“Direct” and “Indirect” Methods to Detect Oxidative Stress During Acute or Chronic High-Altitude Exposure

High Altitude Medicine & Biology , Vol. 0, No. 0.


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An examination of attitudes toward gender and sexual violence among Asian Indians in the United States.

Although issues of gender and violence among immigrant communities have gained some recognition, little is known about the role of cultural factors in attitudes toward gender and sexual violence among Asian Indians in the United States. This study investigated the relationship between ethnic identity and gender-related attitudes, attitudes toward sexual violence among Asian Indians, and whether gender and nativity (U.S.-born and foreign-born) predict attitudes toward gender and sexual violence. Participants were 175 Asian Indians living in the United States (127 women and 48 men; 128 born outside the United States and 47 born in the U.S). Measures of ethnic identity, gender role attitudes, sex role egalitarianism, and rape myth acceptance were administered online. Results indicated that stronger ethnic identity is associated with more traditional gender role attitudes and less sex role egalitarianism. Foreign-born Asian Indians and men reported more traditional gender role attitudes and less sex role egalitarianism when compared with U.S.-born participants and women, respectively. Contrary to expectations, ethnic identity, gender, and nativity did not predict rape myth acceptance. The findings call attention to the intertwined nature of ethnicity and gender, and to differences in ethnic identity and gender role socialization within Asian Indian subgroups. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Microaggressions and self-esteem in emerging Asian American adults: The moderating role of racial socialization.

The current study explores the moderating role of racial socialization in the relation between experiences of racial microaggressions and individual self-esteem and racial microaggressions and collective self-esteem for Asian American emerging adults. Asian American emerging adults (Mage = 23.83 years, SD = 2.83; N = 87) completed the Racial and Ethnic Microaggression Scale, the Perceived Racial Socialization Scale, the Rosenberg Self-Esteem Scale, and the Collective Self-Esteem Scale. Results suggest a negative correlation between racial microaggression experiences with both individual self-esteem, r = −.34, p = .001 and public self-esteem, r = −.35, p = .001, a component of collective self-esteem. Depending on type and level of message, racial socialization may serve as a protective factor in racial microaggressions and self-esteem relations. Specifically, results suggest a significant interaction when promotion of mistrust was tested as a moderator of the microaggressions–individual self-esteem relation (b = .063, SE = .026), t(86) = 2.47, p = .015, where the relation between microaggressions and self-esteem was only significant at low and moderate levels of promotion of mistrust. Promotion of mistrust also moderated the microaggressions–private self-esteem relation (b = .045, SE = .02), t(86) = 2.30, p = .024. However, when promotion of mistrust moderated this relation, the relation was nonsignificant at all levels (low, moderate, and high). An examination of simple slopes suggests a change in the direction of the relation between microaggressions and private self-esteem from negative for low and moderate levels of promotion of mistrust to positive for high levels of promotion of mistrust. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Mental-illness stigma among Korean immigrants: Role of culture and destigmatization strategies.

Mental-illness stigma is a well-documented problem in the Korean American immigrant community, and the need for antistigma programs is widely acknowledged. However, there is limited information on the ways in which this mental-health stigma is manifested in shaping views toward people with mental illness in the Korean-immigrant community—as well as on how to tackle the problem. To address the gap, this study used an exploratory design and 18 key-informant (KI) interviews were conducted via focus-group meetings with key leaders of the Korean-immigrant community in the San Francisco Bay Area. The study findings reveal stigmatized beliefs (e.g., being dangerous, out of control, and abnormal) and behaviors (e.g., social distance) toward people with mental illness, as well as cultural values that reinforce the stigma in the Korean-immigrant community. Our findings demonstrate an urgent need to ameliorate the stigma associated with mental illness. They also suggest that antistigma programs developed for Korean immigrant communities should emphasize community-based education that employs indirect approaches to preserve confidentiality and cultural values, as well as culturally and linguistically competent mental health services. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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MMPI-2 profiles among Asian American missionary candidates: Gendered comparisons for ethnicity and population norms.

There is currently a significant dearth of literature pertaining to the use of popular assessment instruments with ethnic minorities, including the Minnesota Multiphasic Personality Inventory (MMPI)-2. We examined standard MMPI-2 Scale scores from a sample of 508 male (n = 43 Asian Americans) and 665 female (n = 71 Asian Americans) missionary candidates, comparing scale means between ethnicities by gender and, for the Asian American participants, with the gendered MMPI-2 normative samples. Our within-sample findings support the existing literature with regard to Asian Americans obtaining higher mean scores than Whites for scales F, L, and D (among women), and scale Si (both men and women), while comparison with the MMPI-2 norms supported these findings for scales L and D. Other within-sample clinical scale differences were also observed, but mean scores for all these scales were in the modal range and do not suggest an ethnically distinct interpretive strategy. Religious and candidacy influences were a plausible explanation for most of the obtained validity scale means. However, among Asian American women, L scale elevations were significantly higher and may reflect the continuing relevance of ethnic considerations in evaluating MMPI-2 profile validity among even fairly acculturated women. Thus, our findings both support some of the existent research and validate the need for further studies of specific Asian American subgroups. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Developing minority leaders: Key success factors of Asian Americans.

Traditional leadership programs may not address the unique developmental needs of ethnic minorities. Whereas traditional leadership development is based on the assumptions, values, and behaviors of the Western mainstream ideals, our research uses a culture-specific approach to understand the unique needs of ethnic minority leaders, namely, Asian Americans. We focus on Asian Americans because they are least represented in U.S. management ranks, despite having the most education, training, and work experience. Our central research question is "What are the key success factors of Asian American leaders?" Qualitative interviews with 39 key informants (of East Asian descent, and 2 non-Asian Americans), ranging from middle managers to CEOs, at Fortune 500 companies, representing a variety of industries (accounting, aerospace, banking, digital imaging, energy, entertainment, food service, health care, medical, retail, technology, and telecommunication) identified 8 key success factors (i.e., qualities that promote upward mobility in the management hierarchy): cultural acumen, rules of success, leadership branding, communication, social decorum, leadership aspiration, career determinism, and cultural inclusion. Each success factor was defined, along with identification of its key issues, causes, consequences, and actions taken for cultivating the success factors. Results offer guidance for individual leadership development and for organizations to develop culture-specific leadership interventions that complement current mainstream training approaches. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Loss of face, intergenerational family conflict, and depression among Asian American and European American college students.

Asian-American college students have reported higher scores of depression than European-American college students. This study examined the mediating effects of loss of face and intergenerational family conflict between race/ethnicity and depression and hypothesized that these variables would explain previously observed depression differences. The sample consisted of 488 undergraduate students: 209 self-identified as Asian American and 279 as European American. Participants filled out paper-and-pencil questionnaires. As predicted, the study found that Asian Americans reported higher scores on depression, loss of face, and intergenerational family conflict than European Americans. Loss of face explained more variance in depression among Asian Americans than European Americans. However, intergenerational family conflict explained equal levels of variance in depression for both groups. A structural equation model revealed that the relationship between race/ethnicity and depression was fully mediated by loss of face and intergenerational family conflict. In conclusion, using the disentangling approach, differences in depression scores between Asian-American and European-American college students can be explained by differences in culturally relevant constructs, such as loss of face and intergenerational family conflict. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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“Annual Review of Asian American Psychology, 2015”: Correction to Kiang et al. (2016).

Reports an error in "Annual Review of Asian American psychology, 2015" by Lisa Kiang, Charissa S. L. Cheah, Virginia W. Huynh, Yijie Wang and Hirokazu Yoshikawa (Asian American Journal of Psychology, 2016[Dec], Vol 7[4], 219-255). In the article, the last author's name was misspelled. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2016-57154-001.) As the seventh in the series, this annual review of research on Asian American psychology focused on the 332 articles that were identified by PsycINFO as being published in 2015 and that met the inclusion criteria established by prior reviews. Consistent with prior annual reviews, these articles were coded for 4 domain themes: study topic, methodology, participant characteristics (i.e., ethnicity), and age range/developmental period of the sample. In addition to presenting a brief summary of our coding results, we also present a more detailed synthesis and evaluation of empirical work centered around the distinctive status of Asian Americans as members of cultural, immigrant, and minority groups. Trends and patterns in the field and concrete suggestions for future research are discussed throughout the review. A discussion of limitations of our review is also provided. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Social anxiety in Asian Americans: Integrating personality and cultural factors.

The purpose of this study was to obtain a more comprehensive understanding of social anxiety in Asian Americans by integrating personality and cultural factors that might affect social anxiety in this population. Asian American adults (N = 255) responded to an online survey, in which they completed measures of the Big Five traits (BFI; Benet-Martínez & John, 1998), Bicultural Identity Integration (BIIS-1; Benet-Martínez & Haritatos, 2005), acculturation and enculturation (AAMAS; Chung, Kim, & Abreu, 2004), and social anxiety (SIAS; Mattick & Clarke, 1998). As hypothesized, the acculturation/enculturation and BII constructs (BII-Conflict and BII-Distance) were fairly independent. When only cultural variables were considered, acculturation and BII-Conflict were comparable predictors of social anxiety. However, only BII-Conflict, and not BII-Distance or acculturation/enculturation, contributed incremental prediction of social anxiety beyond the Big Five traits. An integrated model—in which selected Big Five traits predicted acculturation/enculturation and BII, which, in turn, predicted social anxiety—fit the data well. In this model, Neuroticism had both a direct and indirect effect via BII-Conflict on social anxiety, Extraversion had only a direct effect on social anxiety, and Extraversion and Openness to Experience predicted some of the cultural variables. Overall, the findings support the value of integrating personality and cultural constructs in predicting social anxiety in Asian Americans. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Parenting variables associated with growth mindset: An examination of three Chinese-heritage samples.

