Autophagy as a potential target for sarcoma treatment

Publication date: Available online 24 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Li Min, Edwin Choy, Raphael E. Pollock, Chongqi Tu, Francis Hornicek, Zhenfeng Duan
Autophagy is a constitutively active, evolutionary conserved, catabolic process for maintaining homeostasis in cellular stress responses and cell survival. Although its mechanism has not been fully illustrated, recent work on autophagy in various types of sarcomas has demonstrated that autophagy exerts an important role in sarcoma cell growth and proliferation, in pro-survival response to therapies and stresses, and in therapeutic resistance of sarcoma. Thus, the autophagic process is being seen as a possibly novel therapeutic target of sarcoma. Additionally, some co-regulators of autophagy have also been investigated as promising biomarkers for the diagnosis and prognosis of sarcoma. In this review, we summarize contemporary advances in the role of autophagy in sarcoma and discuss the potential of autophagy as a new target for sarcoma treatment.



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Orbital apex syndrome as a complication of herpes zoster ophthalmicus

Orbital apex syndrome is a rare neuro-ophthalmic manifestation of herpes zoster virus infection. We report one such case with favourable outcome in an immunocompetent patient. A 60-year-old woman presented with rash in the dermatome of the left ophthalmic nerve (V1), followed by sudden loss of vision with complete left-sided external and internal ophthalmoplegia. MRI of brain and orbits with contrast revealed optic perineuritis and myositis without intracranial involvement confirming the diagnosis of orbital apex syndrome. Functional visual recovery was achieved after a course of intravenous and oral steroids under antiviral cover over a follow-up period of 3 months.

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Lattice-like paraproteinemic keratopathy (PPK) of monoclonal gammopathy of undetermined significance (MGUS)

Description

A male patient aged 71 years presented with a history of progressive visual loss in the past 3 years. Ophthalmological evaluation showed a best-corrected visual acuity of 20/200 bilaterally and the presence of bilateral linear lattice-like corneal opacities similar to lattice dystrophy (LD) and dense nuclear cataracts at slit lamp examination (figure 1). There was no family history of ocular diseases. Serum protein electrophoresis included in the systemic investigation showed a band in the -globulin fraction (figure 2). Nephelometry detected an increased level of light chains—75.6 mg/dL (normal: 3.3–19.4 mg/dL) and a normal level of light chains—14.4 mg/dL (normal: 5.7–26.3 mg/dL) and an increased / ratio of 5.25 (normal: 0.26–1.65). Immunoelectrophoresis also confirmed the IgG- gammopathy. Myelogram showed 2% of plasma cells. No lytic bone lesions were present on plain X-ray. No mutations were found on transforming growth factor β-induced gene (TGFBI) nor on gelsolin gene...

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Rare association of congenital penile urethrocutaneous fistula with Y-type urethral duplication

A 24-year-old man presented with symptoms of difficulty in passage of urine, mixed with gas and stool from penoscrotal junction since birth. He had a history of surgery (posterior sagittal anorectoplasty) for imperforate anus in first week of his life. On physical examination, external meatus was adequate with small 5x5 mm fistulous opening noted at penoscrotal junction with normal anal tone and opening. On evaluation with retrograde urethrography, voiding cystourethrogram, cystoscopy and barium enema, he was found to have penile urethrocutaneous fistula of 0.5x0.5 cm with Y-type incomplete urethral duplication. Urethroanal fistula (Y-type urethral duplication) was of small size (<5 mm), so closed primarily through perineal route with interposition of ischiorectal fat. Penile urethrocutaneous fistula (4 mm) too was closed primarily and covered with tunica vaginalis flap in single sitting. It has been 6 months since surgery and the patient is fully continent and voiding well with no urinary or faecal leak.

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Hypercalcaemia caused by active pulmonary tuberculosis in an elderly person without fever or pulmonary symptoms

Many diseases can cause hypercalcaemia, including primary hyperparathyroidism, cancer, drugs and granulomatous diseases. A nursing home resident aged 81 years was admitted because of altered mental status. The patient did not have fever, cough, sputum or night sweat. Hypercalcaemia was identified as a cause of the consciousness disturbance. Chest radiograph showed no acute process. Laboratory workups revealed elevated serum levels of 1,25-(OH)2 vitamin D₃ and positive T-spot test. Microscopic examination of the suctioned sputum identified acid-fast bacilli, which was confirmed as Mycobactrium tuberculsosis. Tuberculosis should be considered as the important cause of hypercalcaemia since early diagnosis and treatment is recommended for preventing its outbreak among people with close contacts with patients.

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Over 10 years MRI observation of a patient with neuronal intranuclear inclusion disease

We present a sporadic neuronal intranuclear inclusion disease (NIID) patient with neuropathy followed by cognitive dysfunction along with brain MRIs findings of leucoencephalopathy. Her cognitive impairment gradually progressed along with abnormal intensity lesions in diffusion-weighted images. This pathological and clinical deterioration resemble pathological process in prion diseases.

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Emergency cricothyroidotomy following tracheobronchial stenting

A man aged 51 years was referred for tracheobronchial stenting after a poorly differentiated oesophageal carcinoma had progressed to cause stridor. Bronchoscopy revealed a left vocal cord palsy and tumour infiltration into the trachea. A tracheobronchial stent was placed, and after distal migration was endoscopically resited. Returning from theatre, the patient developed severe upper airway obstruction that progressed to cause CO₂ narcosis and loss of consciousness. A rapid sequence induction was initiated, and a Glidescope revealed bilateral vocal cord palsy with severe oedema causing an inability to pass a tube or stylet. Tracheostomy was attempted above the suprasternal notch but was obstructed by the stent. Oxygen saturations dropped steadily, reaching as low as 38%. Emergency cricothyroidotomy was performed, compliant with DAS guidelines, that proved successful. The stent was removed, which was blocked with blood and secretions, and tracheostomy was placed 2 days later. The patient made a full neurological recovery.

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Subretinal abscess

Description

A 32-year-old man with a history of intravenous drug use was admitted to the hospital for evaluation of intermittent fever and chills over the course of several weeks. On examination, the temperature was 39.0°C and pulse rate 110 bpm. A grade 2/6 holosystolic murmur was appreciated at the left lower sternal border. Transthoracic echocardiography with agitated saline contrast demonstrated an echodensity on the septal leaflet of the tricuspid valve associated with mild tricuspid regurgitation and a right-to-left shunt. Blood cultures grew methicillin-resistant Staphylococcus aureus. On the third day of hospitalisation, mild conjunctival erythema of the right eye was observed, which was associated with discomfort and a subjective decrease in vision. Visual fields on confrontation revealed a large inferior scotoma. Bedside indirect ophthalmoscopy established the presence of a yellow, elevated subretinal mass ~10 times the diameter of the optic disc, adjacent to the superior-temporal vascular arcade, with associated intraretinal...

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Could kinesiology taping help mitigate pain, breathlessness and abdominal-related symptoms in cancer?

We present the case of a woman who was an amateur athlete diagnosed with primary breast cancer, and 10 years later with terminal metastatic cancer. This case report was prepared posthumously in co-operation with her next of kin (husband). The patient first presented to a sports physiotherapist (AR) for her pain-management and to help maintain physical fitness so that she could continue with sports and an active lifestyle. The patient continued with physiotherapy for several months to enable her to be active. However, when her health deteriorated significantly due to advancing cancer, the treatment was modified and aimed at improving the patient's general well-being. The physiotherapist applied kinesiology tape over the patient's lower rib cage, diaphragm and abdomen in an attempt to manage pain, breathlessness and abdominal bloating. The patient reported alleviation of pain, breathlessness, abdominal discomfort and nausea, accompanied by improvements in eating, drinking, energy levels and physical function.

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Performance curves of medical researchers during their career: analysis of scientific production from a retrospective cohort

Objectives

To establish the pattern of change in individual scientific production over the career of medical researchers.

Design

Retrospective cohort based on prospectively collected data in a hospital information system.

Setting

Multicentre university hospital in France.

Participants

Two distinct populations of 1835 researchers (full professors vs non-academic physicians) having produced 44 723 publications between 1995 and 2014.

Main outcome measures

Annual number of publications referenced in Medline/PubMed with a sensitivity analysis based on publications as first/last author and in high impact journals. The individual volume of publications was modelled by age using generalised estimating equations adjusted for birth cohort, biomedical discipline and academic position of researchers.

Results

Averaged over the whole career, the annual number of publications was 5.28 (95% CI 4.90 to 5.69) among professors compared to 0.82 (95% CI 0.76 to 0.89) among non-academic physicians (p<0.0001). The performance curve of professors evolved in three successive phases, including an initiation phase with a sharp increase in scientific production between 25 and 35 years (adjusted incidence rate ratio 102.20, 95% CI 60.99 to 171.30), a maturation phase with a slower increase from 35 to 50 years (2.10, 95% CI 1.75 to 2.51) until a stabilisation phase with constant production followed by a potential decline at the end of career (0.90, 95% CI 0.77 to 1.06). The non-academic physicians experienced a slower pace of learning curve at the beginning of their careers (42.38, 95% CI 25.37 to 70.81) followed by a smaller increase in the annual number of publications (1.29, 95% CI 1.11 to 1.51).

Conclusions

Compared to full professors, non-academic physicians had a poor capacity to publish, indicating a low productivity when medical doctors have limited time or little interest in undertaking research. This finding highlights the potential for rethinking the missions of medical doctors towards an enlargement of scientific prerogatives in favour of progress in global knowledge.

