increase and cytosolic Ca2+ oscillations originated from intracellular Ca2+ stores and were followed by store-operated Ca2+ entry. Taken together, our results suggest a new GPR-40 mediated local mechanism of action for delphinidin over intestinal cells that may in part explain its antidiabetic effect. These findings are promising for the search for new prevention and pharmacological treatment strategies for DM2 management.

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### IJMS, Vol. 18, Pages 626: Exome Sequencing Identified a Novel FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, camptodactyly, contrature of major joints, scoliosis, pectus deformities, and crumpled ears. The present study aimed to identify the genetic cause of a three-generation Chinese family with CCA. We successfully identified a novel missense mutation p.G1145D in the fibrillin-2 (FBN2) gene as the pathogenic mutation by whole exome sequencing (WES). The p.G1145D mutation occurs in the 12th calcium-binding epidermal growth factor-like (cbEGF) domain. The p.G1145D mutation caused a hydrophobic to hydrophilic substitution, altering the amino acid property from neutral to acidic. Three-dimensional structural analysis showed that this mutation could alter the conformation of the residue side chain, thereby producing steric clashes with spatially adjacent residues, disrupting the formation of H bonds and causing folding destabilization. Therefore, this amino acid appears to play an important role in the structure and function of FBN2. Our results may also provide new insights into the cause and diagnosis of CCA and may have implications for genetic counseling and clinical management.

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### GC-MS quantitative analysis of black market pharmaceutical products containing anabolic androgenic steroids seized by the Brazilian Federal Police

Substandard, spurious, falsely labelled, falsified and counterfeit (SSFFC) medical products are a serious concern worldwide, reaching any therapeutic class [1]. SSFFC medicines can have no effect at all, result in therapeutic failure, be toxic or even cause death [1,2]. Substandard products, also known as out-of-specification products, are genuine medicines produced by authorized manufacturers that do not meet the quality specifications. Counterfeit (spurious, falsely labelled and falsified products, SFFC) are those deliberately and fraudulently mislabeled with respect to identity and/or source, both branded and generic products, with the wrong ingredients, without active ingredients, with insufficient quantities of correct ingredient(s) or with fake packaging [3].

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### Abstract

The impact of RAS/RAF mutations in localized colon cancer needs clarification. Based on analysis of tumor-specific DNA, this study aimed at elucidating the prognostic influence of mutational status in tumor and serum using an extended panel of mutations.

The study retrospectively included 294 patients with curatively resected stage I–III adenocarcinoma of the colon. Mutations in tumor and serum were determined at time of surgery. Analyses were performed with droplet digital PCR technology. Hazard ratio (HR) for the association between mutational status and survival was estimated in multivariate analysis taking known prognostic factors into account.

Mutational status in tumor did not on its own have significant prognostic impact (P = 0.22). Patients with a RAS mutation simultaneously in tumor and serum had a significantly worse prognosis, overall survival (OS) (HR = 2.30, 95% CI = 1.27–4.15, P = 0.0057), and disease-free survival (DFS) (HR = 2.18, 95%CI = 1.26–3.77, P = 0.0053). BRAF mutation in the serum and proficient mismatch repair (pMMR) protein in tumor also indicated significantly worse prognosis, OS (HR = 3.45, 95% CI = 1.52–7.85, P = 0.0032) and DFS (HR = 3.61, 95% CI = 1.70–7.67, P = 0.0008). In conclusion, RAS mutations in serum, and BRAF mutation in serum combined with pMMR in tumor were strong independent prognostic factors in patients with RAS/RAF mutated tumors.

This work is the first to demonstrate simultaneous RAS/RAF mutational status in tumor and serum in localized colon cancer patients to be a potent prognostic marker.

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### Abstract

Digital breast tomosynthesis (DBT) has shown potential to improve breast cancer screening and diagnosis compared to digital mammography (DM). The FDA approved DBT use in conjunction with conventional DM in 2011, but coverage was approved by CMS recently in 2015. Given changes in coverage policies, it is important to monitor diffusion of DBT by insurance type. This study examined DBT trends and estimated associations with insurance type. From June 2011 to September 2014, DBT use in 22 primary care centers in the Dartmouth -Brigham and Women's Hospital Population-based Research Optimizing Screening through Personalized Regimens research center (PROSPR) was examined among women aged 40–89. A longitudinal repeated measures analysis estimated the proportion of DBT performed for screening or diagnostic indications over time and by insurance type. During the study period, 93,182 mammograms were performed on 48,234 women. Of these exams, 16,506 DBT tests were performed for screening (18.1%) and 2537 were performed for diagnosis (15.7%). Between 2011 and 2014, DBT utilization increased in all insurance groups. However, by the latest observed period, screening DBT was used more frequently under private insurance (43.4%) than Medicaid (36.2%), Medicare (37.8%), other (38.6%), or no insurance (32.9%; P < 0.0001). No sustained differences in use of DBT for diagnostic testing were seen by insurance type. DBT is increasingly used for breast cancer screening and diagnosis. Use of screening DBT may be associated with insurance type. Surveillance is required to ensure that disparities in breast cancer screening are minimized as DBT becomes more widely available.