An incremental theory of intelligence (TOI), the belief that intelligence is malleable and can be improved through effort, is associated with children's academic achievement, mastery goals, and overall psychological well-being. Although the positive impact of TOI is well established, less is known about socialization factors such as parenting that foster these orientations. We posited that both autonomy support (AS) and psychological control (PC) may promote incremental TOI among Chinese heritage fourth- to fifth-grade children and their mothers where socialization has largely been characterized as low in AS and high in PC. However, we examined the possibility that these associations may differ across contexts within the Chinese Diaspora (Beijing, Hong Kong, and Los Angeles) as child rearing evolves as a function of rapid social change and immigration. A multiple-group structural equation model revealed a positive association between child-report of maternal PC and child incremental TOI across all three samples (βBJ = .37, p

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Reciprocal relations between social self-efficacy and loneliness among Chinese international students.

Among international students in the United States, those with a Chinese cultural heritage (e.g., students from China, Taiwan, and Hong Kong) now constitute the largest group, representing over a 3rd of all such students. However, relatively little is known about the psychosocial factors that may predict successful transition into the United States. As such, independent of the effects of perceived English proficiency and social isolation, the present study assessed the relations between social self-efficacy and loneliness among Chinese international students in a 3-wave cross-lagged study (i.e., timeline ranging from prearrival to their 2nd semester in the United States). Their associations with social isolation and sources of friendship (i.e., U.S. friends, Chinese friends, or international friends) were also examined. Participants were 409 Chinese international students (57% female) enrolled in universities across the United States. Findings revealed bidirectional relations between social self-efficacy and loneliness across all 3 time points. Furthermore, we found that those with higher levels of social self-efficacy had a proportionally higher number of American friends during their 1st semester in the United States. In other words, having perceived close friendships with Americans may be an important factor associated with the social adjustment of Chinese international students. Implications of these findings are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved)

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Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes

Abstract

Paraneoplastic neurological syndromes (PNS) are often characterized by the presence of antineuronal antibodies in patient serum or cerebrospinal fluid. The detection of antineuronal antibodies has proven to be a useful tool in PNS diagnosis and the search for an underlying tumor. Here, we describe three patients with autoantibodies to several epitopes of the axon initial segment protein tripartite motif 46 (TRIM46). We show that anti-TRIM46 antibodies are easy to detect in routine immunohistochemistry screening and can be confirmed by western blotting and cell-based assay. Anti-TRIM46 antibodies can occur in patients with diverse neurological syndromes and are associated with small-cell lung carcinoma.

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Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity

Summary

Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long-term follow-up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.

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Mechanisms of Mendelian dominance

Abstract

Genetic dominance has long been considered as a qualitative reflection of interallelic interactions. Dominance arises from many multiple sources whose unifying theme is the existence of non-linear relationships between the genotypic and phenotypic values. One of the clearest examples are dominant negative mutations (DNMs) in which a defective subunit poisons a macromolecular complex. Dominance can also be due to the presence of a heterozygous null allele, as is the case of haploinsufficiency. Dominance can also be influenced by epistatic (interloci) interactions. For instance, a pre-existing genetic variant can make possible the expression of a pathogenic variant in a seemingly 'dominant' fashion. Such interactions, which can make an individual more or less sensitive to a particular pathogenic variant, will also be discussed.

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Directory: AAO Officers and Organizations

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Rate of tooth movement and dentoskeletal effects of rapid canine retraction by dentoalveolar distraction osteogenesis: A prospective study

The purpose of this study was to test the null hypothesis that duration of orthodontic treatment can be significantly reduced by accelerating canine retraction using dentoalveolar distraction (DAD).

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Information for readers

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Influence of different setups of the Frankfort horizontal plane on 3-dimensional cephalometric measurements

The Frankfort horizontal (FH) is a plane that intersects both porions and the left orbitale. However, other combinations of points have also been used to define this plane in 3-dimensional cephalometry. These variations are based on the hypothesis that they do not affect the cephalometric analysis. We investigated the validity of this hypothesis.

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Editorial Board

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Orthodontic-surgical retreatment of facial asymmetry with occlusal cant and severe root resorption: A 3-year follow-up

Our objective was to report the orthodontic and surgical retreatment of a patient who had undergone a prolonged orthodontic treatment with extractions, but who had unsatisfactory results and persistent side effects. The man, aged 25 years 3 months, sought treatment with major complaints of facial and smile asymmetries. The clinical examination showed a mandibular deviation to the right and a maxillary occlusal cant. A Class II Division 1 subdivision right was observed. Radiographic examination showed extensive root resorptions in the maxillary second premolars and absence of the 4 first premolars.

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Table of Contents

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CBCT imaging vs conventional radiography

In their systematic review, Eslami et al acknowledged that CBCT imaging may be more effective than conventional radiography in canine impaction cases that are difficult to diagnose (Eslami E, Barkhordar H, Abramovitch K, Kim J, Masoud MI. Cone-beam computed tomography vs conventional radiography in visualization of maxillary impacted-canine localization: a systematic review of comparative studies. Am J Orthod Dentofacial Orthop 2017;151:248-58). Unfortunately, they may not have provided the best available evidence for making clinical decisions otherwise.

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Residents' journal review

The authors of this retrospective study evaluated the predictability of arch expansion using Invisalign. The sample included 64 white adult patients with an average age of 31.2 years, who had both arches treated by 1 practitioner using Invisalign only. The patients had no missing teeth, and their treatment entailed no interproximal reduction posterior to the distal of the canines. Twenty patients had a dentoalveolar crossbite involving at least 1 tooth, mainly premolars. The mean treatment duration was 56 weeks, and only 1 round of aligners was used; no refinement was included.

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Prognosis of primary and secondary insertions of orthodontic miniscrews: What we have learned from 500 implants

Although the success of using orthodontic miniscrews for primary insertion has been reported in the literature, few studies have followed up on secondary insertions after failure of the first insertion. In this study, we investigated not only the primary but also secondary success rates of miniscrews and considered the risk factors influencing their stability.

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Courtesy counts

Mrs V had a terse and demanding way even as she appointed by phone for her initial examination. She made it clear that she does not take kindly to waiting anywhere— including doctor's offices. You recall that her first visit was scheduled during a busy afternoon that included a chaotic mix of multiple broken brackets, an ill-fitting RPE appliance, and a child who had a messy accident as a result of an upset stomach. You were thus 20 minutes late for Mrs V's appointment, but she had little empathy for your predicament.

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Randomized controlled trial of a patient decision-making aid for orthodontics

Patient decision-making aids (PDAs) are instruments that facilitate shared decision making and enable patients to reach informed, individual decisions regarding health care. The objective of this study was to assess the efficacy of a PDA compared with traditional information provision for adolescent patients considering fixed appliance orthodontic treatment.

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August 2017:152(2)

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Risk factors for tobacco susceptibility in an orthodontic population: An exploratory study

Tobacco use is related to increased periodontal disease, tooth loss, and decreased success of orthodontic appliances, and it may inhibit orthodontic tooth movement. Most smokers start during adolescence. Since most cessation attempts fail, prevention appears necessary.

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Common errors observed at the American Board of Orthodontics clinical examination

The American Board of Orthodontics has developed tools to help examinees select patients to be used for the Board examination. The Case Management Form can be used to evaluate aspects of a patient's treatment that cannot be measured by other tools. The Case Management Form is a structured treatment-neutral assessment of orthodontic objectives and outcomes associated with a patient's treatment. Despite the availability of this form, examiners continue to see problems, including lack of attention to finishing details, inappropriate treatment objectives, excessive proclination of mandibular incisors due to treatment mechanics, excessive expansion of mandibular intercanine width, closing skeletal open bite with extrusion of anterior teeth leading to excessive gingival display, and failure to recognize the importance of controlling the eruption or extrusion of molars during treatment.

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Comparison of survival time and comfort between 2 clear overlay retainers with different thicknesses

I read the article in the March 2017 issue comparing survival time and comfort of 2 clear overlay retainers of different thicknesses with great interest (Zhu Y, Lin J, Long H, Ye N, Huang R, Yang X, et al. Comparison of survival time and comfort between 2 clear overlay retainers with different thicknesses: a pilot randomized controlled trial. Am J Orthod Dentofacial Orthop 2017;151:433-9).

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Caught but released

Several months ago, you finished treatment on Susie, age 15. She wears her retainer like most kids do—or don't. She is still under your care and comes in for routine scheduled retainer checks. One day, her mom bursts into the office, Susie in tow, with a bloody towel over her mouth. Susie was just in a car accident a few blocks away. Mom was close and picked up Susie from the accident site and brought her directly to your office. All of this happened within the last 30 to 45 minutes. You examine Susie and see that 3 maxillary anterior teeth have been subluxated and are partially avulsed.

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Effects of unilateral premolar extraction treatment on the dental arch forms of Class II subdivision malocclusions

A retrospective study evaluating posttreatment symmetry in dental arch form and midlines was carried out in Class II subdivision patients treated with unilateral and bilateral maxillary premolar extractions.

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Poisson regression

In this article, we will describe how to analyze the data used in our previous article1 regarding implant failures with Poisson regression. We are interested in examining whether the rate of implant failure is different between smokers and nonsmokers. In other words, we are interested in the ratio of the rates between smokers and nonsmokers.