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Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial

Introduction

Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ).

Methods and analysis

This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4–8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5–25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a month's fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18–80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m², home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-β=0.90).

Ethics and dissemination

BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal.

Trial registration number

NCT02646397.

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Status of patient safety culture in Arab countries: a systematic review

Objectives

To explore the status of patient safety culture in Arab countries based on the findings of the Hospital Survey on Patient Safety Culture (HSPSC).

Design

Systematic review.

Methods

We performed electronic searches of the MEDLINE, EMBASE, CINAHL, ProQuest and PsychINFO, Google Scholar and PubMed databases, with manual searches of bibliographies of included articles and key journals. We included studies that were conducted in the Arab countries that were focused on patient safety culture. 2 reviewers independently verified that the studies met the inclusion criteria and critically assessed the quality of the studies.

Results

18 studies met our inclusion criteria. The review identified that non-punitive response to error is seen as a serious issue which needs to be improved. Healthcare professionals in the Arab countries tend to think that a ‘culture of blame’ still exists that prevents them from reporting incidents. We found an overall similarity between the reported composite score for dimension of teamwork within units in all of the reviewed studies. Teamwork within units was found to be better than teamwork across hospital units. All of the reviewed studies reported that organisational learning and continuous improvement was satisfactory as the average score of this dimension for all studies was 73.2%. Moreover, the review found that communication openness seems to be a concerning issue for healthcare professionals in the Arab countries.

Conclusions

There is a need to promote patient safety culture as a strategy for improving the patient safety in the Arab world. Improving patient safety culture should include all stakeholders, like policymakers, healthcare providers and those responsible for medical education. This review was limited only to English language publications. The varied settings in which the HSPSC was used may have influenced the areas of strengths and weaknesses as healthcare workers' perception of safety culture may differ.

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Study protocol for a pragmatic randomised controlled trial evaluating efficacy of a smoking cessation e-'Tabac Info Service: ee-TIS trial

Introduction

A French national smoking cessation service, Tabac Info Service, has been developed to provide an adapted quitline and a web and mobile application involving personalised contacts (eg, questionnaires, advice, activities, messages) to support smoking cessation. This paper presents the study protocol of the evaluation of the application (e-intervention Tabac Info Service (e-TIS)). The primary objective is to assess the efficacy of e-TIS. The secondary objectives are to (1) describe efficacy variations with regard to users' characteristics, (2) analyse mechanisms and contextual conditions of e-TIS efficacy.

Methods and analyses

The study design is a two-arm pragmatic randomised controlled trial including a process evaluation with at least 3000 participants randomised to the intervention or to the control arm (current practices). Inclusion criteria are: aged 18 years or over, current smoker, having completed the online consent forms, possessing a mobile phone with android or apple systems and using mobile applications, wanting to stop smoking sooner or later. The primary outcome is the point prevalence abstinence of 7 days at 6 months later. Data will be analysed in intention to treat (primary) and per protocol analyses. A logistic regression will be carried out to estimate an OR (95% CI) for efficacy. A multivariate multilevel analysis will explore the influence on results of patients' characteristics (sex, age, education and socioprofessional levels, dependency, motivation, quit experiences) and contextual factors, conditions of use, behaviour change techniques.

Ethics and dissemination

The study protocol was reviewed by the ethical and deontological institutional review board of the French Institute for Public Health Surveillance on 18 April 2016. The findings of this study will allow us to characterise the efficacy of e-TIS and conditions of its efficacy. These findings will be disseminated through peer-reviewed articles.

Trial registration number

NCT02841683; Pre-results.

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Feasibility and effect of home-based therapy programmes for children with cerebral palsy: a protocol for a systematic review

Introduction

Given the promising advantages of upper extremity home-based programmes in children with cerebral palsy (CP), a systematic review of the available literature on this topic is warranted. The purpose of the systematic review described in this protocol is to investigate currently available home-based occupational therapy and physiotherapy programmes regarding both their feasibility and effect.

Methods and analysis

This protocol describes a systematic review, developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015. Studies will be included in which primary data are collected, participants are children aged <18 years with any type of CP and the intervention of interest is a home-based occupational therapy or physiotherapy intervention. Comparators of interest are: no therapy, care as usual, centre-based occupational therapy or physiotherapy, an alternative home-based programme and a medical intervention. Studies will be included that report either on feasibility (ie, acceptability, demand, implementation, practicality, adaptation, expansion or integration) or on efficacy/effectiveness (ie, child-related upper extremity outcomes within all International Classification of Functioning, Disability and Health levels or parent-related/caregiver-related outcomes on the psychological and social domain). Relevant studies will be identified by searching the databases MEDLINE, EMBASE, CINAHL, PsycINFO, PEDro, OTSeeker and CPCI-S as well as the trial registers ICTRP and CENTRAL, the reference lists of included records and by circulating a bibliography of the included records to authors of included studies. There will be no restrictions on language or year of publication. The search strategy consists of terms related to the population and intervention. Data will be extracted in duplicate using a digital data extraction form.

Ethics and dissemination

The proposed study does not involve collection of primary data. Accordingly, no ethical approval is required. The authors will disseminate the findings of this systematic review through publication in a peer-reviewed journal and conference presentation(s).

Trial registration number

CRD42016043743; pre-results.

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Healthcare usage and economic impact of non-treated obesity in Italy: findings from a retrospective administrative and clinical database analysis

Objectives

Investigate the prevalence of obesity in Italy and examine its resource consumption and economic impact on the Italian national healthcare system (NHS).

Design

Retrospective, observational and real-life study.

Setting

Data from three health units from Northern (Bergamo, Lombardy), Central (Grosseto, Tuscany) and Southern (Naples, Campania) Italy.

Participants

All patients aged ≥18 years with at least one recorded body mass index (BMI) measurement between 1 January 2009 and 31 December 2012 were included.

Interventions

Information retrieved from the databases included primary care data, medical prescriptions, specialist consultations and hospital discharge records from 2009–2013. Costs associated with these data were also calculated. Data are presented for two time periods (1 year after BMI measurement and study end).

Primary and secondary outcome measures

Primary—to estimate health resources consumption and the associated economic impact on the Italian NHS. Secondary—the prevalence and characteristics of subjects by BMI category.

Results

20 159 adult subjects with at least one documented BMI measurement. Subjects with BMI ≥30 kg/m² were defined as obese. The prevalence of obesity was 22.2% (N=4471) and increased with age. At the 1-year observation period, obese subjects who did not receive treatment for their obesity experienced longer durations of hospitalisation (median length: 5 days vs 3 days), used more prescription drugs (75.0% vs 57.7%), required more specialised outpatient healthcare (mean number: 5.3 vs 4.4) and were associated with greater costs, primarily owing to prescription drugs and hospital admissions (mean annual cost per year per patient: 460.6 vs 288.0 for drug prescriptions, 422.7 vs 279.2 for hospitalisations and 283.2 vs 251.7 for outpatient care), compared with normal weight subjects. Similar findings were observed for the period up to data cut-off (mean follow-up of 2.7 years).

Conclusions

Untreated obesity has a significant economic impact on the Italian healthcare system, highlighting the need to raise awareness and proactively treat obese subjects.

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Realist evaluation of intersectoral oral health promotion interventions for schoolchildren living in rural Andean communities: a research protocol

Background

Intersectoral collaboration, known to promote more sustainable change within communities, will be examined in an oral health promotion program (OHPP). In Peru, an OHPP was implemented by the Ministry of Health, to reduce the incidence of caries in schoolchildren. In rural Andean communities, however, these initiatives achieved limited success. The objectives of this project are: (1) to understand the context and the underlying mechanisms associated with Peruvian OHPP's current effects among school children living in rural Andean communities and (2) to validate a theory explaining how and under which circumstances OHP intersectoral interventions on schoolchildren living in rural Andean communities produce their effects.

Methods and analysis

Through a realist evaluation, the context, underlying mechanisms and programme outcomes will be identified. This process will involve five different steps. In the first and second steps, a logic model and an initial theory are developed. In the third step, data collection will permit measurement of the OHHP's outcomes with quantitative data, and exploration of the elements of context and the mechanisms with qualitative data. In the fourth and fifth steps, iterative data analysis and a validation process will allow the identification of Context-Mechanism-Outcome configuration, and validate or refine the initial theory.

Ethics and dissemination

This research project has received approval from the Comité d’éthique de la recherche en santé chez l'humain du Centre hospitalier universitaire de Sherbrooke. The initial theory and research results will be published in relevant journals in public health and oral health. They will also be presented at realist evaluation and health promotion international conferences.

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Inappropriate prescribing among older persons in primary care: protocol for systematic review and meta-analysis of observational studies

Introduction

Inappropriate prescribing has a significant impact on older persons in primary care. Previous reviews on inappropriate prescribing included a heterogeneous range of populations and may not be generalisable to primary care. In this study we aim to conduct a comprehensive systematic review and meta-analysis of the prevalence, risk factors and adverse outcome associated with inappropriate prescribing, specifically among older persons in primary care.

