Cytokines regulating lymphangiogenesis

Miguel Sáinz-Jaspeado | Lena Claesson-Welsh

https://ift.tt/2HQZ24x

Development of next generation hemagglutinin-based broadly protective influenza virus vaccines

Raffael Nachbagauer | Peter Palese

https://ift.tt/2HRoLtX

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies

Abstract

Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov, the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

https://ift.tt/2JdP6lg

IL-13 is produced by tumor cells in Breast Implant Associated Anaplastic Large Cell Lymphoma: Implications for pathogenesis

More than 500 women worldwide have developed a CD30+ T-cell lymphoma around breast implants, strongly suggesting a cause and effect relationship, and designated as breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The mechanism of lymphomagenesis is unknown. Recently, a bacterial biofilm containing gram negative bacilli was discovered on the surface of breast implants associated with ALCL. We and others have described overexpression of the proto-oncogene JUNB and mutations of JAK1/2, TP53 and STAT3 in BIA-ALCL.

https://ift.tt/2vuDiJe

Impaired tissue barriers as potential therapeutic targets for Parkinson’s disease and amyotrophic lateral sclerosis

Abstract

The blood-brain barrier and the intestinal barrier show signs of disruption in patients with idiopathic Parkinson's disease (PD) and animal models of nigrostriatal degeneration, and likewise in amyotrophic lateral sclerosis (ALS) models. A substantial body of evidence shows that defects in epithelial membrane barriers, both in the gut and within the cerebral vasculature, can result in increased vulnerability of tissues to external factors potentially participating in the pathogenesis of PD and ALS. As such, restoration of tissue barriers may prove to be a novel therapeutic target in neurodegenerative disease. In this review, we focus on the potential of new intervention strategies for rescuing and maintaining barrier functions in PD and ALS.

https://ift.tt/2qSWjj5

SWI/SNF Protein Expression Status in Fumarate Hydratase-deficient Renal Cell Carcinoma: Immunohistochemical Analysis of 32 Tumors from 28 Patients

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive RCC type, originally described in the setting of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome which is defined by germline FH gene inactivation. Inactivation of components of the SWI/SNF chromatin remodelling complex is involved in renal medullary carcinoma (SMARCB1/INI1 loss), clear cell RCC (PBRM1 loss) and in subsets of dedifferentiated RCC of clear cell, chromophobe and papillary types (loss of different SWI/SNF components).

https://ift.tt/2qQzv4g

Decreased expression of microRNA-26b in locally advanced and inflammatory breast cancer

Advanced-stage breast cancer patients comprise a smaller proportion of breast cancer patients than do early-stage patients and are more likely to experience a poor outcome. Understanding the underlying molecular mechanisms and identifying new biomarkers for treatment in this subgroup of patients is paramount. With the aim of identifying microRNAs that are regulated in advanced-stage breast cancer, we found lower expression of miR-26b, a member of the miR-26 family, in inflammatory breast cancer and noninflammatory locally advanced breast cancer tissue than in normal breast tissue, by quantitative real-time PCR and in situ hybridization.

https://ift.tt/2vuDpVa

Whole Exome Sequencing Identifies Unique Mutations and Copy Number Losses in Calcifying Fibrous Tumor of the Pleura: Report of Three Cases and Review of the Literature

Calcifying fibrous tumor of the pleura (CFTP) is a rare mesenchymal tumor of unknown pathogenesis. The diagnosis often requires exclusion of other common entities. Our aim was to determine if genomic changes were associated with CFTP that could contribute to mechanisms underlying tumorigenesis. Three cases of CFTP with their corresponding uninvolved control lung tissue were identified. Two patients were male, and one was female (age range: 21–32years). Tumors were multifocal in two cases and solitary in one.

https://ift.tt/2qOUHrz

Loss of ARID1A expression is associated with poor prognosis in patients with gastric cancer

Deletion of the frequently mutated AT-rich interacting domain-containing protein 1A (ARID1A), an SWI/SNF subunit, is associated with poor prognosis in various tumors. This study observed and analyzed ARID1A expression and its correlation with prognosis in gastric carcinoma. Postoperative sections of 98 patients with primary gastric cancer and 40 patients with gastric benign lesions were examined by immunohistochemistry. ARID1A deficiency was observed in 19.39% of gastric cancer tissues, 4.08% of matched paracancerous tissues, and 2.5% of normal gastric mucosa.

https://ift.tt/2HIxIbq

“Suffering” in palliative sedation: Conceptual Analysis and Implications for Decision-Making in Clinical Practice

Palliative sedation is an increasingly used and, simultaneously, challenging practice at the end of life. Many controversies associated with this therapy are rooted in implicit differences regarding the understanding of "suffering" as prerequisite for palliative sedation. The aim of this paper is to inform the current debates by a conceptual analysis of two different philosophical accounts of suffering, (1) the subjective and holistic concept and (2) the objective and gradual concept and by a clinical-ethical analysis of the implications of each account for decisions about palliative sedation.