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Surgery-first orthognathic approach vs traditional orthognathic approach: Oral health-related quality of life assessed with 2 questionnaires

The purposes of the study were to investigate and evaluate the differences detected by the patients between the traditional orthognathic approach and the surgery-first one in terms of level of satisfaction and quality of life.

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Factors Associated with Pain Frequency among Adults with Chronic Conditions

Chronic pain affects approximately 100 million Americans, but little is known about the factors associated with pain frequency.

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Brief Training on Patient Anger Increases Oncology Providers’ Self-Efficacy in Communicating with Angry Patients

Anger is a common reaction to pain and life-limiting and life-threatening illness, is linked to higher levels of pain, and may disrupt communication with medical providers. Anger is understudied compared to other emotions in mental health and healthcare contexts, and many providers have limited formal training in addressing anger.

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Gaps in Provision of Primary and Specialty Palliative Care in the Acute Care Setting by Race and Ethnicity

Previous research has identified a large unmet need in provision of specialist-level palliative care services in the hospital. How much of this gap is filled by primary palliative care provided by generalists or non-palliative specialists has not been quantified. Estimates of racial and ethnic disparities have been inconsistent.

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Obturator hernia: a rare cause of bowel obstruction

An obturator hernia is a rare condition and an unusual cause of intestinal obstruction. With a challenging diagnosis, it has one of the highest mortality rates of all abdominal wall hernias. The authors present a case of an elderly woman with bowel obstruction secondary to an incarcerated obturator hernia. An 80-year-old woman presented at the emergency room with complaints for the last 2 days of nausea, vomiting, constipation and lower right abdominal pain that radiated down to the right medial thigh. Abdominal tenderness to deep palpation of the right iliac fossa and mildly distention were noted. A CT scan demonstrated bowel obstruction secondary to an incarcerated obturator hernia. The patient underwent emergency exploratory laparotomy. The incarcerated bowel was reduced and the defect was repaired with a plug of polypropylene mesh covered with peritoneum. The patient had an uneventful postoperative period and was discharged on the fifth postoperative day.

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A case of deep infection after instrumentation in dorsal spinal surgery: the management with antibiotics and negative wound pressure without removal of fixation

Until today the role of spinal instrumentation in the presence of a wound infection has been widely discussed and recently many authors leave the hardware in place with appropriate antibiotic therapy. This is a case of a 65-year-old woman suffering from degenerative scoliosis and osteoporotic multiple vertebral collapses treated with posterior dorsolumbar stabilisation with screws and rods. Four months later, skin necrosis and infection appeared in the cranial wound with exposure of the rods. A surgical procedure of debridement of the infected tissue and package with a myocutaneous trapezius muscle flap was performed. One week after surgery, negative pressure wound therapy was started on the residual skin defect. The wound healed after 2 months. The aim of this case report is to focus on the utility of this method even in the case of hardware exposure and infection. This may help avoid removing instrumentation and creating instability.

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Thrombolytic therapy for the treatment of acute ischaemic stroke in adults with homozygous sickle cell disease

Stroke is a significant cause of morbidity and mortality in patients with homozygous sickle cell disease (SCD). A specific large-vessel vasculopathy is often responsible for both haemorrhagic and ischaemic strokes in patients with SCD. Although intravenous thrombolysis has been considered as a therapeutic option for acute ischaemic strokes in SCD, its use remains debated because of an increased risk of spontaneous intracranial haemorrhage reported in this disease. This risk of haemorrhage is mainly supported by the presence of a Moyamoya syndrome often associated with the specific vasculopathy in patients with homozygous SCD. We report two cases of patients with homozygous SCD treated with intravenous thrombolysis for an acute ischaemic stroke without haemorrhagic transformation. Our cases suggest that reperfusion strategy in acute ischaemic stroke in patients with homozygous SCD can be considered once associated Moyamoya syndrome has been ruled out. An international registry would be of interest as these situations are rare.

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Longitudinal Midline Sacral Split Fracture - A Rare Entity

Fractures involving the central canal of the sacrum are rare injuries and can be transverse or longitudinal. Transverse fractures are by far common and associated with high incidence of neurological injuries. On the contrary, longitudinal midline split fracture is an extremely rare injury with minimal or no neurological injury. They are always associated with anterior pelvic ring fracture and are vertically stable needing only fixation of the anterior pelvic injury. Plating of the anterior pelvic ring in two planes would be beneficial than single plate to prevent gradual loss of reduction.

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Thalamic and cerebellar hypermetabolism and cortical hypometabolism during absence status epilepticus

We report on a 17-year-old girl with absence status epilepticus who developed recurrent motionless confusional state and continuous generalised 3–4 Hz rhythmic delta waves on electroencephalogram (EEG). The patient had no history of absence, myoclonus or generalised convulsion. Her seizure was resistant to a combination of antiepileptic drugs including carbamazepine. Ictal positron emission tomography using [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG-PET) revealed hypermetabolism of the bilateral thalamus and cerebellum and hypometabolism of the frontal, parietal and posterior cingulate cortices. We diagnosed her seizure as absence status and obtained remission by changing medication. The findings of ictal metabolic alteration in previous studies and in our case confirm the pathogenic importance of the thalamus in absence status and that associated cortical deactivation and cerebellar activation may be related to the generation or maintenance of epileptic EEG discharges.

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Acquired haemophilia A with a recalcitrant high-titre factor VIII inhibitor in the setting of interstitial lung disease

Acquired haemophilia A (AHA) is a bleeding disorder that results from autoantibodies against factor VIII (FVIII). A 70-year-old man with a history of interstitial lung disease presented with spontaneous bleeding into his thigh. He had undetectable FVIII levels and a high-titre FVIII inhibitor (>2000ââ'¬â°Bethesda units/mL) and was diagnosed with AHA. He had several relapses, required multiple haemostatic and immunosuppressive treatments but eventually achieved a stable remission after 2ââ'¬â°years of therapy.

Our patient matches the typical elderly male demographic of AHA. His relapsing course with remarkably high and persistent inhibitor titre highlights the need for close monitoring and aggressive upfront treatment. Whereas cyclophosphamide and steroids are often used first line in AHA, rituximab has also shown efficacy in refractory patients with high inhibitor levels. The FVIII and inhibitor concentration on presentation have been associated with treatment response and may be used as prognostic factors to tailor immunosuppressive regimens.

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Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma

Anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of...

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Impact of intrapatient variability (IPV) in tacrolimus trough levels on long-term renal transplant function: multicentre collaborative retrospective cohort study protocol

Introduction

High intrapatient variability (IPV) in tacrolimus trough levels has been shown to be associated with higher rates of renal transplant failure. There is no consensus on what level of IPV constitutes a risk of graft loss. The establishment of such a threshold could help to guide clinicians in identifying at-risk patients to receive targeted interventions to improve IPV and thus outcomes.

Methods and analysis

A multicentre Transplant Audit Collaborative has been established to conduct a retrospective study examining tacrolimus IPV and renal transplant outcomes. Patients in receipt of a renal transplant at participating centres between 2009 and 2014 and fulfilling the inclusion criteria will be included in the study. The aim is to recruit a minimum of 1600 patients with follow-up spanning at least 2 years in order to determine a threshold IPV above which a renal transplant recipient would be considered at increased risk of graft loss. The study also aims to determine any national or regional trends in IPV and any demographic associations.

Ethics and dissemination

Consent will not be sought from patients whose data are used in this study as no additional procedures or information will be required from participants beyond that which would normally take place as part of clinical care. The study will be registered locally in each participating centre in line with local research and development protocols. It is anticipated that the results of this audit will be disseminated locally, in participating NHS Trusts, through national and international meetings and publications in peer-reviewed journals.

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Relationship between initial therapy and blood pressure control for high-risk hypertension patients in the UK: a retrospective cohort study from the THIN general practice database

Objective

To examine the UK practice patterns in treating newly diagnosed hypertension and to determine whether subgroups of high-risk patients are more or less likely to follow particular therapeutic protocols and to reach blood pressure goals.

Design

Retrospective cohort study.

Setting

This study examined adults in The Health Improvement Network (THIN) UK general practice medical records database who were initiated on medication for hypertension.

Participants

48 131 patients with essential hypertension diagnosed between 2008 and 2010 who were registered with a participating practice for a minimum of 13 months prior to, and 6 months following, initiation of therapy. We excluded patients with gestational hypertension or secondary hypertension. Patients were classified into risk groups based on blood pressure readings and comorbid conditions.

Primary and secondary outcome measures

Odds of receiving single versus fixed or free-drug combination therapy and odds of achieving blood pressure control were assessed using multivariable logistic regression.

Results

The vast majority of patients (95.8%) were initiated on single drug therapy. Patients with high cardiovascular risk (patients with grade 2–3 hypertension or those with high normal/grade 1 hypertension plus at least one cardiovascular condition pretreatment) had a statistically significant benefit of starting immediately on combination therapy when blood pressure control was the desired goal (OR: 1.23; 95% CI: 1.06 to 1.42) but, surprisingly, were less likely than patients with no risk factors to receive combination therapy (OR: 0.53; 95% CI: 0.47 to 0.59).

Conclusions

Our results suggest that combination therapy may be indicated for patients with high cardiovascular risk, who accounted for 60.6% of our study population. The National Institute for Health and Care Excellence guideline CG34 of 2006 (in effect during the study period) recommended starting with single drug class therapy for most patients, and this advice does seem to have been followed even in cases where a more aggressive approach might have been considered.

http://ift.tt/2tKWxZW

Enteric Salmonella in humans and food in the Middle East and North Africa: protocol of a systematic review

Introduction

Non-typhoidal Salmonella is considered one of the leading causes of foodborne disease worldwide. This protocol provides methods that will be used to synthesise available epidemiological data on non-typhoidal enteric Salmonella in humans and food in Middle East and North Africa (MENA) region and to characterise the morbidity of human salmonellosis in this region.