Methods and analysis

We will search PubMed, Embase, CINAHL, Web of Science, Scopus, PsycINFO and references of other review articles for observational studies related to the keywords ‘older persons’, ‘primary care’ and ‘inappropriate prescribing’. Two reviewers will independently select the eligible articles. For each included article, the two reviewers will independently extract the data and assess the risk of bias using the Newcastle–Ottawa Scale. If appropriate, meta-analyses will be performed to pool the data across all the studies. In the presence of heterogeneity, meta-regression and subgroup analyses will also be performed. The quality of the evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Ethics and dissemination

The results will be disseminated through conference presentations and peer-reviewed publications. They will provide consolidated evidence to support informed actions by policymakers to address inappropriate prescribing in primary care, thus reducing preventable and iatrogenic risk to older persons in primary care.

Trial registration number

CRD42016048874.

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Advance care planning uptake among patients with severe lung disease: a randomised patient preference trial of a nurse-led, facilitated advance care planning intervention

Objective

Advance care planning (ACP) clarifies goals for future care if a patient becomes unable to communicate their own preferences. However, ACP uptake is low, with discussions often occurring late. This study assessed whether a systematic nurse-led ACP intervention increases ACP in patients with advanced respiratory disease.

Design

A multicentre open-label randomised controlled trial with preference arm.

Setting

Metropolitan teaching hospital and a rural healthcare network.

Participants

149 participants with respiratory malignancy, chronic obstructive pulmonary disease or interstitial lung disease.

Intervention

Nurse facilitators offered facilitated ACP discussions, prompted further discussions with doctors and loved ones, and assisted participants to appoint a substitute medical decision-maker (SDM) and complete an advance directive (AD).

Outcome measures

The primary measure was formal (AD or SDM) or informal (discussion with doctor) ACP uptake assessed by self-report (6 months) and medical notes audit. Secondary measures were the factors predicting baseline readiness to undertake ACP, and factors predicting postintervention ACP uptake in the intervention arm.

Results

At 6 months, formal ACP uptake was significantly higher (p<0.001) in the intervention arm (54/106, 51%), compared with usual care (6/43, 14%). ACP discussions with doctors were also significantly higher (p<0.005) in the intervention arm (76/106, 72%) compared with usual care (20/43, 47%). Those with a strong preference for the intervention were more likely to complete formal ACP documents than those randomly allocated. Increased symptom burden and preference for the intervention predicted later ACP uptake. Social support was positively associated with ACP discussion with loved ones, but negatively associated with discussion with doctors.

Conclusions

Nurse-led facilitated ACP is acceptable to patients with advanced respiratory disease and effective in increasing ACP discussions and completion of formal documents. Awareness of symptom burden, readiness to engage in ACP and relevant psychosocial factors may facilitate effective tailoring of ACP interventions and achieve greater uptake.

Trial registration number

ACTRN12614000255684.

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What is the influence of single-entry models on access to elective surgical procedures? A systematic review

Background

Single-entry models (SEMs) for the management of patients awaiting elective surgical services are designed to increase access and flow through the system of care. We assessed scope of use and influence of SEMs on access (waiting times/throughput) and patient-centredness (patient/provider acceptability).

Methods

Systematic review of articles published in 6 relevant electronic databases included studies from database inception to July 2016. Included studies needed to (1) report on the nature of the SEM; (2) specify elective service and (3) address at least 1 of 3 research questions related to (1) scope of use of SEMs; (2) influence on timeliness and access; (3) patient-centredness and acceptability. Article quality was assessed using a modified Downs and Black checklist.

Results

11 studies from Canada, Australia and the UK were included with mostly weak observational design—2 simulations, 5 before–after, 2 descriptive and 2 cross-sectional studies. 9 studies showed a decrease in patient waiting times; 6 showed that more patients were meeting benchmark waiting times; and 5 demonstrated that waiting lists decreased using an SEM as compared with controls. Patient acceptability was examined in 6 studies, with high levels of satisfaction reported. Acceptability among general practitioners/surgeons was mixed, as reported in 1 study. Research varied widely in design, scope, reported outcomes and overall quality.

Conclusions

This is the first review to assess the influence of SEMs on access to elective surgery for adults. This review demonstrates a potential ability for SEMs to improve timeliness and patient-centredness of elective services; however, the small number of low-quality studies available does not support firm conclusions about the effectiveness of SEMs to improve access. Further evaluation with higher quality designs and rigour is required.

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Factors associated with hospitalisations in chronic conditions deemed avoidable: ecological study in the Spanish healthcare system

Objectives

Potentially avoidable hospitalisations have been used as a proxy for primary care quality. We aimed to analyse the ecological association between contextual and systemic factors featured in the Spanish healthcare system and the variation in potentially avoidable hospitalisations for a number of chronic conditions.

Methods

A cross-section ecological study based on the linkage of administrative data sources from virtually all healthcare areas (n=202) and autonomous communities (n=16) composing the Spanish National Health System was performed. Potentially avoidable hospitalisations in chronic conditions were defined using the Spanish validation of the Agency for Health Research and Quality (AHRQ) preventable quality indicators. Using 2012 data, the ecological association between potentially avoidable hospitalisations and factors featuring healthcare areas and autonomous communities was tested using multilevel negative binomial regression.

Results

In 2012, 151 468 admissions were flagged as potentially avoidable in Spain. After adjusting for differences in age, sex and burden of disease, the only variable associated with the outcome was hospitalisation intensity for any cause in previous years (incidence risk ratio 1.19 (95% CI 1.13 to 1.26)). The autonomous community of residence explained a negligible part of the residual unexplained variation (variance 0.01 (SE 0.008)). Primary care supply and activity did not show any association.

Conclusions

The findings suggest that the variation in potentially avoidable hospitalisations in chronic conditions at the healthcare area level is a reflection of how intensively hospitals are used in a healthcare area for any cause, rather than of primary care characteristics. Whether other non-studied features at the healthcare area level or primary care level could explain the observed variation remains uncertain.

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Evaluating the relative effectiveness of high-intensity and low-intensity models of behaviour change communication interventions for abortion care-seeking in Bihar and Jharkhand, India: a cross-sectional study

Background

This study aimed to compare the effectiveness of a high-intensity model (HIM) and a low-intensity model (LIM) of behaviour change communication interventions in Bihar and Jharkhand states of India designed to improve women's knowledge and usage of safe abortion services, as well as the dose effect of intervention exposure.

Methods

We conducted two cross-sectional household surveys among married women aged 15–49 years in intervention and comparison districts. Difference-in-difference models were used to assess the efficacy of the intervention, adjusting for sociodemographic characteristics.

Results

Although both intervention types improved abortion knowledge, the HIM intervention was more effective in improving comprehensive knowledge about abortion. In particular, there were improvements in knowledge on legality of abortion (AOR=2.2; 95% CI 1.6 to 2.9) and nearby sources of safe abortion care (AOR=1.7; 95% CI 1.2 to 1.3).

Conclusions

Higher level of exposure to abortion-related messages was related to more accurate knowledge about abortion within both intervention groups. Evidence was mixed on changes in abortion care-seeking behaviour. More work is needed to ensure that women seek safe abortion services in lieu of informal services that may be more likely to lead to postabortion complications.

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The accuracy of timed maximum local anaesthetic dose calculations with an electronic calculator, nomogram, and pen and paper

Summary

Forty anaesthetists calculated maximum permissible doses of eight local anaesthetic formulations for simulated patients three times with three methods: an electronic calculator; nomogram; and pen and paper. Correct dose calculations with the nomogram (85/120) were more frequent than with the calculator (71/120) or pen and paper (57/120), Bayes Factor 4 and 287, p = 0.01 and p = 0.0003, respectively. The rates of calculations at least 120% the recommended dose with each method were different, Bayes Factor 7.9, p = 0.0007: 14/120 with the calculator; 5/120 with the nomogram; 13/120 with pen and paper. The median (IQR [range]) speed of calculation with pen and paper, 38.0 (25.0–56.3 [5–142]) s, was slower than with the calculator, 24.5 (17.8–37.5 [6–204]) s, p = 0.0001, or nomogram, 23.0 (18.0–29.0 [4–100]) s, p = 1 × 10⁻⁷. Local anaesthetic dose calculations with the nomogram were more accurate than with an electronic calculator or pen and paper and were faster than with pen and paper.

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Gouty arthritis

Gouty arthritis: An attack that is usually extremely painful of joint inflammation due to deposits of uric acid crystals in the joint fluid (synovial fluid) and joint lining (synovial lining). Intense joint inflammation occurs as white blood cells engulf the uric acid crystals, causing pain, heat, and redness of the joint tissues. The term "gout" commonly is used to refer to these painful arthritis attacks but gouty arthritis is only one manifestation of gout.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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IJMS, Vol. 18, Pages 496: Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions

Ischemic stroke constitutes the major cause of death and disability in the industrialized world. The interest in microglia arose from the evidence outlining the role of neuroinflammation in ischemic stroke pathobiology. Microglia constitute the powerhouse of innate immunity in the brain. Microglial cells are highly ramified, and use these ramifications as sentinels to detect changes in brain homeostasis. Once a danger signal is recognized, cells become activated and mount specialized responses that range from eliminating cell debris to secreting inflammatory signals and trophic factors. Originally, it was suggested that microglia play essentially a detrimental role in ischemic stroke. However, recent reports are providing evidence that the role of these cells is more complex than what was originally thought. Although these cells play detrimental role in the acute phase, they are required for tissue regeneration in the post-acute phases. This complex role of microglia in ischemic stroke pathobiology constitutes a major challenge for the development of efficient immunomodulatory therapies. This review aims at providing an overview regarding the role of resident microglia and peripherally recruited macrophages in ischemic pathobiology. Furthermore, the review will highlight future directions towards the development of novel fine-tuning immunomodulatory therapeutic interventions.