https://ift.tt/2qR0iMZ

Endoscopically resected long giant polypoidal lesion caused by arteriovenous malformation

https://ift.tt/2F5H63r

Use of diphenhydramine as an adjunctive sedative for colonoscopy in patients on chronic opioid therapy: a randomized controlled trial

Chronic opioid use increases tolerance to sedatives. Diphenhydramine is recommended for difficult-to-sedate patients during endoscopic procedures. We hypothesized that the addition of diphenhydramine to midazolam and fentanyl would improve objective and subjective measures of procedural sedation.

https://ift.tt/2HUiopK

Unexpected amoebic colitis: presented by rectal bleeding and perforation after biopsy

https://ift.tt/2HimAyd

Association of Neuronal Injury in the Genu and Body of Corpus Callosum Following Cranial Irradiation in Children with Impaired Cognitive Control: A Prospective Study

The purpose of this prospective study was to examine white matter integrity as measured by DTI and the association with region specific radiation therapy dose and neuropsychological functioning in children treated with cranial irradiation. These data suggest that subcortical white matter, especially the genu and body of the corpus callosum, may be regions with increased susceptibility to radiation-induced injury with implications for cognitive function.

https://ift.tt/2HfxXLo

Stereotactic Ablative Radiotherapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site

We performed a prospective study to assess the systemic immune response 1-2 weeks following stereotactic radiation (SAR) to different organs using flow cytometry for immunophenotyping and Luminex analysis. Our results suggest SAR to parenchymal sites (lung and liver) induces systemic immune changes, including a decrease in total and cytotoxic NK cells and an increase in TIM-3+ NK cells and activated memory CD4+ and CD8+ T cells. SAR to non-parenchymal sites did not induce these changes.

https://ift.tt/2qSKMAj

Outcomes of Patients with Sinonasal Squamous Cell Carcinoma Treated with Particle Therapy Using Protons or Carbon Ions

We investigated outcomes of patients with sinonasal squamous cell carcinoma (SCC) treated only with particle therapy; i.e., proton therapy (PT) or carbon ion therapy (CIT). In this largest retrospective study of its kind to date, PT and CIT were effective against sinonasal SCC, with no significant difference in outcomes between the two modalities and few toxicities. These data suggest an important role for these modalities in SCC treatment.

https://ift.tt/2Hfy0H4

Pretreatment Multiparametric Magnetic Resonance Imaging Findings Are More Accurate Independent Predictors of Outcome Than Clinical Variables In Localized Prostate Cancer

To prospectively determine whether multiparametric MRI (mpMRI) based staging is a more accurate independent predictor of outcome than traditional clinical variables in patients treated with brachytherapy (BT) and external-beam-radiotherapy (EBRT).

https://ift.tt/2HfxZmu

Consolidative Whole Brain Radiotherapy vs Autologous Stem Cell Transplant for Primary Central Nervous System Lymphoma: A large dose of perspective and perhaps a lower dose of radiation are in order

https://ift.tt/2qVmHJp

First experience with markerless on-line 3D spine position monitoring during SBRT delivery using a conventional LINAC

Spine stereotactic body radiation therapy requires highly accurate patient positioning to reduce toxicity risks to nearby organs-at-risk such as the spinal cord. However, positional verification is often lacking during irradiation. We report our initial experience with markerless on-line 3D spine position monitoring during volumetric modulated arc therapy on a standard LINAC using the gantry-mounted kV imager.

https://ift.tt/2qPFdTc

How to get the most out of costly Barrett’s oesophagus surveillance

Current endoscopic surveillance protocols for Barrett's oesophagus have several limitations, mainly the poor cost-effectiveness and high miss rate. However, there is sufficient evidence that patients enrolled in a surveillance program have better survival chances of oesophageal cancer due to earlier tumor stages at diagnosis compared to patients with de novo diagnosed oesophagus cancer. Risk stratifications aim to identify patients at highest risk of developing adenocarcinoma of the oesophagus; most of them base on the length of the Barrett's segment and the presence of dysplasia.

https://ift.tt/2HSpF9p

Impact of age at diagnosis on natural history of patients with elderly-onset ulcerative colitis: a French population-based study

Recent population-based study of elderly-onset Crohńs disease patients reported age-related differences in disease phenotype and outcome.

https://ift.tt/2F5y8mL

Harvesting Venom Toxins from Assassin Bugs and Other Heteropteran Insects

Although many insects in the suborder Heteroptera (Insecta: Hemiptera) are venomous, their venom composition and the functions of their venom toxins are mostly unknown. This protocol describes methods to harvest heteropteran venoms for further characterization, using electrostimulation, harassment, and gland dissection.