Methods and analysis

A systematic review will be conducted based on the Cochrane Collaboration handbook and will be reported following the items outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We will search PubMed, Embase, CAB Direct and Global Health Library (WHO) databases in order to identify relevant reports. Additionally, the literature search will be supplemented by checking references of the included reports and the identified reviews. Furthermore, we will hand-search conference proceedings and Ministry of Health's website of each country of the MENA region. We will use comprehensive search criteria with no time and no language restrictions. We will extract data on report and study characteristics, biological assay characteristics, individuals' demographic characteristics and on primary and secondary outcomes of interest. If appropriate, meta-analysis will be conducted in order to estimate pooled prevalence measures using DerSimonian and Laird random-effects models. We will conduct meta-regression analysis to explore the effect of study-level characteristics as potential sources of heterogeneity.

Ethics and dissemination

The results of the systematic review will be disseminated in a peer-reviewed journal and presented at relevant conferences.

Trial registration number

The trial registration number is CRD42016046360.

http://ift.tt/2v7R8iW

Treatment and clinicopathological characteristics of lupus nephritis with anti-neutrophil cytoplasmic antibody positivity: a case-control study

Objective

To assess the clinical features, pathological presentations, treatments and outcomes of lupus nephritis (LN) with anti-neutrophil cytoplasmic antibody (ANCA) positivity.

Design

A case–control study.

Methods

Patients (n=49) were retrospectively included from Jinling Hospital in China if presenting with biopsy-proven ANCA-positive LN between 1985 and 2008. Clinicopathological characteristics and outcomes were analysed and compared with those of a control group (n=1279). We further compared treatment responses and outcomes of ANCA-positive LN patients based on the treatment issued.

Results

The study included 40 women and 9 men (median age 33 years at biopsy): 38 with myeloperoxidase (MPO)-ANCA, 7 with proteinase 3 (PR3)-ANCA and 4 with double positivity. ANCA-positive LN patients exhibited higher haematuria, serum creatinine levels and systemic lupus erythematosus disease activity index scores. On pathological evaluation, class IV LN was predominant, accounting for 61.22% of cases. Light microscopy revealed significantly higher activity index and chronicity index scores, including cellular crescents, interstitial inflammation, tubular atrophy and interstitial fibrosis. ANCA-positive LN patients receiving mycophenolate mofetil as induction therapy had a higher remission rate and better renal outcomes than those receiving cyclophosphamide. During follow-up, end-stage renal disease developed in seven (14.29%) ANCA-positive LN patients, all of them were MPO-ANCA positive.

Conclusions

The characteristics of ANCA-positive LN were massive haematuria and advanced renal insufficiency. We observed a higher remission rate and better prognoses when using mycophenolate mofetil than when using cyclophosphamide as induction therapy.

http://ift.tt/2tLo3X0

Study on factors inducing workplace violence in Chinese hospitals based on the broken window theory: a cross-sectional study

Objectives

To explore the potential components of hospital workplace violence (HWPV) from the perspectives of hospital administrators and patients, and put forward corresponding strategies for its prevention and control.

Setting

Using convenience sampling methods, 116 hospitals in 14 provinces of China were surveyed using a self-designed questionnaire.

Methods

A cross-sectional study was used.

Participants

Hospital administrators and patients from 116 hospitals in 14 provinces of China.

Results

First, hospital administrators point of workplace factors included six factors, with the following weighting coefficients: hospital administrator factors (29.40%), patient-related factors (20.08%), hospital environmental factors (19.45%), policy and institutional factors (11.92%), social psychological factors (10.26%), objective events factors (8.89%). Second, patients from the hospital workplace predisposing factors included three common factors. The weight coefficients of these were hospital-related factors (60.27%), social and governmental factors (23.64%) and patient-related factors (16.09%).

Conclusions

A wide range of factors according to hospital administrators, patients and in the hospital environment play important roles in HWPV. From the perspectives of hospital administrators, communication skills and attitude to the service are important factors for inducing HWPV. From the perspective of patients, the characteristics of staff personalities and medical cognition are more important inducing factors. As far as social factors are concerned, economic compensation of medical malpractice is an important inducing factor for HWPV. In terms of environmental factors, management of Chinese medical hospitals, medical procedures and the layout of departments are all potential factors for the occurrence of violence. Corresponding defects were exposed in the health legal system and the supervision system for influencing public opinion.

http://ift.tt/2v85Kim

Drug-eluting stents in clinical routine: a 1-year follow-up analysis based on German health insurance administrative data from 2008 to 2014

Objectives

To describe the use of drug-eluting stents (DESs) in the largest population of statutory health insurance members in Germany, including newly developed bio-resorbable vascular scaffolds (BVSs), and to evaluate 1-year complication rates of DES as compared with bare metal stents (BMSs) in this cohort.

Design

Routine data analysis of statutory health insurance claims data from the years 2008 to 2014.

Setting

The German healthcare insurance Allgemeine Ortskrankenkasse covers approximately 30% of the German population and is the largest nationwide provider of statutory healthcare insurance in Germany.

Participants and interventions

We included all patients with a claims record for a percutaneous coronary intervention (PCI) with either DES or BMS and additionally, from 2013, BVS. Patients with acute myocardial infarction (AMI) were excluded. Main outcome measure: major adverse cerebrovascular and cardiovascular event (MACCE, defined as mortality, AMI, stroke and transient ischaemic attack), bypass surgery, PCI and coronary angiography) at 1 year after the intervention.

Results

A total of 243 581 PCI cases were included (DES excluding BVS: 143 765; BVS: 1440; BMS: 98 376). The 1-year MACCE rate was 7.42% in the DES subgroup excluding BVS and 11.29% in the BMS subgroup. The adjusted OR for MACCE was 0.72 (95% CI 0.70 to 0.75) in patients with DES excluding BVS as compared with patients with BMS. In the BVS group, the proportion of 1-year MACCE was 5.0%.

Conclusion

The analyses demonstrate a lower MACCE rate for PCI with DES. BVSs are used in clinical routine in selected cases and seem to provide a high degree of safety, but data are still sparse.

http://ift.tt/2tLit71

Assessing the effects of changes in care commissioning guidelines at a tertiary centre in London on the provision of NHS-funded procedures of limited clinical effectiveness: an 11-year retrospective database analysis

Objectives

The main objective of this study was to assess the impact of changes in care commissioning policies on National Health Service (NHS)-funded cosmetic procedures over an 11-year period at our centre.

Setting

The setting was a tertiary care hospital in London regulated by the North Central London Hospitals NHS Trust care commissioning group.

Participants

We included all patients logged on to our database at the time of the study which was 2087 but later excluded 61 from analysis due to insufficient information.

Primary and secondary outcome measures

The main outcome measures were the results of tribunal assessment for different cosmetic surgeries which were either accepted, rejected or inconclusive based on the panel meeting.

Results

There were a total of 2087 patient requests considered between 2004 and 2015, of which 715 (34%) were accepted, 1311 (63%) were declined and 61 (3%) had inconclusive results. The implementation of local care commissioning guidelines has reduced access to cosmetic surgeries. Within this period, the proportion of procedures accepted has fallen from 36% in 2004 to 21% in 2015 (²; p<0.05, 95% CI).

Conclusion

Local guidance on procedures of limited clinical effectiveness is a useful, although not evidence-based selection process to reduce access to cosmetic surgery in line with increasing financial constraints. However, patients with a physical impairment may not receive treatment in comparison to previous years, and this can have a negative impact on their quality of life.

http://ift.tt/2v8it4B

Connecting cancer to its causes requires incorporation of effects on tissue microenvironments

In a recent paper in Science, Tomasetti et al. present an expanded model for cancer risk, which they claim demonstrates the relative contribution of mutations caused by replication errors, environment and heredity. The foundation of this model is the theory that the overwhelming driver of cancer risk is mutations. This perspective will present experimental evidence and evolutionary theory to challenge the basis of this underlying theory. An argument will be presented that the mutation-centric model of cancer suggests unrealistic solutions to cancer and distracts the research community from more promising approaches that consider tissue context.

http://ift.tt/2tR81z2

NSD1 inactivation and SETD2 mutation drive a convergence toward loss-of-function of H3K36 writers in clear-cell renal cell carcinomas

Extensive dysregulation of chromatin-modifying genes in clear-cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the crosstalk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear-cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of vascular endothelial growth factor receptor genes (FLT4, FLT1 and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss-of-function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC.

http://ift.tt/2u6vPKM

Adipose progenitor cell secretion of GM-CSF and MMP9 promotes a stromal and immunological microenvironment that supports breast cancer progression

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

http://ift.tt/2tR3XPt

Androgen receptor variants mediate DNA repair after prostate cancer irradiation

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

http://ift.tt/2u6xxLZ

Spi-B-mediated silencing of Claudin-2 promotes early dissemination of lung cancer cells from primary tumors

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

http://ift.tt/2tQKyhH

Integrating models to quantify environment mediated drug resistance

Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialogue between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated melanoma; the model describes tumor-stroma dynamics both with and without treatment. Integration of experimental data into our model revealed significant variation in either the intensity of stromal promotion or intrinsic tissue carrying capacity across animal replicates.