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PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment

Abstract

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis usually manifesting as skin ulcers with undermined erythematous-violaceous borders. It may be isolated, associated with systemic conditions or occurring in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis) or PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis). From a physiopathological point of view, all these conditions share common mechanisms consisting of over-activation of the innate immune system leading to increased production of the interleukin (IL)-1 family and ‘sterile’ neutrophil-rich cutaneous inflammation. From a genetic point of view, a number of mutations affecting the proteins of the inflammasome complex (the molecular platform responsible for triggering autoinflammation) or the proteins that regulate inflammasome function have been described in these disorders. As these debilitating entities are all associated with the over-expression of IL-1 and tumour necrosis factor (TNF)-α, biological drugs specifically targeting these cytokines are currently the most effective treatments but, given the emerging role of IL-17 in the pathogenesis of these syndromes, IL-17 antagonists may represent the future management of these conditions.

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Weekly cisplatin (30–40 mg/m2) as radiosensitizer: Is it high or moderate emetic agent?

A Karpe, VM Patil, A Joshi, V Noronha, S Gupta, A Ramaswamy, A Sahu, V Doshi, T Gupta, S Rath, S Banavali, K Prabhash

Indian Journal of Cancer 2016 53(3):454-456

PURPOSE: The American Society of Clinical Oncology (ASCO) guideline recommends a high antiemetic prophylaxis for any dose of cisplatin. This hypothesis was tested by us in this analysis of solid tumor patients who received weekly cisplatin as a radiosensitizer in a dose range of 30–40 mg/m2. METHODS: This was a retrospective analysis of 181 solid tumor patients who received weekly cisplatin (in the dose range of 30–40 mg/m2) as a radiosensitizer between July 2015 and August 2015. The antiemetic prophylaxis schedule provided was classified as optimal (if a high antiemetic prophylaxis was provided) or suboptimal (if a nonhigh antiemetic prophylaxis was provided). The incidence of acute, delayed and breakthrough vomiting after chemotherapy was noted. SPSS version 20 was used for analysis. Fisher's exact test was used to determine the association between antiemetic schedule (suboptimal vs. optimal) and postchemotherapy emesis. RESULTS: In the present study, of 181 patients, only 25 patients (13.8%) received optimal antiemetic prophylaxis while the remaining 156 (86.2%) received suboptimal prophylaxis. In the cohort of patients with suboptimal prophylaxis, dexamethasone was omitted in all patients (100%) while NK receptor antagonist was omitted in 76 patients (48.7%). The rate of vomiting was lower in patients receiving optimal prophylaxis as compared to that in patients receiving suboptimal prophylaxis (12% vs. 39.75%; P - 0.005). CONCLUSION: Omission of dexamethasone followed by aprepitant was the main reason for suboptimal prophylaxis. High antiemetic prophylaxis in accordance with ASCO guidelines overall decreased the risk of emesis in patients receiving CTRT with weekly cisplatin in the dose range of 30–40 mg/m2.

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Efficacy and safety of sorafenib in advanced renal cell cancer and validation of Heng criteria

A Joshi, A Ramaswamy, V Noronha, VM Patil, A Chandrasekharan, A Goel, A Sahu, N Sable, A Agrawal, S Menon, K Prabhash

Indian Journal of Cancer 2016 53(3):423-428

INTRODUCTION: Sorafenib is an established upfront treatment option for metastatic RCC (mRCC). There is no published literature regarding its performance in Indian Patients. We present an analysis of Sorafenib use in our institute and attempt to validate the Heng criteria as a prognostic score in these patients. MATERIALS AND METHODS: Patients who received Sorafenib as first line treatment for advanced RCC from June 2012 to December 2015 were prognosticated by Heng criteria and retrospectively analysed for baseline demographics, toxicity, response and outcomes. RESULTS: 82 patients (65 males, 17 females) with a median age of 57 years were included for final analysis. Median ECOG PS was 1, 95.2 % of the patients had Stage IV disease and clear cell was the predominant histology (79.4%). 23.2%, 42.7% and 34.1% of patients were classified as low, intermediate and high risk by Heng's criteria, respectively. Dose reduction was required in 24.4% of patients, while 14.6% required permanent cessation of Sorafenib due to intolerable or recurrent side effects. Common adverse events included HFS (68.2%), mucositis (35.3%), fatigue (35.3%), rash (32.9%) and hypertension (25.6%). Response rate observed was 18.2%, while clinical benefit rate was 57.2% in the 57 patients where response was evaluable. Median progression free survival was 7.75 months (5.45-10.05) and median overall survival (OS) was 12.18 months (9.61 – 14.76). Median OS was 19.6, 16.1 and 10.3 months respectively for low, intermediate and high risk patients by Heng criteria and the criteria was statistically discriminatory for the 3 groups for OS (p=0.045, chi-square test). CONCLUSION: Sorafenib is a viable upfront treatment option for metastatic RCC in Indian patients with acceptable PFS, although a high incidence of HFS, mucositis and rash is observed. The Heng score has discriminatory value in mRCC with Sorafenib and can be considered for routine use in the clinic.

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Applicability of a single 5 color cytoplasmic markers tube as primary panel for immunophenotyping of acute leukemia: A Gujarat Cancer and Research Institute experience

BP Parikh, SP Patel, BN Raiya, HH Vora, DH Jetly

Indian Journal of Cancer 2016 53(3):349-352

INTRODUCTION: Flow cytometry is highly sensitive for detection and quantitative analysis of surface and intracellular antigens in malignant hemopoietic cells. Immunophenotyping is a routine practice for classification and lineage assignment of acute leukemia. In the present study, our aim is to identify the role of a single 5 color, CD45, myeloperoxidase (MPO), cCD79a, cCD3, and Tdt, cytoplasmic markers combination as a primary tube. We compared with final diagnosis on the basis of morphology, cytochemistry, and primary and secondary panels of immunophenotyping and also with other study. MATERIALS AND METHODS: We have included 455 new cases of acute leukemias with applied primary and secondary panels of markers for immunophenotyping. We analyzed sensitivity and specificity of different subsets with combination of positive and negative markers. RESULTS: MPO was positive in 61.4% of acute myeloid leukemia (AML) cases. All 184 (100%) cases of the AML were negative for cCD3 and cCD79a co-expression. cCD79a expression was highly sensitive as 98.5% B-acute lymphoblastic leukemia (B-ALL) expressed it. cCD3 expression was detected in 100% cases of T-ALL, and its co-expression was not seen in B-ALL and AML. CONCLUSION: Our study indicates that there was very good correlation of 5-color cytoplasmic tube-based diagnosis versus final diagnosis based on morphology, cytochemistry, and flow cytometry. We can use this 5-color cytoplasmic tube method to make immunophenotyping cost-effective.

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Does magnetic resonance imaging accurately predict residual disease after unplanned excision of soft-tissue sarcomas?

S Patkar, A Gulia, S Juvekar, B Rekhi, A Puri

Indian Journal of Cancer 2016 53(3):408-411

BACKGROUND: Often, it is difficult to assess the presence of residual disease after an unplanned excision in soft-tissue sarcomas. Inadequate excision leads to disease recurrence and inferior oncological outcomes while unnecessary excision may lead to additional surgical procedures with inherent morbidity and increased cost of treatment. There is a paucity of literature comparing the preoperative imaging findings with the final histopathology report to accurately assess the presence of residual disease. MATERIALS AND METHODS: The clinical details of 55 patients who had oncological scar excision after unplanned prior excision were retrieved. Histopathological evaluation of scar was compared with presurgery magnetic resonance imaging (MRI) for the presence of residual disease. Sensitivity, specificity, and positive and negative predictive value (NPV) of MRI for detection of residual disease were calculated. RESULTS: On MRI, residual disease was seen in 28 cases, no disease in 24 cases whereas findings of three patients were indeterminate. On final histopathology, residual disease was present in 30 (55%) patients whereas no residual tumor was seen in 25 (45%) patients. Two patients in whom MRI suggested the presence of residual disease had no tumor on final histopathology. No evidence of residual disease was reported in MRI of 24 patients. Of these, twenty patients were confirmed to have no tumor on final histopathology, whereas four patients had a residual tumor. Sensitivity: 86.66%, specificity: 90.90%, positive predictive value (PPV): 92.85%, NPV: 83.33%. CONCLUSION: MRI can aid in preoperative planning by identifying the site and extent of the previous surgery. It has a high PPV (92%) for detection of residual disease. However, a negative scan (NPV 83%) does not reliably exclude the presence of residual disease.