https://ift.tt/2vwRxNI

Juvenile Trabecular Ossifying Fibroma—a Case Report

Abstract

Ossifying fibroma is a benign osteogenic mesenchymal tumor that is classified in the fibro-osseous lesions. Fibro-osseous lesions contain minerals, blood vessels, and giant cells that have the same radiographic and pathologic features but have different clinical behaviors, and were replaced with the normal bone. These lesions include fibrous dysplasia, cemento-osseous dysplasia, and ossifying fibroma. Juvenile ossifying fibroma is a type of uncommon and has invasive behavior, high incidence and occurs in young men, especially in maxilla, and is different from the type of adult in age, location, and clinical behavior and microscopic view. Pathologically, ossifying fibroma is divided into two types of trabecular and psammomatoid. The trabecular type is characterized by the presence of the osteoid trabeculae and the woven bone, and the type of psammomatoid by the presence of round, integrated, and small ossicles that are similar to the components of the psammoma. The purpose of this report is the clinical examination, radiography, pathology, and the treatment of a rare case of ossifying fibroma (trabecular) in mandible in a 7-year-old boy.

https://ift.tt/2F6bXN5

Challenges to studying population effects of medical treatments

https://ift.tt/2qPiyq8

How accurately is euthanasia reported on death certificates in a country with legal euthanasia: a population-based study

Abstract

Background

Death certificates are the main source of information on the incidence of the direct and underlying causes of death, but may be unsuitable for monitoring the practice of medical assistance in dying, e.g. euthanasia, due to possible underreporting. This study examines the accuracy of certification of euthanasia.

Methods

Mortality follow-back survey using a random sample of death certificates (N = 6871). For all cases identified as euthanasia we checked whether euthanasia was reported as a cause of death on the death certificate. We used multivariable logistic regression analysis to evaluate whether reporting varied according to patient and decision-making characteristics.

Results

Through the death certificates, 0.7% of all deaths were identified as euthanasia, compared with 4.6% through the mortality follow-back survey. Only 16.2% of the cases identified from the survey were reported on the death certificate. Euthanasia was more likely to be reported on the death certificate where death was from cancer (14% covered), neurological diseases (22%) and stroke (28%) than from cardiovascular disease (7%). Even when the recommended drugs were used or the physician self-labelled the end-of-life decision as euthanasia, euthanasia was only reported on the death certificate in 24% of cases.

Conclusions

Death certificates substantially underestimate the frequency of euthanasia as a cause of death in Belgium. Mortality follow-back studies are essential complementary instruments to examine and monitor the practice of euthanasia more accurately. Death certificate forms may need to be modified and clear guidelines provided to physicians about recording euthanasia to ensure more accurate certification.

https://ift.tt/2HhvNev

Does burst-suppression achieve seizure control in refractory status epilepticus?

The general principles in the administration of anesthetic drugs entail not only the suppression of seizure activity but also the achievement of electroencephalography burst suppression (BS). However, previous...

https://ift.tt/2qQmXcl

Effect of Trigonella foenum-graecum Linn . seeds methanol extract on learning and memory

Abstract

Prevention and delay in the onset of memory disorders will have a great impact on society by reducing the disease burden and finances. Drugs available for the treatment of learning and memory disorders are few. There is need to develop a better drug, several studies have shown the therapeutic effectiveness of herbal extracts for the learning and memory disorders because of their neuroprotective effects, hence herbs should be evaluated scientifically to form a basis for the future discovery of newer drugs. In this study, effect of Trigonella-foenum graecum L. seeds methanol extract (TFGS-ME) was evaluated in mice on learning and memory process by both exteroceptive and interoceptive behavioral models at three different doses. Elevated plus maze test was employed to assess the effect on learning and memory as an exteroceptive behavioral test. Scopolamine-induced amnesia was performed to assess effect on learning and memory as interoceptive behavior test. In both tests, it was found that animals received extract at 200 mg/kg exhibited a highly noteworthy decline in transfer latency on both acquisition and retention days in contrast to control animals, suggestive of improved learning and memory process. Results were equivalent to the standard drug piracetam at similar dose indicating that TFGS-ME improves learning and memory process and has significant potential as an antiamnesic agent. Hence there is need to separate the dietary components which may play a vibrant role in the future invention of novel drugs.

https://ift.tt/2vyfHHU

Ibuprofen, acetaminophen more effective than opioids in treating dental pain

Ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) alone or in combination with acetaminophen are better at easing dental pain than opioids, according to new research.