Major Findings. Through the integration of a simple mathematical model with in vitro and in vivo experimental growth dynamics of melanoma cell lines (both with and without drug), we were able to dissect the relative contributions of intrinsic versus environmental resistance. Our study revealed significant heterogeneity in vivo, indicating that there is a diversity of either stromal promotion or tumor carrying capacity under targeted therapy. We believe this variation may be one possible explanation for the heterogeneity observed across patients and within individual patients with multiple metastases. Therefore, quantifying this variation both within in vivo model systems and in individual patients could have a significant impact on the design of future treatment strategies that target both tumor and stroma. Further, we present guidelines for building more effective and longer lasting therapeutic strategies utilizing our experimentally calibrated model. These strategies explicitly consider the protective nature of the stroma and utilize inhibitors that modulate it.

http://ift.tt/2u6ayAP

Src inhibits the Hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1

The Hippo pathway regulates cell proliferation, apoptosis and stem cell self-renewal and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers but the underlying mechanisms are not fully understood. Here we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription co-activator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis.

http://ift.tt/2tQU6cv

Gemcitabine and Chk1 inhibitor AZD7762 synergistically suppress the growth of Lkb1-deficient lung adenocarcinoma

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

http://ift.tt/2u6L0mZ

Transglutaminase 2 inhibition reverses mesenchymal transdifferentiation of glioma stem cells by regulating C/EBP{beta} signaling

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NFκB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radio-resistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM.

http://ift.tt/2tRpo2Y

Opening Marrow Niches in Patients Undergoing Autologous Hematopoietic Stem Cell Gene Therapy

Successful gene therapy for genetic disorders requires marrow niches to be opened to varying degrees to engraft gene-corrected hematopoietic stem cells (HSC). For example, in severe combined immunodeficiency, relatively limited chimerism is necessary for both T- and B-cell immune reconstitution, whereas for inborn errors of metabolism maximal donor chimerism is the goal. Currently, alkylating chemotherapy is used for this purpose. Significant pharmacokinetic variability exists in drug clearance in children less than 12 years old. Thus, pharmacokinetic monitoring is needed to achieve the targeted exposure goal for busulfan.

http://ift.tt/2tLt9T7

Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus

Recent genome-wide association studies (GWAS) have identified variants associated with high-density lipoprotein cholesterol (HDL-C) located in or near the ANGPTL8 gene. Given the extensive sharing of GWAS loci across populations, we hypothesized that at least one shared variant at this locus affects HDL-C. The HDL-C-associated variants are coincident with expression quantitative trait loci for ANGPTL8 and DOCK6 in subcutaneous adipose tissue; however, only ANGPTL8 expression levels are associated with HDL-C levels. We identified a 400-bp promoter region of ANGPTL8 and enhancer regions within 5 kb that contribute to regulating expression in liver and adipose. To identify variants functionally responsible for the HDL-C association, we performed fine-mapping analyses and selected 13 candidate variants that overlap putative regulatory regions to test for allelic differences in regulatory function. Of these variants, rs12463177-G increased transcriptional activity (1.5-fold, P=0.004) and showed differential protein binding. Six additional variants (rs17699089, rs200788077, rs56322906, rs3760782, rs737337, and rs3745683) showed evidence of allelic differences in transcriptional activity and/or protein binding. Taken together, these data suggest a regulatory mechanism at the ANGPTL8 HDL-C GWAS locus involving tissue-selective expression and at least one functional variant.

http://ift.tt/2vRKStS

A Functional Link Between Bir1 and the Saccharomyces cerevisiae Ctf19 Kinetochore Complex Revealed Through Quantitative Fitness Analysis

The chromosomal passenger complex (CPC) is a key regulator of eukaryotic cell division, consisting of the protein kinase Aurora B/Ipl1 in association with its activator (INCENP/Sli15) and two additional proteins (Survivin/Bir1 and Borealin/Nbl1). Here we report a genome-wide genetic interaction screen in Saccharomyces cerevisiae using the bir1-17 mutant, identifying through quantitative fitness analysis deletion mutations that act as enhancers and suppressors. Gene knockouts affecting the Ctf19 kinetochore complex were identified as the strongest enhancers of bir1-17, while mutations affecting the large ribosomal subunit or the mRNA nonsense-mediated decay (NMD) pathway caused strong phenotypic suppression. Thus cells lacking a functional Ctf19 complex become highly dependent on Bir1 function and vice versa. The negative genetic interaction profiles of bir1-17 and the cohesin mutant mcd1-1 showed considerable overlap, underlining the strong functional connection between sister chromatid cohesion and chromosome bi-orientation. Loss of some Ctf19 components such as Iml3 or Chl4 impacted differentially on bir1-17 compared with mutations affecting other CPC components: despite the synthetic lethality shown by either iml3 or chl4 in combination with bir1-17, neither gene knockout showed any genetic interaction with either ipl1-321 or sli15-3. Our data therefore imply a specific functional connection between the Ctf19 complex and Bir1 that is not shared with Ipl1.

http://ift.tt/2tR18Od

Genome-Wide Analysis of the First Sequenced Mycoplasma capricolum Subsp. capripneumoniae Strain M1601

Mycoplasma capricolum subsp. capripneumoniae (Mccp) is a common pathogen of goats that causes contagious caprine pleuropneumonia. We closed the gap and corrected rRNA operons in the draft genome of Mccp M1601, a strain isolated from an infected goat in a farm in Gansu, China. The genome size of M1601 is 1,016,707 bp with a GC content of 23.67%. We identified 915 genes (occupying 90.27% of the genome), of which 713 are protein-coding genes (excluding 163 pseudogenes). No genomic islands and complete insertion sequences were found in the genome. Putative determinants associated with the organism's virulence were analyzed, and 26 genes (including one adhesion protein gene, two capsule synthesis gene clusters, two lipoproteins, hemolysin A, ClpB, and proteins involved in pyruvate metabolism and cation transport) were potential virulence factors. In addition, two transporter systems (ATP-binding cassette transporters and phosphotransferase) and two secretion systems (Sec and signal recognition particle pathways) were observed in the Mccp genome. Genome synteny analysis reveals a good collinear relationship between M1601 and Mccp type strain F38. Phylogenetic analysis based on 11 single-copy core genes of 31 Mycoplasma strains revealed good collinearity between M1601 and Mycoplasma capricolum subsp. capricolum and close relationship among Mycoplasma mycoides cluster strains. Our genome-wide analysis of Mccp M1601 provides helpful information on the pathogenic mechanisms and genetics of Mccp.

http://ift.tt/2vRQ5BA

Tumor Purity As an Underlying Key Factor in Glioma

Purpose: <span style="font-size: 11px;">Glioma tissues consist not only of glioma cells but also glioma-associated non-tumor cells, such as stromal cells and immune cells. These non-tumor cells dilute the purity of glioma cells and play important roles in glioma biology. Currently, the implications of variation in glioma purity are not sufficiently clarified.</span><br /><br /><br />Experimental Design: <span style="font-size: 11px;">Here, tumor purity was inferred for 2249 gliomas and 29 normal brain tissues from five cohorts. Based on the transcriptomic profiling method, we classified CGGA and TCGA-RNAseq cohorts as the RNAseq set for discovery. Cases from TCGA-microarray, REMBRANDT, and GSE16011 cohorts were grouped as a microarray set for validation. Tissues from the CGGA cohort were reviewed for histopathologic validation.</span><br /><br /><br />Results: <span style="font-size: 11px;">We found that glioma purity was highly associated with major clinical and molecular features. Low purity cases were more likely to be diagnosed as malignant entities and independently correlated with reduced survival time. Integrating glioma purity into prognostic nomogram significantly improved the predictive validity. Moreover, most recognized prognostic indicators were no longer significantly effective under different purity conditions. These results highlighted the clinical importance of glioma purity. Further analyses found distinct genomic patterns associated with glioma purity. Low purity cases were distinguished by enhanced immune phenotypes. Macrophages, microglia, and neutrophils were mutually associated and enriched in low purity gliomas, while only macrophages and neutrophils served as robust indicators for poor prognosis.</span><br /><br /><br />Conclusions: Glioma purity and relevant non-tumor cells within microenvironment confer important clinical, genomic and biological implications, which should be fully valued for precise classification and clinical prediction.

http://ift.tt/2u6uJOX

An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2-years following UCBT in AL patients. <p>Experimental design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n=2362, 65%) and validation set (n=778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.</p> <p>Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2-years OS and LFS, ranging from 70.21% (68.89-70.71, 95% CI) and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2-years OS and LFS, respectively.</p> <p>Conclusion: The UCBT score is a simple tool for risk stratification of AL patient undergoing UCBT. Widespread application of the score will require further independent validation.

http://ift.tt/2tRlqHj

TP53 mutation and its prognostic significance in Waldenstrom's Macroglobulinemia

Purpose: TP53 is a tumor suppressor gene that functions as regulator influencing cellular responses to DNA damage, and TP53 alteration are associated to pejorative outcome in most of B lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's Macroglobulinemia (WM). <p>Experimental design: Here we have explored the incidence of TP53 alteration using sanger sequencing and ultra-deep targeted sequencing in 125 WM and 10 IgM MGUS, along with the clinical features and the associated genomic landscape using SNP array and mutational landscape in an integrative study.</p> <p>Results: Overall, we have identified alteration of TP53 locus including mutation, deletion and copy neutral loss of heterozygosity in 11,2% of WM. TP53 mutation was acquired in 7,3% of WM patients at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of IPSSWM score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signalling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, Prima^Met or CP31398 that bypass p53 pathway in WM, paving the path for future treatment tailored options.</p> <p>Conclusion: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice.