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Epidemiological and survival analysis of triple-negative breast cancer cases in a retrospective multicenter study

R Sarin, L Khandrika, RNM Hanitha, A Avula, M Batra, S Kaul, H Raj, S Shivkumar, S Gupta, E Khan, TPS Bhandari, SVSS Prasad, VA Reddy, G Swarnalata, M Bakre, S Chatterjee, J Jain

Indian Journal of Cancer 2016 53(3):353-359

INTRODUCTION: This is a retrospective study with data collected from breast cancer cases from five major Apollo Hospitals across India, as part of a biobanking process. One aspect of our study focused specifically on data from triple-negative breast cancer (TNBC) cases. The aim of this study was to analyze epidemiology, treatment options, and survival of the patients with TNBC. Our goal was to draw conclusions on the preponderance of the disease and also to understand the outcomes using the existing therapy options. MATERIALS AND METHODS: Data were collected after due ethical clearances and were coded with regard to patient identifiers to protect patient privacy. Data were not only from the various departments of the respective hospitals and the treating physicians but also from the follow-up made by hospital staff and social workers. RESULTS: About 20% of all cases of breast cancer comprised TNBC. Although the disease is generally thought to be an early onset disease, there was no major difference in the median age of diagnosis of TNBC compared to other breast cancer cases. More than 85% of the TNBC cases were of early stage disease with <4% of the cases of metastatic cancer. Data on follow-up were somewhat sporadic as a good number of cases were lost to follow-up, but from the available data, recurrence rate was about 11%. Death, when it occurred, was mostly in the early periods of treatment with 35% of the events occurring before 3 years. The overall survival rates beyond 3 years were more than 86%. CONCLUSIONS: Data and sample collection are an ongoing process, so we expect this data set to be enriched with more cases and longer duration of follow-up in a year. Preliminary analysis sheds light on the potential of such a collection both for understanding the epidemiology of the disease and also for conducting future studies with an eye toward improving treatment outcomes.

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Cancer and cure: A critical analysis

PS Roy, BJ Saikia

Indian Journal of Cancer 2016 53(3):441-442

Cancer is one of the most dreaded diseases of the 20th century and spreading further with continuance and increasing incidence in the 21st century. The situation is so alarming that every fourth person is having a lifetime risk of cancer. India registers more than 11 lakh new cases of cancer every year, whereas, this figure is above 14 million worldwide. Is cancer curable? The short answer to this question is “Yes.” In fact, all cancers are curable if they are caught early enough. Cancer cells continue to grow unless one of four things occur: (1) The cancerous mass is removed surgically; (2) using chemotherapy or another type of cancer-specific medication, such as hormonal therapy; (3) using radiation therapy; or (4) the cancer cells shrink and disappear on their own.

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The male breast cancer: Epidemiological data from the North of Peru

G Flores-Trujillo, E Serrano-LaBarrera

Indian Journal of Cancer 2016 53(3):359-359



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Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?

J Bajpai, A Ramaswamy, S Gupta, J Ghosh, S Gulia

Indian Journal of Cancer 2016 53(3):464-467

BACKGROUND: Drugs targeting mammalian target of rapamycin signaling pathway have been recently approved for treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). However, there is lack of real world data from India on the use of this therapeutic strategy. MATERIALS AND METHODS: A retrospective analysis of MBC patients who had recurrence or progression while receiving aromatase inhibitors (AI's) and further treated with everolimus and either tamoxifen/AI/fulvestrant between March 2012 and June 2014, was undertaken. RESULTS: There were 41 patients with median age 55 years, 73% with visceral metastasis, and 73% with ≥2 sites of metastases. Thirty (73%) patients had received 3 prior lines of therapy including AI (100%), tamoxifen (94%), fulvestrant (39%), and chemotherapy (100%) while the remaining had received <3 lines of prior therapy. The commonest Grade 3/4 adverse events were stomatitis (19%), hyperglycemia (new/worsening, 17%), fatigue (14.5%), nonneutropenic infections (14%), anemia (12%) and pneumonitis (7%). Everolimus dose reductions were required in 31% patients. There were 30% partial responses, 38% prolonged disease stabilizations and 32% disease progression as best responses to everolimus. The median progression-free survival was 22 weeks (5 months). CONCLUSIONS: Everolimus based treatment has meaningful activity in heavily pretreated patients with HR-positive MBC but is associated with considerable toxicity and requirement for dose adjustment.

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Incidence and pattern of bone metastases at presentation in Indian carcinoma breast patients

SM Doddala, A Suryadevara, SK Chinta, AL Madisetty

Indian Journal of Cancer 2016 53(3):360-362

BACKGROUND: Breast cancer (BC) is the most common female cancer and frequently metastases to the bones. Breast cancer among Indian women occurs a decade earlier and more aggressive than the western population. Screening guidelines are based on western studies. The aim of our study is to assess the role of Technitium99m bone scan (TBS) in screening Indian EBC patients at presentation. We also looked at the pattern of BM in all stages of BC. METHODS: Patients with BC who had TBS at presentation from January 2012 to September 2015 were included in the study. RESULTS: Bone metastases were seen in 23.42% (241/1029). Of these, 10.06% (31/308) EBC, 25.60% (169/660) locally advanced BC (LABC) and 63.93% (39/61) of metastatic BC (MBC) patients had BM. Most common sites of BM were spine and pelvis. In long bone and sternum, proximal part was commonly involved. CONCLUSION: The incidence of BM in Indian BC patients at presentation is higher than western population. The incidence of BM per stage is similar to west. So TBS should be done in LABC and symptomatic EBC. There is high incidence of BM to spine and pelvis. In pelvis, SI joints and ilium and in long bones and sternum, proximal parts were commonly involved.

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Pattern of care in operable endometrial cancer treated at a rural-based tertiary care cancer center

SB Dessai, D Adrash, M Geetha, S Arvind, J Bipin, S Nayanar, K Sachin, MS Biji, S Balasubramanian

Indian Journal of Cancer 2016 53(3):416-419

PURPOSE: An audit was planned to study the demographics, staging, treatment details, and outcomes of operable endometrial cancers. METHODOLOGY: All operable endometrial cancers treated between January 2009 and October 2014 were included in the study. The details regarding demographics, staging, surgical procedure, pathological staging, adjuvant treatment, and outcomes were extracted from the case records. Descriptive statistics was performed. The time-to-event analysis was done by Kaplan–Meier method. Univariate and multivariate analyses were done for disease-free survival (DFS) and overall survival (OS). RESULTS: There were 55 patients with a median age of 59 years (35–73 years). The Eastern Cooperative Oncology Group performance status was 1 in 52 patients (94.5%) and 2 in 3 patients (5.5%). Forty-nine patients (89.1%) had disease restricted to endometrium while 6 patients (10.9%) had cervical involvement. The surgery done was Type I hysterectomy in 49 patients (89.1%), Type II in 5 patients (9.1%), and Type III in 1 patient (1.8%). Pelvic lymph node dissection was done in all patients while para-aortic (infrahilar) dissection was done in 48 patients (87.3%). The pathological stages were Stage IA in 19 patients, Stage IB in 15 patients, Stage II in 4 patients, Stage IIIA in 3 patients, Stage IIIB in 2 patients, Stage IIIC1 in 5 patients, Stage IIIC2 in 4 patients, and Stage IV in 3 patients. Grade 1 tumors were seen in 23 patients, Grade 2 in 13 patients, and Grade 3 in 19 patients. The histology was endometrioid in 44 patients, serous in 6 patients, clear cell in 3 patients, and others in 2 patients. Adjuvant treatment was received by 40 patients. With a median follow-up of 2.5 years, the 3-year DFS and OS were 78% and 82%, respectively. Age >59 years, Stage III or greater, and Grade 3 tumors were independent prognostic factors adversely affecting both DFS and OS. CONCLUSION: The outcomes in our study are comparable to that seen in Western literature. Elderly status, higher stage, and a poorly differentiated tumor are associated with poor outcomes.

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The pattern of invasive lobular carcinoma in the patients diagnosed with breast cancer from Balochistan

AH Baloch, AN Khosa, N Bangulzai, H Sadia, M Ahmed, F Khan, M Jan, M Tareen, MH Kakar, J Shuja, HK Naseeb, J Ahmad

Indian Journal of Cancer 2016 53(3):363-365

Introduction: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer accounting for 5%–15% of all the breast cancer cases. The present study was performed on 171 breast cancer patients from Balochistan registered in CENAR (Center for Nuclear Medicine and Radiotherapy), Quetta. Materials and Methods: Written consent was obtained from the patients. The history of the disease was taken from the patients, and the patients' enrollment files were retrieved. Results: Of the 171 patients, 5 (2.96%) were diagnosed with ILC with tumor Grade II, and stage of the cancer reported was Grade III in all the 5 patients affected with ILC. Conclusion: ILC is the second most common type of breast cancer diagnosed with comparatively lower grade but almost reported infiltrating.

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Prevalence of depression and anxiety disorder in cancer patients: An institutional experience

A Shankar, C Dracham, S Ghoshal, S Grover

Indian Journal of Cancer 2016 53(3):432-434

AIM: This study aimed to screen the patients with various malignancies for the presence of depressive disorders and anxiety disorder using standardized rating scales. MATERIALS AND METHODS: Five hundred and thirty-four (n = 534) patients attending the radiotherapy outpatient services completed the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 (GAD-7) Questionnaire. RESULTS: About half (n = 248; 46.4%) of the patients had psychiatric morbidity either in the form of depressive disorder or in the form of GAD. Higher stage of malignancy (from early, advanced to metastasis) was associated with higher prevalence of depressive disorder and GAD. The presence of psychiatric morbidity, especially anxiety disorder, was associated with being from low socioeconomic status. CONCLUSION: The present study suggests that psychiatric morbidity in the form of depressive and anxiety disorders is very common among patients with malignancies. Accordingly, there is a need for close liaison between oncologists and mental health professionals to improve the outcome of patients with various malignancies.