https://ift.tt/2qP7nxG

Neb. county equips public places with AEDs

Platte County voted to purchase seven automated defibrillators that can save lives of members of the public and employees who suddenly suffer cardiac arrest

https://ift.tt/2F5y9H2

From John Snow to omics: the long journey of environmental epidemiology

Abstract

A major difference between infectious and non-communicable diseases is that infectious diseases typically have unique necessary causes whereas noncommunicable diseases have multiple causes which by themselves are usually neither necessary nor sufficient. Epidemiology seems to have reached a limit in disentangling the role of single components in causal complexes, particularly at low doses. To overcome limitations the discipline can take advantage of technical developments including the science of the exposome. By referring to the interpretation of the exposome as put forward in the work of Wild and Rappaport, I show examples of how the science of multi-causality can build upon the developments of omic technologies. Finally, I broaden the picture by advocating a more holistic approach to causality that also encompasses social sciences and the concept of embodiment. To tackle NCDs effectively on one side we can invest in various omic approaches, to identify new external causes of non-communicable diseases (that we can use to develop preventive strategies), and the corresponding mechanistic pathways. On the other side, we need to focus on the social and societal determinants which are suggested to be the root causes of many non-communicable diseases.

https://ift.tt/2K2Bmes

Pure red cell aplasia and HIV infection: what to suspect?

Description

A 15-year-old boy of black ethnicity presented with anorexia, fatigue and weight loss for 3 months. The patient's medical record included malaria infection at the age of 18 months and diagnosis of HIV infection at age 7 years treated with Tenofovir (TDF)/Emtricitabine (FTC)+ Efavirenz (EFV). The adolescent first went to a Congo's Hospitalar Unit, where antiretroviral (ART) therapy was changed to TDF/FTC+ Lopinavir (LPV)/ritonavir (r) due to elevated HIV viral load and low CD4⁺ T lymphocytes. The compliance was irregular, and 1 month later he was admitted. The laboratory study revealed severe anaemia (haemoglobin (Hb) 4.1 g/dL), and he received multiple transfusions. Due to the absence of clinical improvement, parents brought him to Oporto's Paediatric Hospital in Portugal. 

On physical examination he presented with pallor and weight loss. The rest of his physical examination findings were normal. The initial laboratory study showed normocytic normochromic anaemia (Hb 7.3 g/dL, red cell distribution width...

https://ift.tt/2qPN8Qo

Corpus callosum demyelination associated with acquired stuttering

Compared with developmental stuttering, adult onset acquired stuttering is rare. However, several case reports describe acquired stuttering and an association with callosal pathology. Interestingly, these cases share a neuroanatomical localisation also demonstrated in developmental stuttering. We present a case of adult onset acquired stuttering associated with inflammatory demyelination within the corpus callosum. This patient's disfluency improved after the initiation of immunomodulatory therapy.

https://ift.tt/2HlubAs

MonoMac syndrome with associated neurological deficits and longitudinally extensive cord lesion

We present a case of monocytopaenia and mycobacteria-related infection (MonoMac) syndrome in a 30-year-old man of Indian origin. The clinical diagnosis of GATA2 haploinsufficiency was suspected after an unusual neurological presentation on a background of myelodysplastic syndrome and childhood pulmonary tuberculosis. The patient had a longitudinally extensive spinal cord lesion and a lesion in the medulla. No obvious infective cause for the spinal cord MRI abnormality was found, and the lesions were presumed to be inflammatory in nature. The family history consisted of autosomal dominant clinical features suggestive of GATA2 haploinsufficiency. Genetic testing in peripheral leucocytes revealed a pathogenic mutation in GATA2. This is the first-ever published case of possible MonoMac syndrome with a neurological presentation. The case highlights the rarity and complexity of the diagnosis and the clinical sequelae that ensued with the patient dying of gram-negative septicaemia while receiving intravenous steroid therapy for the spinal cord lesion.

https://ift.tt/2qLCg6a

Periurethral abscess drained by iatrogenic urethral fistula in a middle-aged man

Description

A 35-year-old man was referred to our urology department in June 2016 from a local hospital. The patient initially presented with high-grade fever, painful scrotal swelling and acute urinary retention (AUR) 3 months back to a local practitioner and was diagnosed as a case of periurethral abscess. He was advised oral antibiotics, and a small calibre (8 Fr) catheter was placed per-urethrally in the bladder. After few days, the catheter got removed accidentally, and the patient again went into AUR. The discharge card given to the patient mentioned that the patient had multiple failed attempts of per-urethral catheterisation, and in order to relieve the patient's symptoms, the treating practitioner just attempted a blind incision over the swelling. Pus mixed with urine came out. This turned out to be a blessing in disguise as it drained urine and led to resolution of the abscess. Subsequently, a urethral catheter was...