http://ift.tt/2tQHHFv

Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8⁺ TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8⁺BTLA⁺TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. <br /><br />Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8⁺ TIL and mouse CD8⁺ T cells. Functional assays were used including single cell analysis, Reverse Phase Protein Array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as Patient-Derived Xenograft (PDX) model using Immunodeficient NOD-scid IL2Rgamma^null (NSG) tumor-bearing mice treated with autologous TIL.<br /> <p>Results: CD8⁺BTLA^- TIL could not control tumor growth in vivo as well as their BTLA⁺ counterpart and antigen-specific CD8⁺BTLA^- T cells had impaired recall response to a vaccine. However CD8⁺BTLA⁺ TIL displayed improved survival following the killing of a tumor target and heightened "serial killing" capacity. Using mutants of BTLA signaling motifs we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. <br /><br />Conclusions:Our data portrays BTLA as a molecule with the singular ability to provide both co-stimulatory and co-inhibitory signals to activated CD8⁺ T cells, resulting in extended survival, improved tumor control and the development of a functional recall response.

http://ift.tt/2uKEvZb

Real Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype

Purpose: <br /><br />Experimental Design: <br /><br />Results: <br /><br />Conclusions:

http://ift.tt/2u6V27K

Under-reporting of Research Biopsies from Clinical Trials in Oncology

Purpose: Research biopsies are frequently incorporated within clinical trials in oncology, and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting.<br /><br />Experimental Design: We identified a cohort of therapeutic clinical trials where non-diagnostic research biopsies were performed between January, 2005-October, 2010 from an IR database at our institution. Clinical trial protocols were compared with the highest level of corresponding publication as a manuscript or registry report.<br /><br />Results: A total of 866 research biopsies were performed across 46 clinical trials, with a median of 8 patients biopsied/trial and 19 biopsies collected/trial. After a median follow-up time of 4.3 years from trial completion, 36/46 trials(78%) reported trial results: published manuscripts(n=35), or registry report(n=1). A total of 635 conducted biopsies were reported in 18/46 trials(39%). Six(33%) of these 18 trials under-reported the number of biopsies performed. Of 33 trials with mandatory research biopsies, 13(39%) trials reported on these biopsies. Biopsy complications occurred in 8 trials (n=39 patients, 6 Grade 3/4 AEs) but only 1 trial reported these. Factors associated with biopsy reporting included a larger number of biopsies(P<0.001), and serial biopsies(P<0.001). Twelve of 16 (75%) trials with >12 biopsies performed reported on these biopsies compared to only 20%(6/30) that performed ≤12 biopsies.<br /><br />Conclusions: Despite ethical obligations to report research biopsies, the majority (61%) of trials do not report results from research biopsies. Complications are rarely reported in these studies. Improved reporting of results and AEs from research biopsies is needed.

http://ift.tt/2tQEyFs

Nivolumab Has Antitumor Activity in dMMR/MSI-H Colorectal Cancer [Research Watch]

Nivolumab is safe and achieves durable responses in metastatic dMMR/MSI-H colorectal cancer.

http://ift.tt/2vRuERl

Integrative Genomics Characterize Medulloblastoma Subtypes [Research Watch]

Integrative genomic analysis characterized the genomic landscapes of medulloblastoma subtypes.

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ASCL1 Promotes Differentiation of Glioblastoma Stem Cells [Research Watch]

ASCL1 promotes neuronal gene expression to induce differentiation and suppress glioblastoma growth.

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Chromosome Loop Anchors Are Susceptible to DNA Double-Strand Breaks [Research Watch]

TOP2B induces double-strand breaks at CTCF-bound DNA loop anchors, increasing genomic rearrangements.

http://ift.tt/2uGlCba

Simultaneous Targeting of RAF, MEK, and ERK Limits Drug Resistance [Research Watch]

Sequential targeting of RAF, MEK, or ERK in BRAF-mutant PDXs promotes BRAF amplification and resistance.

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CAR T Cells Infiltrate Brain, Safely Target Tumors [News in Brief]

However, antigen heterogeneity and immune resistance could undermine the therapy's efficacy.

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Meet Our Editorial Board Member

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Novel Hybrid Molecules on the Basis of Steroids and (5Z,9Z)-Tetradeca-5,9-dienoic Acid: Synthesis, Anti-Cancer Studies and Human Topoisomerase I Inhibitory Activity

Novel steroid derivatives of 5Z,9Z-dienoic acids were prepared by the DCC/DMAP-catalyzed esterification of (5Z,9Z)-tetradeca-5,9-dienoic acid with hydroxy steroids. High cytotoxicity towards the HEK293, Jurkat, K562 cancer cell lines and human topoisomerase I (hTop1) inhibitory activity in vitro were found for the synthesized acids. A probable mechanism of topoisomerase I inhibition was hypothesized on the basis of in silico studies resorting to docking.

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FLT3 Inhibitors in the Management of Acute Myeloid Leukemia

In recent years there has been a great improvement in molecular characterization of acute myeloid leukemia (AML) allowing the stratification of patients in different rate of risk. Patients with FLT3 mutated AML have poor prognosis because of resistance to induction chemotherapy or early relapse. Several first and second generation molecules, able to inhibit FLT3 signaling have been developed and many single agent or combination studies are ongoing. Of these, quizartinib seems to have the best clinical activity. Unfortunately, resistance to FLT3 inhibitors has been observed and many scientists are currently investigating new strategy to restore sensitivity to FLT3 inhibitors.

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Novel [1,2,4] Triazol [4,3-a] Pyridine Derivatives as Potential Selective c-Met Inhibitors with Improved Pharmacokinetic Properties

Aims: Total twenty-nine [1,2,4]triazolo[4,3-a]pyrazine derivatives were designed and synthesized. Method: The target compounds, especially 4aa, showed potent activity to inhibit c-Met both in an enzyme assay and a cellular assay. The comprehensive screening for the inhibition of 60 different kinases revealed that 4aa could selectively inhibit c-Met while had no effect on other kinases, indicating 4aa is an excellent c-Met selective inhibitor. Result: The flow cytometry studies found that 4aa had a similar behavior to the positive control SGX-523 in terms of causing the tumor cell apoptosis and blocking cell-cycle progression. More importantly, 4aa showed much better pharmacokinetic properties than SGX-523. Altogether, the findings suggested the target compounds may be potential anti-tumor drug candidates.

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Personalized Nanoparticles for Cancer Therapy: A Call for Greater Precision

Nanotechnology has brought about the advent of personalized medicine in the era of targeted therapeutic strategies for cancer therapy. The ability to exploit tumor features for therapeutic gain has made it possible to manufacture more effective nanomedicines for cancer treatment. However, known obstacles, including the inability to overcome pathophysiological barriers of tumors, have impeded disease management. In spite of this, recent efforts have been made to develop more functionalized nanosystems that utilize the active-targeting approach. This article reviews the FDA-approved cancer drug delivery systems in the general framework of personalized nanomedicine. We discuss the latest efforts in the development of functionalized nano-systems, and summarize relevant ongoing preclinical and clinical trials.

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The Effect of A Hexanoic Acid Linker Insertion on the Pharmacokinetics and Tumor Targeting Properties of the Melanoma Imaging Agent 99mTc-HYNIC-cycMSH

Background: Lactam cyclized alpha-melanocyte stimulating hormone (α-MSH) analogues exhibit high stability and affinity for the MC1-R receptors over expressed in melanoma cells. Recently, we reported a novel ^99mTc-HYNIC-cycMSH_4-13 analogue with the HYNIC chelator directly attached to the lactam cyclized ring. Objective: In this study we proposed the introduction of a 6-aminohexanoic acid (Ahx) linker between the HYNIC chelator and lactam cyclized peptide cycMSH_4-13 to reduce steric hindrance and improve the melanoma targeting and imaging proprieties of the radiolabeled peptide. Method: HYNIC-Ahx-cycMSH_4-13 peptide was synthesized on an automated peptide synthesizer and displayed an IC⁵⁰ of 0.3 nM using B16/F1 cells. The ^99mTc/tricine radiolabeled peptide was examined for radiochemical purity, stability and cell binding. In vivo, biodistribution and planar gamma imaging studies were performed in B16/F1 melanoma tumor bearing C57BK mice. Results: ^99mTc-HYNIC-Ahx-cycMSH_4-13 was obtained with a radiochemical purity >95%, was stable up to 24 h at room temperature and exhibited high binding and rapid internalization in B16/F1 cells. In vivo biodistribution studies showed a tumor uptake of 4.92 ± 0.92 % ID/g and 2.78 ± 1.48 % ID/g at 2 h and 4 h post injection, respectively. Whole-body clearance was rapid through urinary excretion. The melanoma tumors were clearly visualized by planar gamma imaging. Conclusion: ^99mTc-HYNIC-Ahx-cycMSH_4-13was shown radiochemically stability and exhibited rapid and selective uptake in melanoma cells and tumors. Imaging studies yielded promising preclinical results, warranting further evaluation of ^99mTc-HYNIC-cycMSH analogs as melanoma specific imaging agents.

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Bruton Kinase Inhibitors in Chronic Lymphocytic Leukemia

Abnormality of the B-cell receptor (BCR) signaling is correlated to origin of many B-cell malignancies. Bruton's tyrosine kinase (BTK), is described as a possible target in a many B-cell neoplasms. Ibrutinib is the most used inhibitor of BTK and has great tolerability and efficacy in chronic lymphocytic leukemia. This review summarizes results with ibrutinib in clinical trials and novel BTK inhibitors of interest.