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Utility of driver mutation

V Sharma, VM Patil, V Noronha, A Joshi, K Prabhash

Indian Journal of Cancer 2016 53(3):365-365



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Epidemiology and resistance pattern of bacterial isolates among cancer patients in a Tertiary Care Oncology Centre in North India

U Batra, P Goyal, P Jain, A Upadhyay, N Sachdeva, M Agarwal, D Bhurani, V Talwar, SK Gupta, DC Doval

Indian Journal of Cancer 2016 53(3):448-451

OBJECTIVES: To examine the epidemiology of microbiologically documented bacterial infection and the resistance pattern, among cancer patients undergoing treatment at RGCIRC, Delhi. DESIGN AND SETTING: Retrospective observational study in which culture reports obtained over 1 year in 2013, were analyzed. RESULTS: 13329 cultures were obtained over 1 year in 2013 and were analyzed. 23.6 % samples showed positive culture with majority being gram negative isolates (67.9 %). E. coli was the commonest gram negative isolate (49.4%) followed by klebsella (29.7%) and Staph. aureus was the commonest gram positive isolate. There was high incidence of ESBL in blood and urine (87.2% & 88.5%) and BLBLI were also high (78% & 83.9%). Carbapenem resistance was comparatively low (10%) and colistin sensitivity was quiet high (> 95%). CONCLUSIONS: Prevalence of MRSA and VRE in our institute is very less, whereas prevalence of ESBLs and BLBLI isolates amongst gram negative infections is around 80%. Gram negative isolates had poor sensitivity to cephalosporins and fluoroquinolones.

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Alteration in steroid hormone and Her-2/neu receptor status following neoadjuvant chemotherapy in locally advanced breast cancer: Experience at a tertiary care centre in India

P Ramteke, V Seenu, R Prashad, SD Gupta, V Iyer, SVS Deo, A Gogia, S Mathur

Indian Journal of Cancer 2016 53(3):366-371

CONTEXT: Use of neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC) enables tumor reduction and conservative surgery. It is proposed in some studies that there may be an alteration in the hormonal receptor (HR) status and human epidermal growth factor receptor 2 (Her-2)/neu immune-expression following NACT. AIMS: To study the status of estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu receptor before and after NACT in LABC. MATERIALS AND METHODS: HR and Her-2/neu status were evaluated by immunohistochemistry on 100 core needle biopsy of primary tumors and surgical specimens after receiving NACT (NACT group); fifty patients without NACT served as non-NACT group, and discordance was compared between the two groups. RESULTS: In the NACT group, discordance of 17%, 13%, and 11% was noted in ER, PR, and Her-2/neu status, while in non-NACT group, discordance seen in ER, PR, and Her-2/neu was 8%, 8%, and 4%, respectively. CONCLUSIONS: There was a significant alteration in ER and Her-2/neu status from the core biopsy to the treated resected tumor in the study group. As these changes may impact treatment, HR and Her-2/neu expression reanalysis in final surgical specimens is recommended.

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Sensorineural deafness: An uncommon irreversible adverse effect of bortezomib

Parameswaran Anoop, Channappa N Patil, Vaishnavi S Joshi, Poonam Maurya, Pradeep Hosamani

Indian Journal of Cancer 2016 53(3):459-459



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Induction chemotherapy with cisplatin and ifosfamide in locally advanced inoperable squamous cell carcinoma of the head and neck: A single-institution experience

S Zaheer, SA Siddiqui, M Akram, SA Hasan

Indian Journal of Cancer 2016 53(3):372-376

BACKGROUND: Induction chemotherapy (ICT) in patients with head and neck cancer has been studied since a long time. The addition of taxanes to the cisplatin and 5-fluorouracil (5FU) (PF) regimen results in superior antitumor activity. We did this study to see the response and toxicity of ICT with cisplatin and ifosfamide followed by concurrent chemoradiotherapy (CRT) in locally advanced, unresectable squamous cell carcinoma of head and neck (SCCHN). AIMS: The aim of this study was to see the results of ICT using cisplatin and ifosfamide regimen in locally advanced unresectable SCCHN in terms of acute and chronic toxicity and response to treatment. MATERIALS AND METHODS: Patients with Stage III and IV, nonmetastatic SCCHN were enrolled in the study. They were given two cycles of ICT with cisplatin and ifosfamide followed by CRT. RESULTS: After ICT, the overall response rate (ORR) was 75.0% at the primary site and 70.0% at the nodal site. ORR for combined primary and nodal disease was observed to be 67.5%. The complete response (CR) and partial response (PR) for combined primary and nodal site were seen in 4 (10.0%) and 23 (57.5%) patients. Of 32 patients who received CRT after ICT, CR was 53.1% and PR was 31.3%. Mucositis, skin reaction, and pharyngeal and laryngeal toxicities were the most common but tolerable. CONCLUSION: ICT with cisplatin and ifosfamide gives comparable results to the standard paclitaxel, PF regimen. We conclude that this combination regimen for ICT is not only an economical alternative of taxol-based regimen but also well tolerated by the patients.

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Epidermal growth factor receptor expression in gastric tumors and its relationship with the germline polymorphisms − 216 G>T, −191 C>A, (CA) n IVS1, and R521K

JH Torres-Jasso, AR Bustos-Carpinteyro, JR Garcia-Gonzalez, J Peregrina-Sandoval, JA Cruz-Ramos, E Santiago-Luna, JY Sanchez-Lopez

Indian Journal of Cancer 2016 53(3):345-348

BACKGROUND: Gastric cancer (GC) is the third worldwide leading cause of cancer-related death affecting both sexes. The aberrant expression of epidermal growth factor receptor (EGFR) gene has been detected in many human epithelial malignancies and linked to advanced disease, more aggressive phenotype, and poor prognosis. AIMS: To analyze the relation that the expression of EGFR in gastric tumors holds with pathological characteristics and with the germline polymorphisms −216 G>T, −191 C>A, (CA) n IVS1, and R521K. MATERIALS AND METHODS: We studied 22 biopsies from gastric tumors obtained by endoscopy. EGFR expression was determined by relative quantification real-time polymerase chain reaction with the glyceraldehyde-3-phosphate dehydrogenase reference gene (as for messenger RNA [mRNA]) and by immunohistochemistry (IHC) (as for protein). EGFR germline polymorphisms were analyzed by sequencing, GeneScan, and restriction fragment length polymorphisms. RESULTS: EGFR mRNA expression was increased (>2-fold) in 13.6% of GC cases, decreased (<0.5-fold) in 68.2%, and normal in 18.2%; overexpression was related to well-differentiated gastric tumors, whereas underexpression was linked to moderate or poorly differentiated gastric tumors (P < 0.001). EGFR protein expression was high (IHC 2+ and 3+) in 29.4% of gastric tumors and was normal or low (score 0 to 1+) in 70.6% cases. EGFR expression, in both mRNA and protein, was not related to any EGFR polymorphism (P > 0.05). CONCLUSIONS: Most gastric tumors showed low EGFR expression (mRNA and protein), whereas EGFR overexpression was related to well-differentiated gastric tumors. Furthermore, germinal polymorphisms −216, −191, (CA) n IVS1, and R521K were not related to EGFR expression (mRNA or protein).

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Seminoma of solitary testis: A case report

I Rana, A Lukram

Indian Journal of Cancer 2016 53(3):376-376



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A cohort study of vulvar cancer over a period of 10 years and review of literature

N Singh, N Negi, K Srivastava, G Agarwal

Indian Journal of Cancer 2016 53(3):412-415

OBJECTIVE: The objective of this study was to study the risk factors, management protocols, and the outcome of vulvar cancer cases over a period of 10 years in a tertiary care hospital. METHODOLOGY: It is a retrospective cohort study. The hospital records of 41 patients with histologically proven vulvar cancer were studied from the Department of Obstetrics and Gynaecology and the Department of Radiotherapy (RT). The presence of risk factors, stage of disease, treatment modalities used, and disease outcomes in terms of survival were studied. The data collected were analyzed and compared with the published literature. RESULTS: The mean age for the diagnosis of vulvar cancer was 52 years and the peak incidence was seen in the age group of 50–70 years. Incidence was significantly more in multiparous (P = 0.001) and postmenopausal women (P = 0.007). An average of 4.1 cases were seen per year. Nearly, 97.56% of the cases were squamous cell carcinomas. Twenty cases belonged to the early stage of the disease (Stage I and II) whereas 21 cases had advanced disease (Stage III and IV). Nearly, 48.78% of the cases were primarily treated with surgery, 26.83% with RT, 7.3% with chemotherapy, and 17.07% with combined chemoradiation. Seventy-eight percent of the surgically treated cases had a mean survival of 5 years. Mean survival of 1 year was recorded in advanced disease cases. Limitation of the study was poor follow-up after treatment. CONCLUSION: Incidence of vulvar cancer is significantly high in multiparous and postmenopausal women. Conservative surgical treatment is the best option in the early stage of the disease (Stage I and II) and gives high survival rates whereas advanced disease treated with chemoradiation has a poor survival.