https://ift.tt/2HhLaDB

Cluster of exertional rhabdomyolysis in three young women

Three young women, aged 18–24 years, presented to general practice with signs and symptoms of exertional rhabdomyolysis in 2016. All attended the same gym and had undertaken an intensive physical workout. Presenting symptoms were severe muscle pain and swelling, significantly reduced range of motion in affected muscles and, in two cases, dark-coloured urine. One case had presented to the out-of-hours service 4 months previously with similar symptoms but rhabdomyolysis was not considered, although retrospective history taking suggests that was the likely diagnosis. All three women were admitted to hospital, treated with intravenous fluids and discharged between 1 and 6 days later. All made a full recovery with no renal sequelae. The cases were questioned about potential risk factors, and the only commonality was unaccustomed strenuous exercise.

https://ift.tt/2qPkMGc

Risperidone-associated sinus tachycardia potentiated by paliperidone palmitate in a patient with no prior cardiovascular disease: role of risperidone-related autonomic instability

Risperidone and paliperidone palmitate are two antipsychotic drugs well tolerated in the management of schizophrenia and other psychiatric conditions. There have been few reports of tachycardia induced by either drugs. Here, we report on a 21-year-old man, with a history of schizophrenia, and who developed persistent sinus tachycardia after he was restarted on risperidone, which later worsened after administration of paliperidone palmitate for long-term management. He had no cardiovascular risk factors other than obesity, and a prior well-tolerated risperidone treatment. Clinicians must be aware of the possibility of patients developing sinus tachycardia due to autonomic instability from a prior risperidone treatment, even though overall, these drugs are well tolerated.

https://ift.tt/2HgKEFL

Xp11 translocation renal cell carcinoma paraneoplastic syndrome presenting as cutaneous vasculitis: first reported case of yet another mask

Renal cell carcinoma is historically known as the 'great masquerader' with 40% of patients experiencing a paraneoplastic syndrome. Translocation carcinoma represents one-third of renal cancer in paediatric patients but less than 3% of renal cancers in patients aged 18–45 years where the clinical course is often rapidly terminal. There are less than 10 reported cases of leucoclastic vasculitis associated with clear cell carcinoma reported in the literature and 10 case reports of translocation carcinoma in adults. To our knowledge, we present the first reported case of Xp11 translocation carcinoma presenting as cutaneous vasculitis, as part of a paraneoplastic syndrome, in an adult patient. Our case highlights that renal cell cancers are truly the 'great masquerader' and a rash can be the first sign of renal malignancy.

https://ift.tt/2qLC1bg

Pneumocystis jiroveci pneumonia in a patient taking Benepali for rheumatoid arthritis

We present a case of a 57-year-old woman who contracted Pneumocystis jiroveci pneumonia while on Benepali, the biosimilar version of etanercept for rheumatoid arthritis. She had seropositive erosive disease. She was admitted to clinic with a 2-week history of dyspnoea, dry cough and fever. Her initial examination showed her to be hypoxic on air with saturations of 77% and left basal crackles. Her admission chest X-ray showed fine reticular shadowing, with an initial suspicion of pulmonary fibrosis. She was empirically treated for community-acquired pneumonia but continued to deteriorate with a worsening type 1 respiratory failure. She was intubated and ventilated on intensive care. The suspicion was raised of P. jiroveci pneumonia given her immunosuppression, hypoxic presentation and chest X-ray changes. This was confirmed on sputum PCR. She was treated with a 3-week course of steroids and co-trimoxazole. She was discharged home after a 2-week admission.

https://ift.tt/2Hlu0VO

Rare case of otomastoiditis due to Coxiella burnetii chronic infection

Q fever is a zoonotic disease caused by Coxiella burnetii that usually presents with non-specific or benign constitutional symptoms. Diagnosis is often challenging and, after acute Q fever, 1%–5% of patients can develop chronic disease. We present an 80-year-old male patient who was admitted due to a 3 months history of fever, productive cough, myalgia, weight loss, headache and hearing loss. Chronic Q fever was confirmed by positive antiphase I immunoglobulin G. Frequent locations of chronic infection was discarded, and ear CT revealed a right mastoid infection. He was treated with doxycycline and hydroxychloroquine for 18 months with significant improvement. This is a rare case of chronic Q fever presenting with otomastoiditis that has never been described.

https://ift.tt/2qL7wmM

A smartphone application for reporting symptoms in adults with cystic fibrosis: protocol of a randomised controlled trial

Introduction

In people with cystic fibrosis (CF), exacerbations have been shown to have profound and prolonged negative effects such as reducing physical activity and health-related quality of life, increasing the rate of decline of lung function and healthcare costs, and ultimately increasing the risk of mortality. Delayed initiation of treatment following the signs of an exacerbation has been shown to be associated with failure to recover to baseline. Therefore, the late identification and treatment of an exacerbation due to delayed presentation will potentially worsen short-term and long-term outcomes. We have developed a smartphone application, containing questions which require yes or no responses relating to symptoms suggestive of a respiratory exacerbation. Its use is intended to facilitate the early identification of symptoms suggestive of a respiratory exacerbation, and allow the CF team to initiate treatment sooner, thereby potentially reducing the risk of severe exacerbations which require intravenous antibiotics (IVAB) and often a hospital admission.