Digital breast tomosynthesis (DBT) is increasingly used for breast cancer screening and diagnosis. Our study finds screening DBT to be associated with insurance type, with lowest use among those with Medicaid and the uninsured. Surveillance is required to ensure that insurance-related disparities in breast cancer screening are minimized as DBT becomes more widely available.

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### Abstract

Childhood cancer survivors (CCS) experience higher hospitalization rates compared to the general population for neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. We studied trends in hospitalization rates and associated patient and treatment-specific risk factors for diagnosis subgroups among these four diseases. We performed medical record linkage of a ≥5-year CCS cohort with national registers, and obtained a random reference sample matched on age, gender and calendar year per CCS. For each diagnosis subgroup we compared hospitalization rates and trends over time in CCS and the reference population. Further, we analyzed risk factors for hospitalizations within the four CCS diagnosis groups. We used multivariate Poisson regression for all models. We retrieved hospitalization data from 1382 CCS and 26,583 reference persons. CCS had increased hospitalization rates for almost all diagnosis subgroups examined. Hospitalization rates for endocrine/nutritional/metabolic diseases appeared to increase with longer time since primary cancer diagnosis up to 30 years after primary cancer diagnosis. Survivors initially treated with radiotherapy had increased hospitalization rates for neoplasms (P < 0.001), those initially treated with anthracyclines (2.5 [1.1–5.5]) and radiotherapy to thorax and/or abdomen (9.3 [2.4–36.6]) had increased hospitalization rates for diseases of the circulatory system, and those initially treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases (6.7 [3.5–12.7]) and diseases of the eye (3.6 [1.5–8.9]). Our study highlights that long-term health problems resulting in hospitalizations are still clinically relevant later in life of CCS. The identified treatment-related risk factors associated with hospitalizations support targeted follow-up care for these risk groups of CCS.

Childhood cancer survivors experience higher hospitalization rates compared to the general population for almost all diagnosis subgroups within neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. This study supports the prioritization of follow-up care for the risk groups we identified, namely those survivors originally treated with anthracyclines and radiotherapy to thorax and/or abdomen and head and/or neck.

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### It has got harder to access sexual health services in the UK

In the UK, people should get a clinic appointment within 2 days 98 per cent of the time, but a study suggests fewer than 91 per cent of those with symptoms do

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### A Solution to Refugee Children Healthcare in Greece

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### Abstract

Colorectal cancer (CRC) screening prevalence remains low among Asians and Pacific Islanders. This study examined disparities and predictors of CRC screening compliance in adults age 50–75 years in Asians and Pacific Islanders in Hawai'i. Hawai'i Behavioral Risk Factor Surveillance System (BRFSS) data for 2011–2014 were analyzed. CRC screening status was dichotomized. Logistic regression was used to examine ethnic differences in and predictors of CRC screening status. Filipinos (OR 0.56), Chinese (OR 0.70), and Hawaiians (OR 0.75) were significantly less likely than whites to be CRC compliant. Higher education and income, employment, regular health provider, and routine checkups were important predictors of CRC compliance. Findings confirm lower CRC screening compliance in three of the four largest Asian and Pacific Islander groups in Hawai'i and that CRC screening compliance is influenced by several factors. Culturally tailored education and navigation services may be effective in reducing these disparities.

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### It has got harder to access sexual health services in the UK

In the UK, people should get a clinic appointment within 2 days 98 per cent of the time, but a study suggests fewer than 91 per cent of those with symptoms do

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### The Color of Determination - Champaign/Urbana News-Gazette (blog)

 The Color of Determination Champaign/Urbana News-Gazette (blog) Blog Photo The same year his wife was being treated for breast cancer, Querio's brother was diagnosed with tongue cancer. Both of them were treated successfully and are healthy now. Last year, though, another family member was diagnosed with cancer.

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### Drug makes head-and-neck cancer more sensitive to radiotherapy - The Institute of Cancer Research

 The Institute of Cancer Research Drug makes head-and-neck cancer more sensitive to radiotherapy The Institute of Cancer Research A drug that has shown promise in breast and lung cancer trials also makes the combination of chemotherapy and radiotherapy more successful at killing head-and-neck cancers, a new study has found. The research could lead to more effective treatments for ...

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### Magnetic resonance imaging predicts chronic dizziness after benign paroxysmal positional vertigo

We aimed to evaluate the clinical implications of magnetic resonance imaging (MRI) findings in patients with benign paroxysmal positional vertigo (BPPV).

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### Quantitative imaging analysis of transcanal endoscopic Infracochlear approach to the internal auditory canal

A transcanal endoscopic infracochlear surgical approach to the internal auditory canal in a human temporal bone model has been described. The proportion of patients with favorable anatomy for this novel surgical technique is unknown. Herein, we perform a quantitative analysis of the infracochlear corridor to the IAC based on computed tomography.

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