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Targeting Leptin as a Therapeutic Strategy against Ovarian Cancer Peritoneal Metastasis

Background/Aims: Epithelial ovarian cancer (OC) is the leading cause of death in patients with gynecologic malignancy. Malignant ascites, a shared symptom of advanced OC patients, plays an important role in the peritoneal metastasis cascade of OC. Since leptin existed in great amount in malignant ascites, we speculated that it might be involved in the modulation of tumor cells malignant behavior. Method: Here, we demonstrated that blocking of leptin could significantly suppress ovarian malignant ascitesinduced metastatic aggravation of OC cells. Furthermore, our results suggested that leptin was highly expressed in OC and correlated with poor outcome of OC patients. Recombinant leptin notably promoted the migration, invasion and proliferation of OC cells. Result: Mechanistically, we found that leptin induced epithelial-mesenchymal transition (EMT) program in OC cells through the activation of the PI3K/Akt/mTOR pathway. Pharmacological inhibition of the PI3K/Akt/mTOR pathway partly impaired leptin-induced malignant transformation of OC cells. More importantly, our in vivo xenograft experiment showed that blocking of leptin could dramatically inhibit OC cells peritoneal dissemination. Conclusion: Collectively, this study emphasized the importance of leptin in OC progression and illustrated a novel mechanism that the PI3K/Akt/mTOR pathway was involved in leptin-induced EMT. Our findings provide new insights into leptin exertion on OC metastasis and identify the potential of leptin neutralizing as a novel strategy against OC peritoneal dissemination.

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Current Progresses in Metal-based Anticancer Complexes as Mammalian TrxR Inhibitors

Reactive oxygen species (ROS) are produced as normal products of cellular metabolism, which are essential for numerous cell biological functions. Due to aberrant metabolism, oncogenic signaling activation and mitochondrial dysfunction, cancer cells generate excessive ROS that cause severe oxidative damage, finally leading to tumor cell death. Thioredoxin reductase (TrxR), as an important ROS-scavenging enzyme, is overexpressed in various human tumors and plays an important role in regulating intracellular redox homeostasis to protect cancer cells from cell death induced by substantial ROS. Hence, TrxR has emerged as a promising target for anticancer agent development. Currently, metallodrugs with anticancer activity, especially gold- and platinum-complexes, have an enormous impact on clinical cancer chemotherapy. This review provides a comprehensive overview of various metal complexes (gold, platinum, ruthenium, rhodium, iridium, iron, palladium, silver, antimony, bismuth, tin) targeting mammalian TrxR and discusses their cytotoxicity in tumor cells.

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Inhibition of Epithelial-mesenchymal Transition in Response to Treatment with Metformin and Y27632 in Breast Cancer Cell Lines

Background: ROCK-1 expression is associated with the malignant character of tumors, while inhibiting this molecule results in a significant suppression of tumor metastasis. Likewise, transforming growth factor beta (TGF-β) is associated with this malignancy by having the ability to induce epithelial-mesenchymal transition (EMT). Metformin, a drug used in the treatment of diabetes, has previously been shown to inhibit EMT in breast cancer cells. Objective: The aim of this study is to evaluate the TGF-β1 action model for induction of EMT and the action of metformin and ROCK-1 inhibitor (Y27632) in EMT process in breast cancer cell lines. Method: MCF-7 and MDA-MB-231 cell lines were treated with metformin and Y27632, after induction of EMT by TGF-β1, to examine the effects on cell migration as well as the protein expression of the ROCK-1 markers, vimentin, E-cadherin, CD44 and CD24 by immunocitochemistry. Results: There was a lower protein expression of ROCK-1, vimentin, CD44 and CD24 in both cell lines after treatment with metformin and Y27632. In MDA-MB-231 cells, E-cadherin expression was increased in all treatment groups. Treatment of MDA-MB-231 cell line with metformin and Y27632 significantly reduced the invasion of these cells. Conclusion: This study confirms the benefits of metformin and Y27632 as potential therapeutic agents in mammary tumors, by blocking EMT process and metastatic potential.

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Synthesis and Anticancer Study of Novel 4H-Chromen Derivatives

Objective/Method: A series of 4H-chromen-4-one derivatives (A1-A16) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Furthermore, their biological activities were evaluated in vitro. Result: Compounds A03 and A10 displayed the most potent antiproliferative activity against human osteosarcoma cell line (U2OS) and A16 displayed the most potent antiproliferative activity against human melanoma cancer cell line (A375) in vitro, which was valuable to study further.

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In Vitro Anticancer Evaluation of Platinum(II/IV) Complexes with Diisoamyl Ester of (S,S)-ethylenediamine-N,N’-di-2-propanoic Acid

Aims: Platinum(II) and platinum(IV) complexes [PtCln{(S,S)-(i-Am)2eddip}] (n = 2, 4: 1, 2, respectively; (S,S)-(i-Am)2eddip = O,O'-diisoamyl-(S,S)-ethylenediamine-N,N'-di-2-propanoate) were synthesized and characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy and mass spectrometry. Method: Quantum chemical calculations were used to predict formed isomers of 1 and 2. Furthermore, reduction of 2 with ascorbic acid was followed by time-dependant 13C NMR spectroscopy in order to enable assignation of the formed isomers for complex 1. In vitro cytotoxic activity was determined for 1 and 2 on a panel of five human tumor cell lines derived from cervix adenocarcinoma (HeLa), alveolar basal adenocarcinoma (A549), breast adenocarcinoma (MDA-453), colorectal cancer (LS 174), erythromyeloblastoid leukemia (K562), as well as one non-malignant human lung fibroblast cell line (MRC-5), using MTT assay. Result: Both complexes exhibited high (2 against K562: IC50 = 5.4 μM), more active than cisplatin, to moderate activity (1). Both complexes caused considerable decrease of cell number in K562 cells in G1, S and G2 phases, concordantly increasing subpopulation in sub-G1 fraction. Morphological analysis of K562 cell death induced by platinum(II/IV) complexes indicate apoptosis.

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Anticancer Activities of New N-hetaryl-2-cyanoacetamide Derivatives Incorporating 4,5,6,7-Tetrahydrobenzo[b]thiophene Moiety

Aims: Novel series of N-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) cyanoacetamide derivatives are synthesized. Method: The structure of these compounds was elucidated using different spectral tools. Compounds were evaluated for their cytotoxic activities against different types of human cancer cell lines including, breast (MCF-7, T47D, MDA MB231); liver (HEPG-2); colon (HCT116); prostate (PC3); and cervix (HELA) cells. In this study, we used compounds 11 and 12 that showed the highest cytotoxicity on PC3 and HEPG2 cells, to explore their effects on apoptosis, metastasis and angiogenesis of cancer cells. Results: Results revealed that the growth inhibition produced by the two selected compounds was due to cytocidal and not due to cytostatic effect in both cell lines. This cytocidal effect was due to up-regulation of caspases-3, and- 9. In addition, the two compounds inhibited the expression of metalloproteinases-2 and 9 (MMP 2&9). Moreover, HIF-1alpha and VEGF expressions were inhibited by both compounds. Conclusion: In conclusion, N-(4, 5, 6, 7-tetrahydrobenzo[b]thiophen-2-yl) cyanoacetamide derivatives showed different anticancer potential against different cancer cell lines. Compounds 11 and 12 showed the most active cytotoxicity against PC3 and HepG2 cells. Both compounds have apoptotic, anti- metastatic and anti-angiogenic effects.

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Ring A-modified Derivatives from the Natural Triterpene 3-O-acetyl-11-keto-β-Boswellic Acid and their Cytotoxic Activity

Background: Natural triterpene boswellic acids (BAs) have attracted much interest due to their anticancer activity, but more chemical modification is necessary to explore their pharmacological value. In addition to subtle functionalization, transformations that alter the triterpene skeleton are viewed as an alternative approach. Objective: In this study, transformations altering ring A of 3-O-acetyl-11-keto-β-boswellic acid (AKBA) were performed to obtain A-lactone, A-lactam, A-seco and A-contracted derivatives. Method: Thirty-two new derivatives were synthesized, and their structures were confirmed by NMR and MS. Their anticancer activity against human cancer cell lines K562, PC3, A549 and HL60 was screened. Results: Biological evaluation indicated that the ring A cleavage or contraction transformations themselves did not significantly enhance the cytotoxic activity, but most of the derivatives based on these ring A-modified skeletons exhibited good cytotoxic activity. Significantly improved cytotoxicity was discovered for the esterified analogues of the A-lactone and A-lactam series and the amidated analogues of the A-seco and ring A contracted series, especially those bearing two nitrogen-containing substituents. Among them, compounds 6a, 11b, 12k and 18e showed strong cytotoxic activity, with IC50 values of 5.0~3.5 μM against K562 cells, almost ninefold stronger than that of AKBA. Further study proposed that the antiproliferative activities of 6a, 11b, 12k and 18e may be due to apoptosis induction. Conclusion: The transformations of the ring A skeleton of AKBA provide new platforms to discover anticancer candidates.

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Erratum Regarding “AJKD Atlas of Renal Pathology: Kidney Disease in Primary Sjögren Syndrome” (Am J Kidney Dis. 2017;69[6]:e29-e30)

In the article entitled "AJKD Atlas of Renal Pathology: Kidney Disease in Primary Sjögren Syndrome" that appeared as an online-only article in the June issue of AJKD (Fogo et al, volume 69, issue 6, pages e29-e30), there was an error in the second sentence, where the sex ratio was inadvertently reversed. The sentence has been corrected to read "It affects 0.01%-0.1% of the population and occurs primarily from age 50 onward, with a female to male ratio of 9:1." This correction was made to the HTML and PDF versions of the article as of June 29, 2017.