Methods

We will undertake a randomised controlled trial. 60 adults with CF will be recruited and randomised to either the intervention or control group. The intervention group will use the smartphone application weekly for 12 months, or earlier than the next weekly reporting time if they feel their symptoms have worsened. The control group will continue to receive usual care, involving regular (approximately 3 monthly) CF outpatient clinic appointments. The primary outcome measure will be courses and days of IVAB.

Ethics and dissemination

Approval was obtained from the Sir Charles Gairdner Group Human Research Ethics Committee for WA Health (2015-030) and Curtin University Human Research Ethics Committee (HR212/2015), and has been registered with the Australian and New Zealand Clinical Trials Registry. Results of this study will be presented at international conferences and published in peer-reviewed journals in accordance with the Consolidated Standards of Reporting Trials statement.

Trial registration number

ACTRN12615000599572.

https://ift.tt/2qPScUR

Association of seasonal viral acute respiratory infection with pneumococcal disease: a systematic review of population-based studies

Objective

Animal and in vitro studies suggest that viral acute respiratory infection (VARI) can predispose to pneumococcal infection. These findings suggest that the prevention of VARI can yield additional benefits for the control of pneumococcal disease (PD). In population-based studies, however, the evidence is not in accordance, possibly due to a variety of methodological challenges and problems in these studies. We aimed to summarise and critically review the methods and results from these studies in order to inform future studies.

Methods

We conducted a systematic review of population-based studies that analysed the association between preceding seasonal VARI and subsequent PD. We searched MEDLINE, Embase and Global Health databases using tailored search strategies.

Results

A total of 28 studies were included. After critically reviewing the methodologies and findings, 11 studies did not control for seasonal factors shared by VARI and PD. This, in turn, could lead to an overestimation of the association between the two illnesses. One case–control study was limited by its small sample size (n case=13). The remaining 16 studies that controlled for seasonal factors suggested that influenza and/or respiratory syncytial virus (RSV) infections were likely to be associated with the subsequent occurrence of PD (influenza: 12/14 studies; RSV: 4/5 studies). However, these 16 studies were unable to conduct individual patient data-based analyses. Nevertheless, these studies suggested the association between VARI and subsequent PD was related to additional factors such as virus type and subtype, age group, comorbidity status, presentation of PD and pneumococcal serotype.

Conclusions

Population-based studies do not give consistent support for an association between preceding seasonal VARI and subsequent PD incidence. The main methodological challenges of existing studies include the failure to use individual patient data, control for seasonal factors of VARI and PD, or include other factors related to the association (eg, virus, age, comorbidity and pneumococcal serotype).

http://bmjopen.bmj.com/cgi/content/short/8/4/e019743?rss=1

SPECT V/Q for the diagnosis of pulmonary embolism: protocol for a systematic review and meta-analysis of diagnostic accuracy and clinical outcome

Introduction

Single photon emission computed tomography ventilation/perfusion (SPECT V/Q) imaging has many proponents within the nuclear medicine community and has already largely replaced planar V/Q scintigraphy in daily practice for the diagnosis of pulmonary embolism (PE). However, the test is still described in clinical guidelines as an experimental test because of insufficient evidence.

Methods and analysis

We will conduct a systematic review and a meta-analysis of diagnostic accuracy and management outcome studies involving patients evaluated with V/Q SPECT for suspected acute PE. We will search from inception to 19 December 2017 MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for diagnostic accuracy studies, randomised controlled trials and observational cohort studies. Two reviewers will conduct all screening and data collection independently. The methodological quality and risk of bias of eligible studies will be carefully and rigorously assessed using the Quality Assessment of Diagnostic Accuracy Studies-2, the Cochrane Collaboration's tool and the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. The primary outcomes will be sensitivity, specificity and likelihood ratios of V/Q SPECT for the diagnosis of acute PE. The secondary outcomes will be the rate of venous thromboembolism during a 3-month follow-up period in patients left untreated after a negative diagnostic work-up based on SPECT V/Q.

Ethics and dissemination

This study of secondary data does not require ethics approval. It will be presented internationally and published in the peer-reviewed literature.