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Characterization of acid- and pepsin-soluble collagen extracted from the skin of Nile tilapia (Oreochromis niloticus)

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Leilei Sun, Hu Hou, Bafang Li, Yan Zhang
Acid-soluble (ASC) and pepsin-soluble (PSC) collagen were extracted from the skin of Nile tilapia (Oreochromis niloticus), purified and physicochemically examined. Amino acid content analyses revealed that glycine accounted for approximately one-third of the total amino acid residues. The proline and hydroxyproline contents of Nile tilapia ASC and PSC were 189 residues and 205 residues/1000 residues, respectively, and the rate of proline hydroxylation was found to be 41.8% and 42.0%, respectively. Denaturation temperatures (Td), as measured by an Ubbelohde viscometer, were 35.2°C and 34.5°C, respectively, 6°C lower than that of the type I collagen found in calf skin. In this study, we measured the intrinsic viscosity, circular dichroism (CD) and, X-ray diffraction (XRD), and employed Fourier transform infrared spectroscopy (FTIR) analyses to confirm that the ASC and PSC samples from Nile tilapia skin were native and undenatured, and therefore, maintained their original, intact triple helical structure. Our SDS-PAGE results showed that the extracted ASC and PSC peptides were in their native molecular form; (α1)2α2 (type I collagen). Furthermore, the loose, fibrous, and porous structures, shown in the cross-sections of ASC and PSC, indicate that Nile tilapia skin collagen represents a powerful physical foundation for further use in biomaterial applications.

Graphical abstract

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Pilose antler peptide protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Yang Chunhui, Cai Wenjun, Wen Hui, Sha Liquan, Zhao Changwei, Zhang Tianzhu, Zhao Wenhai
Epidermal growth factor (EGF)/EFG receptor (EGFR) signaling plays an important role in the osteoblastogenesis. The potential effects of pilose antler peptide (PAP) on osteoblast cell damages was investigated in our present study through EGF/EGFR signaling. In MC3T3-E1 osteoblastic cells, PAP treatment significantly inhibited the production of inflammatory cytokines by decreasing the levels of serum proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). PAP treatment also alleviated the oxidative responses as indicated by increased activities of catalase (SOD) and decreased levels of malondialdehyde (MDA). EGF inhibition, by siRNA knockdown, almost abolished PAP-induced osteoblast cytoprotection against inflammation and oxidant stress. Further, our results showed that PAP stimulated the nuclear erythroid factor 2-related factor 2 (Nrf2)2/heme oxygenase-1(HO-1) signaling, and inhibited the activation of uclear factor kappa B (NF-κB) pathway in MC3T3-E1 cells. On the other hand, EGF siRNA knockdown inhibited PAP-induced cytoprotection, which decreased the expression of Nrf-2, HO-1 and increased the level of p-NF-κBp65, p-IκBα in MC3T3-E1 cells. Thus, our research demonstrated that PAP protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.



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Ternary complexes of folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugate, siRNA and low-molecular-weight polysaccharide sacran as a novel tumor-selective siRNA delivery system

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Ayumu Ohyama, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima
We previously developed a tumor-selective siRNA carrier by preparing polyamidoamine dendrimer (generation 4, G4) conjugates with α-cyclodextrin and folate-polyethylene glycol (Fol-PαC (G4)). In the present study, we developed ternary complexes of Fol-PαC (G4)/siRNA with low-molecular-weight-sacrans to achieve more effective siRNA transfer activity. Among the different molecular-weight sacrans, i.e. sacran 100, 1000 and 10,000 (MW 44,889Da, 943,692Da and 1,488,281Da, respectively), sacran 100 significantly increased the cellular uptake and the RNAi effects of Fol-PαC (G4)/siRNA binary complex with negligible cytotoxicity in KB cells (folate receptor-α positive cells). In addition, the ζ-potential and particle size of Fol-PαC (G4)/siRNA complex were decreased by the ternary complexation with sacran 100. Importantly, the in vivo RNAi effect of the ternary complex after the intravenous administration to tumor-bearing BALB/c mice was significantly higher than that of the binary complex. In conclusion, Fol-PαC (G4)/siRNA/sacran 100 ternary complex has a potential as a novel tumor-selective siRNA delivery system.



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Magnetic bionanocomposites from cellulose nanofibers: Fast, simple and effective production method

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Quim Tarrés, Alexandre Deltell, F. Xavier Espinach, M. Àngels Pèlach, Marc Delgado-Aguilar, Pere Mutjé
Nanocellulose is becoming a topic of great interest due to its lightweight, huge availability and its interesting properties. Among these properties, it is worthy to distinguish its specific surface and its strength. Both properties allow producing films with great mechanical properties able to retain nanoparticles which can provide the nanopaper of much functionality. Many applications for nanocellulose nanocomposites have been reported, demonstrating the interesting opportunities that this product has in a near future. In this sense, the present work attempts to produce membranes based on cellulose nanofibers (CNF) filled with magnetite nanoparticles with the purpose of developing membranes for loudspeakers. The main advantage of this is the avoiding of the iron core that one can find in any loudspeaker, since the membrane itself acts as that core. Bionanocomposites ranging from 10 to 70% of magnetite nanoparticles were produced by filtration in a nitrocellulose membrane with a pore size of 0,22μm. Tensile tests showed that mechanical properties were decreased as the amount of magnetite was increased. They were observed by FE-SEM to see the interactions between nanoparticles and CNF. Finally, a loudspeaker prototype was developed in order to evaluate the sonorous efficiency of the resulting membranes.



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In vitro drug release profiles of pH-sensitive hydroxyethylacryl chitosan/sodium alginate hydrogels using paracetamol as a soluble model drug

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Pitchaya Treenate, Pathavuth Monvisade
The aim of this study is to investigate in vitro drug release profiles of pH-sensitive hydrogels composed of hydroxyethylacryl chitosan (HC) and sodium alginate (SA). The hydrogels were crosslinked by dipping method using different ionic crosslinkers (e.g., Ca²⁺, Zn²⁺ and Cu²⁺). The crosslinking reaction was confirmed by FT-IR. Swelling behavior and stability of the hydrogels in simulated digestive media were investigated. The result indicated that the combination between HC and SA could delay the degradation time of the hydrogels. Calcium crosslinking system showed higher stability than that of zinc or copper crosslinking system. In vitro drug release profiles were studied using paracetamol as a soluble model drug. The amount of paracetamol release in simulated gastric fluid (SGF) was relatively low (<20%). In simulated intestinal fluid (SIF), the burst release of paracetamol was depressed with increasing HC content and/or applying crosslinker. The HC75SA25 formulation demonstrated the linearity of drug release profile. Additionally, the amount of drug release from the 0.5M calcium HC50SA50 hydrogel in SIF was lower than 20%. The comprehensive results of this study suggested their potential in the application of site-specific oral drug delivery in intestine and colon.



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Preparation and characterization of bionanocomposite film based on tapioca starch/bovine gelatin/nanorod zinc oxide

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Mohammad Mehdi Marvizadeh, Nazila Oladzadabbasabadi, Abdorreza Mohammadi Nafchi, Maryam Jokar
To exploring a nano-packaging materials for using as coating or edible films, tapioca starch/gelatin/nanorod ZnO (ZnON) bionanocomposites were prepared via solution casting technique. The effects of nanofiller addition on the mechanical, physicochemical, and crystalline structures, as well as the barrier properties of bionanocomposite films were investigated. X-ray diffraction analysis showed that the bionanocomposite film incorporated with ZnON at a concentration of 3.5% w/w exhibited high intensity peaks compared with control samples. Results of UV–vis spectra analysis showed that incorporation of ZnON into the films can absorb the whole UV light. Tensile strength of the films was increased from 14 to 18MPa whereas elongation at breaks decreased from 18 to 8 percent and oxygen permeability decreased from 151.03 to 91.52cm³μm/(m²–day) by incorporation of 3.5% ZnON into biopolymer matrix. In summary combined starch/gelatin films supported by ZnON showed better properties compared to starch or gelatin alone. Thus, the bionanocomposite films can be used in food, medicine, and pharmaceutical packaging.



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UV protective poly(lactic acid)/rosin films for sustainable packaging

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Meenu Narayanan, Sravanthi Loganathan, Ravi Babu Valapa, Sabu Thomas, T.O. Varghese
Recently, biopolymer based plastic materials are regarded as potential alternative for conventional plastics of fossil fuel origin in order to compensate depleting petroleum resources and address environmental pollution issues. Poly(lactic acid) (PLA) is one among the biopolymers which is rapidly commercialized for food packaging application. However, the demerits accompanied with PLA like brittle nature, slower crystallization rate, poor gas barrier and high ultraviolet radiation transmission properties confines its commercial application in food packaging sector. Studies on the improvement of ductility, crystallization rate and gas barrier properties are markedly reported. Much emphasis is not given in the literature on improving UV shielding properties which plays important role in preventing oxidation degradation of PLA. Therefore, the current work is focused on fabrication of eco-friendly poly(lactic acid)/rosin (RS) based biocomposite films with improved UV shielding along with ductility and oxygen barrier properties. The PLA-RS biocomposite films containing different loadings (1, 3, 5, 10 and 20wt%) of RS with an average thickness of 50μm are fabricated via solution casting technique. The PLA-RS film demonstrated noteworthy light barrier feature by shielding the passage of ∼98%, 92% and 53% in UV-B, UV-A and visible light regime, respectively. In case of UV-C region, complete blockage of UV transmission through the PLA-RS biocomposite film is noticed. In addition to this, the presence of RS in the PLA matrix brought considerable improvement in terms of ductility and oxygen barrier characteristics. This in turn indicates PLA-RS biocomposite films hold significant potential for sustainable food packaging application.