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Phase Contrast Cell Detection Using Multi-level Classification

Summary

In this paper, we propose a fully automated learning based approach for detecting cells in time-lapse phase contrast images. The proposed system combines two machine learning approaches to achieve bottom-up image segmentation. We apply pixel-wise classification using random forests (RF) classifiers to determine the potential location of the cells. Each pixel is classified into four categories (cell, mitotic cell, halo effect, and background noise). Various image features are extracted at different scales to train the RF classifier. The resulting probability map is partitioned using the k-means algorithm to form potential cell regions. These regions are expanded into the neighboring areas to recover some missing or broken cell regions. In order to validate the cell regions, another machine learning method based on the bag-of-features and spatial pyramid encoding is proposed. The result of the second classifier can be a validated cell, a merged cell, or a non-cell. In the case that the cell region is classified as a merged cell, it is split by using the seeded watershed method. The proposed method is demonstrated on several phase contrast image datasets, i.e. U2OS, HeLa, and NIH 3T3. In comparison to state-of-the-art cell detection techniques, the proposed method shows improved performance, particularly in dealing with noise interference and drastic shape variations. This article is protected by copyright. All rights reserved.

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Compounded Triamicinolone and Moxifloxacin Product for Intravitreal Injection by Guardian Pharmacy Services: Alert to Health Professionals - Serious Adverse Events Reported

Audience: Ophthalmology, Pharmacy, Patient [Posted 07/28/2017] ISSUE: FDA received adverse event reports on April 5 and June 1, 2017, concerning at least 43 patients who were administered intravitreal (eye) injections of a drug containing...

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Reliability of EUS indices to detect inflammation in ulcerative colitis

EUS is a potentially useful modality to assess severity of inflammation in ulcerative colitis (UC). We assessed the reliability of existing EUS indices and correlated them with endoscopic and histologic scores.

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The potential of proton therapy to reduce acute haematological toxicity in concurrent chemoradiotherapy for oesophageal cancer

Radiotherapy dose escalation is predicted to improve local tumour control in oesophageal cancer, yet any increase in acute haematological toxicity (HT) could limit the predicted improvement in patient outcome. We investigated the bone marrow dose of VMAT, proton plans, and marrow-sparing VMAT plans for oesophageal tumours. Improved marrow sparing was possible with VMAT, but only protons showed significant sparing for bone V10Gy and bone mean dose, especially for patients with larger PTV size.

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Reirradiation for Recurrent Pediatric CNS Malignancies: A Multi-Institutional Review

This is a unique study evaluating the treatment parameters, toxicity, and outcomes of pediatric CNS reirradiation through a multi-national, multi-institutional pediatric research consortium. Low rates of radiation necrosis were observed and patients experienced reasonable survival rates following repeat radiation therapy to recurrent CNS tumors that may justify the risks of reirradiation.

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A model to estimate survival in ambulatory patients with hepatocellular carcinoma: can it predict the natural course of hepatocellular carcinoma?

Several hepatocellular carcinoma (HCC) staging systems are available including the newly developed staging system, the Model to Estimate Survival in Ambulatory HCC patients (MESIAH); however, whether these staging systems could predict the natural course of HCC is largely unknown.

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Renal function changes in HCV-infected patients with chronic kidney disease during and after treatment with direct antiviral agents

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An Unusual Cause of Upper Gastrointestinal Bleeding

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Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero

Abstract

Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V–VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15–52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.

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Message from the Editor-in-Chief

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Compounded Triamicinolone and Moxifloxacin Product for Intravitreal Injection by Guardian Pharmacy Services: Alert to Health Professionals - Serious Adverse Events Reported

Audience: Ophthalmology, Pharmacy, Patient [Posted 07/28/2017] ISSUE: FDA received adverse event reports on April 5 and June 1, 2017, concerning at least 43 patients who were administered intravitreal (eye) injections of a drug containing...

http://ift.tt/2tQWi3z

To Become Senders, Songbirds Must be Receivers First

Abstract

Courtship signals are attractive; in other words, receivers are motivated to approach courtship signals. Though the concept of a receiver is commonly associated in the literature with that of a mate seeker, young songbirds that are learning to sing by imitating conspecifics are also receivers. Juvenile songbirds are attracted to conspecific songs, which has been shown by juveniles working to hear song in operant chambers. The mechanisms explaining this attraction are poorly understood. Here, I review studies that hint at the mechanisms by which conspecific song becomes attractive. In at least some species, juveniles imitate individuals with which they have a strong social bond, such as the father. Such cases suggest that social reward plays a role in the process of song becoming attractive. In addition, experiments using birds reared in isolation from conspecific song have shown that juveniles imitate songs that have acoustic features that are typically found in conspecific song. Those studies suggest that such features are attractive to juveniles regardless of their social experience. The relative contributions of social reward and species-typical acoustic features to the attractiveness of a song can be determined using methods such as operant conditioning. For example, juvenile songbirds can be given control over the playback of songs that differ in a given attribute, such as acoustic similarity to the song of the father. The juveniles will frequently elicit playback of the songs that are attractive to them. Investigating the mechanisms that contribute to the attractiveness of conspecific song to learners will broaden our understanding of the evolution of song as a courtship signal, because the preferences of learners may ultimately determine what will be sung to potential mates.

http://ift.tt/2w7hwH8

Peripheral blood lymphocytes immunophenotyping predicts disease activity in clinically isolated syndrome patients

Clinically isolated syndrome (CIS) represents first neurological symptoms suggestive of demyelinating lesion in the central nervous system (CNS). Currently, there are no sufficient immunological or genetic mar...

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Comparative analysis of stirred catalytic basket bio-reactor for the production of bio-ethanol using free and immobilized Saccharomyces cerevisiae cells

The successful industrial production of ethanol and fine chemicals requires the development of new biocatalytic reactors and support materials to achieve economically viable processes. In this work, a Stirred-...

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Predictors of positive esophagogastroduodenoscopy outcomes in children and adolescents: a single center experience

Esophagogastroduodenoscopy (EGD) has become a key element in the diagnosis and therapy of many gastrointestinal diseases affecting children. The aim of this study was to evaluate predictors of positive outcome...

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Bacteriological assessment of stethoscopes used by healthcare workers in a tertiary care centre of Nepal

Stethoscope is a medical device universally used by health care workers. Stethoscope may transmit pathogens among patients and health care workers if it is not disinfected. The objective of this study was to, ...

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Characterizing expanded access and compassionate use programs for experimental drugs

We sought to determine the characteristics of "expanded access" and "compassionate use" programs registered in ClinicalTrials.gov and to determine the percentage of drugs provided through these programs that u...

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Antibacterial efficacy of local plants and their contribution to public health in rural Ethiopia

Proper hand hygiene with soap and detergents prevents the transmission of many infectious diseases. However, commercial detergents are less likely to be accessible or affordable to poor people in remote rural ...

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Comparison of neuropsychiatric symptoms and diffusion tensor imaging correlates among patients with subcortical ischemic vascular disease and Alzheimer’s disease

The causes of behavioral and psychological symptoms of dementia (BPSD) vary according to the dementia subtype and associated neuropathology. The present study aimed to (i) compare BPSD between patients with su...

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Man arrested after stealing ambulance from hospital

Ricky Lewis Reams, 57, was charged with larceny of a motor vehicle and trying to elude law enforcement in a motor vehicle

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Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

This article provides a detailed procedure on the solid-phase synthesis, purification, and characterization of dodecamers of RNA modified at the C2'-O-position. UV-vis and circular dichroism photometric analyses are used to quantify and characterize structural aspects, i.e., single-strands or double-strands.

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Changes in cardiac function and hemodynamics during robot-assisted laparoscopic prostatectomy with steep head-down tilt: a prospective observational study

Robot-assisted laparoscopic prostatectomy requires the patient to be placed in a steep head-down tilt. The aim of our study was to investigate changes in cardiac index and left ventricular end-diastolic volume...

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Retrofitting the BAC cloning vector pBeloBAC11 by the insertion of a mutant loxP site

Human genomic libraries constructed in bacterial artificial chromosome vectors were utilized to make physical maps of all 23-chromosome pairs and as the templates for DNA sequencing to aid in the completion of...

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Tuberculous monoarthritis of the wrist in a patient with systemic lupus erythematosus: a case report

Unusual forms of tuberculosis are common among immune-suppressed patients, leading to challenges in diagnosis and management. We present a Sri Lankan patient with systemic lupus erythematosis, investigated for...

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Evaluation of microvascular endothelial function in patients with infective endocarditis using laser speckle contrast imaging and skin video-capillaroscopy: research proposal of a case control prospective study

Infective endocarditis is a severe condition with high in-hospital and 5-year mortality. There is increasing incidence of infective endocarditis, which may be related to healthcare and changes in prophylaxis r...

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Serological and PCR investigation of Yersinia pestis in potential reservoir hosts from a plague outbreak focus in Zambia

Plague is a bacterial zoonotic disease, caused by Yersinia pestis. Rodents are the natural hosts with fleas as the vehicle of disease transmission. Domestic and wild dogs and cats have also been identified as pos...

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Effect of a herbal extract powder (YY-312) from Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode on body fat mass in overweight adults: a 12-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial

YY-312 is a herbal extract powder from Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode, which have health promoting effects, including body fat reduction. We aimed to evaluate t...

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Herbal formula SC-E1 suppresses lipopolysaccharide-stimulated inflammatory responses through activation of Nrf2/HO-1 signaling pathway in RAW 264.7 macrophages

SC-E1 is a novel herbal formula consisting of five oriental medicinal herbs used frequently in traditional herbal medicine for the treatment of inflammatory diseases in Korea. This study examined the effects o...

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