PROSPERO registration number

CRD42018084095.

https://ift.tt/2qQFG7x

Does the age of acute care physicians impact their (1) crisis management performance and (2) learning after simulation-based education? A protocol for a multicentre prospective cohort study in Toronto and Ottawa, Canada

Introduction

The proportion of older acute care physicians (ACPs) has been steadily increasing. Ageing is associated with physiological changes and prospective research investigating how such age-related physiological changes affect clinical performance, including crisis resource management (CRM) skills, is lacking. There is a gap in the literature on whether physician's age influences baseline CRM performance and also learning from simulation. We aim to investigate whether ageing is associated with baseline CRM skills of ACPs (emergency, critical care and anaesthesia) using simulated crisis scenarios and to assess whether ageing influences learning from simulation-based education.

Methods and analysis

This is a prospective cohort multicentre study recruiting ACPs from the Universities of Toronto and Ottawa, Canada. Each participant will manage an advanced cardiovascular life support crisis-simulated scenario (pretest) and then be debriefed on their CRM skills. They will then manage another simulated crisis scenario (immediate post-test). Three months after, participants will return to manage a third simulated crisis scenario (retention post-test). The relationship between biological age and chronological age will be assessed by measuring the participants CRM skills and their ability to learn from high-fidelity simulation.

Ethics and dissemination

This protocol was approved by Sunnybrook Health Sciences Centre Research Ethics Board (REB Number 140–2015) and the Ottawa Health Science Network Research Ethics Board (#20150173–01H). The results will be disseminated in a peer-reviewed journal and at scientific meetings.

Trial registration number

NCT02683447; Pre-results.

https://ift.tt/2HksqmI

Strengths and Difficulties Questionnaire: internal validity and reliability for New Zealand preschoolers

Objectives

This observational study examines the internal construct validity, internal consistency and cross-informant reliability of the Strengths and Difficulties Questionnaire (SDQ) in a New Zealand preschool population across four ethnicity strata (New Zealand European, Māori, Pasifika, Asian).

Design

Rasch analysis was employed to examine internal validity on a subsample of 1000 children. Internal consistency (n=29 075) and cross-informant reliability (n=17 006) were examined using correlations, intraclass correlation coefficients and Cronbach's alpha on the sample available for such analyses.

Setting and participants

Data were used from a national SDQ database provided by the funder, pertaining to New Zealand domiciled children aged 4 and 5 and scored by their parents and teachers.

Results

The five subscales do not fit the Rasch model (as indicated by the overall fit statistics), contain items that are biased (differential item functioning (DIF)) by key variables, suffer from a floor and ceiling effect and have unacceptable internal consistency. After dealing with DIF, the Total Difficulty scale does fit the Rasch model and has good internal consistency. Parent/teacher inter-rater reliability was unacceptably low for all subscales.

Conclusion

The five SDQ subscales are not valid and not suitable for use in their own right in New Zealand. We have provided a conversion table for the Total Difficulty scale, which takes account of bias by ethnic group. Clinicians should use this conversion table in order to reconcile DIF by culture in final scores. It is advisable to use both parents and teachers' feedback when considering children's needs for referral of further assessment. Future work should examine whether validity is impacted by different language versions used in the same country.

https://ift.tt/2qOiXct

Patient trajectories and their impact on mobility, social participation and quality of life in patients with vertigo/dizziness/balance disorders and osteoarthritis (MobilE-TRA): study protocol of an observational, practice-based cohort study

Introduction

Mobility limitations have a multitude of different negative consequences on elderly patients including decreasing opportunities for social participation, increasing the risk for morbidity and mortality. However, current healthcare has several shortcomings regarding mobility sustainment of older adults, namely a narrow focus on the underlying pathology, fragmentation of care across services and health professions and deficiencies in personalising care based on patients' needs and experiences. A tailored healthcare strategy targeted at mobility of older adults is still missing.

Objective

The objective is to develop multiprofessional care pathways targeted at mobility sustainment and social participation in patients with vertigo/dizziness/balance disorders (VDB) and osteoarthritis (OA) .

Methods

Data regarding quality of life, mobility limitation, pain, stiffness and physical function is collected in a longitudinal observational study between 2017 and 2019. General practitioners (GPs) recruit their patients with VDB or OA. Patients who visited their GP in the last quarter will be identified in the practice software based on VDB and OA-related International Classification of Diseases 10th Revision. Study material will be sent from the practice to patients by mail. Six months and 12 months after baseline, all patients will receive a mail directly from the study team containing the follow-up questionnaire. GPs fill out questionnaires regarding patient diagnostics, therapy and referrals.