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Cell physiology regulation by hypoxia inducible factor-1: Targeting oxygen-related nanomachineries of hypoxic cells

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Morteza Eskandani, Somayeh Vandghanooni, Jaleh Barar, Hossein Nazemiyeh, Yadollah Omidi
Any dysfunctionality in maintaining the oxygen homeostasis by mammalian cells may elicit hypoxia/anoxia, which results in inescapable oxidative stress and possible subsequent detrimental impacts on certain cells/tissues with high demands to oxygen molecules. The ischemic damage in turn can trigger initiation of a number of diseases including organs ischemia, metabolic disorders, inflammatory diseases, different types of malignancies, and alteration in wound healing process. Thus, full comprehension of molecular mechanism(s) and cellular physiology of the oxygen homeostasis is the cornerstone of the mammalian cells metabolism, energetic pathways and health and disease conditions. An imbalance in oxygen content within the cellular microenvironment activates a cascade of molecular events that are often compensated, otherwise pathologic condition occurs through a complexed network of biomolecules. Hypoxia inducible factor-1 (HIF-1) plays a key transcriptional role in the adaptation of cell physiology in relation with the oxygen content within a cell. In this current study, we provide a comprehensive review on the molecular mechanisms of oxygen sensing and homeostasis and the impacts of HIF-1 in hypoxic/anoxic conditions. Moreover, different molecular and biochemical responses of the cells to the surrounding environment are discussed in details. Finally, modern technological approaches for targeting the hypoxia related proteins are articulated.



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Protective effect of polysaccharide from maca (Lepidium meyenii) on Hep-G2 cells and alcoholic liver oxidative injury in mice

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Lijun Zhang, Qingsheng Zhao, Liwei Wang, Mingxia Zhao, Bing Zhao
To study the characterization and hepatoprotective activity of polysaccharide from maca (Lepidium meyenii), the main polysaccharide from maca (MP-1) was obtained by DEAE-52 cellulose column. The average molecular weight of MP-1 was 1067.3kDa and the polysaccharide purity was 91.63%. In order to assess the antioxidant activities of MP-1, four kinds of methods were used, including scavenging hydroxyl radical, DPPH, superoxide anion radical, and FRAP, and the results indicated high antioxidant activities. Furthermore, hepatoprotective activity of MP-1 was studied both in vitro and vivo. In vitro, the alcohol induced Hep-G2 cells model was established to evaluate the protective effect of MP-1, which demonstrated MP-1 can alleviate alcohol damage in Hep-G2 cells. In vivo, the Institute　of　Cancer　Researcch (ICR) mice were used to evaluate hepatoprotecive effects of MP-1 on alcoholic liver disease (ALD). Supplement with MP-1 supressed the triglyceride level both in serum and in hepatic tissue. In addition, MP-1 ameliorated serous transaminases increase induced by alcohol, including aspartate transaminase, alanine aminotransferase, and γ-glutamyl transpeptidase. Moreover, MP-1 also dramatically increased the superoxide dismutase, glutathione peroxidase, and glutathione s-transferase levels in alcoholic mice. Meantime, histopathologic results MP-1 lighten inflammation induced by alcohol. These results indicate that MP-1 possesses hepatoprotective activity against hepatic injury induced by alcohol.



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Chikungunya Infection: a Global Public Health Menace

Abstract

Chikungunya virus (CHIKV) has been involved in epidemics in African and Asian subcontinents and, of late, has transcended to affect the Americas. Aedes aegypti and Aedes albopictus are the major vectors for CHIKV infection, which results in dissemination of virus to various vital organs. Entry of virus into these tissues causes infiltration of innate immune cells, monocytes, macrophages, neutrophils, natural killer cells, and adaptive immune cells. Macrophages bearing the replicating virus, in turn, secrete pro-inflammatory cytokines IL-1β, TNF-α, and IL-17. Together, this pro-inflammatory milieu induces osteoclastogenesis, bone loss, and erosion. CHIKV is characterized by fever, headache, myalgia, rash, and symmetric polyarthritis, which is generally self-limiting. In a subset of cases, however, musculoskeletal symptoms may persist for up to 3–5 years. Viral culture and isolation from blood cells of infected patients are the gold standards for diagnosis of CHIKV. In routine practice, however, assays for anti-CHIKV IgM antibodies are used for diagnosis, as elevated levels in blood of infected patients are noted from 10 days following infection for up to 3–6 months. Early diagnosis of CHIKV is possible by nucleic acid detection techniques. Treatment of acute CHIKV is mainly symptomatic, with analgesics, non-steroidal anti-inflammatory agents (NSAIDs), and low-dose steroids. No vaccines or anti-viral medicines have been approved for clinical therapy in CHIKV as yet. Hydroxychloroquine and methotrexate have been used in chronic CHIKV infection with variable success.

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TarSeqQC: Quality Control on Targeted Sequencing Experiments in R

ABSTRACT

Targeted sequencing is growing as a screening methodology used in research and medical genetics to identify genomic alterations causing human diseases. In general, a list of possible genomic variants is derived from mapped reads through a variant calling step. This processing step is usually based on variant coverage, although it may be affected by several factors. Therefore, under-covered relevant clinical variants may not be reported, impacting on pathology diagnosis or treatment. Thus, a prior quality control of the experiment is critical to determine variant detection accuracy and to avoid erroneous medical conclusions. There are several quality control tools, but they are focused on issues related to whole genome sequencing. However, in targeted sequencing, quality control should assess experiment, gene and genomic region performances based on achieved coverages.

Here, we propose TarSeqQC R package for quality control in targeted sequencing experiments. The tool is freely available at Bioconductor repository. TarSeqQC was used to analyze two datasets; low-performance primer pools and features were detected, enhancing the quality of experiment results. Read count profiles were also explored, showing TarSeqQC's effectiveness as an exploration tool. Our proposal may be a valuable bioinformatic tool for routinely targeted sequencing experiments in both research and medical genetics.

This article is protected by copyright. All rights reserved

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EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state

Abstract

Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases.

We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (that is, in association with Hirschsprung disease) and heterozygous mutations in isolated Hirschsprung disease. Screening of a WS2 cohort led to the identification of an overall of 6 heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5–6% of WS2.

This article is protected by copyright. All rights reserved

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IFC/ Editorial Board

Publication date: 1 March 2017
Source:Experimental Cell Research, Volume 352, Issue 1





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Modulation of Hepatic Stellate Cells and Reversibility of Hepatic Fibrosis

Publication date: Available online 24 February 2017
Source:Experimental Cell Research
Author(s): Yu Huang, Xin Deng, Jian Liang
Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal.



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Hypoxia regulates microRNA expression in the human carotid body

Publication date: Available online 24 February 2017
Source:Experimental Cell Research
Author(s): Souren Mkrtchian, Kian Leong Lee, Jessica Kåhlin, Anette Ebberyd, Lorenz Poellinger, Malin Jonsson Fagerlund, Lars I Eriksson
The carotid body (CB) is the key sensing organ for physiological oxygen levels in the body. Under conditions of low oxygen (hypoxia), the CB plays crucial roles in signaling to the cardiorespiratory center in the medulla oblongata for the restoration of oxygen homeostasis. How hypoxia regulates gene expression in the human CB remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the identity and impact of important post-transcriptional regulators such as non-coding RNAs, and in particular miRNAs are not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins.



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Identification of Potential Target Genes of ROR-Alpha in THP1 and HUVEC cell lines

Publication date: Available online 24 February 2017
Source:Experimental Cell Research
Author(s): Cagri Gulec, Neslihan Coban, Bilge Ozsait-Selcuk, Sema Sirma-Ekmekci, Ozlem Yildirim, Nihan Erginel- Unaltuna
ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocyte and endothelial cell lines.We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha.Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3,000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha.Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembran transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses.



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Genomewide bisulfite sequencing reveals the origin and time-dependent fragmentation of urinary cfDNA

Publication date: Available online 24 February 2017
Source:Clinical Biochemistry
Author(s): Timothy H.T. Cheng, Peiyong Jiang, Jacqueline C.W. Tam, Xiao Sun, Wing-Shan Lee, Stephanie C.Y. Yu, Jeremy Y.C. Teoh, Peter K.F. Chiu, Chi-Fai Ng, Kai-Ming Chow, Cheuk-Chun Szeto, K.C. Allen Chan, Rossa W.K. Chiu, Y.M. Dennis Lo
Urinary cell-free (cf) DNA holds great potential as a completely noninvasive form of liquid biopsy. Knowledge of the composition of cfDNA by tissue of origin is useful for guiding its clinical uses. We conducted a global survey of urinary cfDNA composition using genomewide bisulfite sequencing. While previous studies focused on detecting cfDNA from a single source at a time, genomewide tissue specific methylation signatures allow us to simultaneously deduce the proportional contribution from each contributing tissue. The proportional contributions derived from methylation deconvolution are highly correlated with those calculated using allograft-derived donor-specific genetic markers in the urine of hematopoetic stem cell and renal transplant recipients. We found a large variation of proportional contributions from different tissues. We then assessed if cfDNA undergoes time-dependent fragmentation in urine by conducting in vitro incubation experiments. In vitro incubation at 37°C showed that urinary cfDNA concentration decreased under first order kinetics with a half-life of 2.6 to 5.1h. This is reflected in parallel by a decrease in the proportion of long fragments and increase in amplitude of 10bp periodicity seen in the cfDNA size profile. This global survey of urinary cfDNA has deepened our understanding of the composition, degradation and variation of cfDNA in the urinary tract and has laid a foundation for the use of genomewide urinary cfDNA sequencing as a molecular diagnostics tool.



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