Ethics and dissemination

The study was approved by the ethical committee of the Ludwig-Maximilians-Universität München and of the Technische Universität Dresden. Results will be published in scientific, peer-reviewed journals and at national and international conferences. Results will be disseminated via newsletters, the project website and a regional conference for representatives of local and national authorities.

https://ift.tt/2HinqiM

Impact of dexmedetomidine infusion during general anaesthesia on incidence of postoperative delirium in elderly patients after major non-cardiac surgery: study protocol of a randomised, double-blinded and placebo-controlled trial

Introduction

Delirium is a common complication in the elderly after surgery and is associated with worse outcomes. Multiple risk factors are related with postoperative delirium, such as exposure to general anaesthetics, pain and postoperative inflammatory response. Preclinical and clinical studies have shown that dexmedetomidine attenuated neurotoxicity induced by general anaesthetics, improved postoperative analgesia and inhibited inflammatory response after surgery. Several studies found that intraoperative use of dexmedetomidine can prevent postoperative delirium, but data were inconsistent. This study was designed to investigate the impact of dexmedetomidine administered during general anaesthesia in preventing delirium in the elderly after major non-cardiac surgery.

Methods and analysis

This is a randomised, double-blinded and placebo-controlled trial. 620 elderly patients (age ≥60 years) who are scheduled to undertake elective major non-cardiac surgery (with an expected duration ≥2 hours) are randomly divided into two groups. For patients in the dexmedetomidine group, a loading dose dexmedetomidine (0.6 µg/kg) will be administered 10 min before anaesthesia induction, followed by a continuous infusion at a rate of 0.5 µg/kg/hour until 1 hour before the end of surgery. For patients in the control group, normal saline will be administered with an identical rate as in the dexmedetomidine group. The primary endpoint is the incidence of delirium during the first five postoperative days. The secondary endpoints include pain intensity, cumulative opioid consumption and subjective sleep quality during the first three postoperative days, as well as the incidence of non-delirium complications and all-cause mortality within 30 days after surgery.

Ethics and dissemination

The study protocol was approved by the Clinical Research Ethics Committee of Peking University First Hospital (2015–987) and registered at Chinese Clinical Trial Registry (http://www.chictr.org.cn) with identifier ChiCTR-IPR-15007654. The results of the study will be presented at academic conferences and submitted to peer-reviewed journals.

Trial registration number

ChiCRR-IPR-15007654; Pre-results.

https://ift.tt/2qPDkpM

Body mass index, abdominal fatness, weight gain and the risk of psoriasis: a systematic review and dose–response meta-analysis of prospective studies

Abstract

Greater body mass index (BMI) has been associated with increased risk of psoriasis in case–control and cross-sectional studies, however, the evidence from prospective studies has been limited. We conducted a systematic review and dose–response meta-analysis of different adiposity measures and the risk of psoriasis to provide a more robust summary of the evidence based on data from prospective studies. PubMed and Embase databases were searched for relevant studies up to August 8th 2017. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model. The summary relative risk (RR) for a 5 unit increment in BMI was 1.19 (95% CI 1.10–1.28, I² = 83%, n = 7). The association appeared to be stronger at higher compared to lower levels of BMI, p_nonlinearity < 0.0001, and the lowest risk was observed at a BMI around 20. The summary RR was 1.24 (95% CI 1.17–1.31, I² = 0%, p_{heterogeneity} = 0.72, n = 3) per 10 cm increase in waist circumference, 1.37 (95% CI 1.23–1.53, I² = 0%, p_{heterogeneity} = 0.93, n = 3) per 0.1 unit increase in waist-to-hip ratio, and 1.11 (95% CI 1.07–1.16, I² = 47%, p_{heterogeneity} = 0.15, n = 3) per 5 kg of weight gain. Adiposity as measured by BMI, waist circumference, waist-to-hip ratio, and weight gain is associated with increased risk of psoriasis.

https://ift.tt/2Jeit7b

Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves’ disease

https://ift.tt/2Jd3slO

Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking

European Journal of Neuroscience, EarlyView.


https://ift.tt/2qNMRhU

Connecting the Dots

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2HP2blD

Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination

Abstract

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen—a marker for blood–brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.

https://ift.tt/2K2x72o

Connecting the Dots

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2HP2blD

Comparing Rock-inhabiting Microbial Communities in Different Rock Types from a High Arctic Polar Desert

Abstract

Although rocks are habitable places for microbes in extreme environments, microbial diversity in these lithic environments is still poorly understood. The diversity and abundance of rock-inhabiting microbial communities in different types of rock in Svalbard, Norwegian High Arctic were examined using NGS sequencing of bacterial 16S rRNA genes and fungal 28S rRNA genes. Compositions of both bacterial and fungal communities varied across different rock types: sandstone, limestone, basalt, granite, and travertine. Bacterial communities were dominated by Actinobacteria, Proteobacteria, Chloroflexi, Bacteroidetes, and Acidobacteria. Fungal communities consisted of Eurotiomycetes, Lecanoromycetes, Dothideomycetes, and Leotiomycetes. Both bacterial and fungal community compositions were significantly correlated with the geochemical characteristics of rocks. Bacterial communities were considerably correlated with the rock elements such as Mg and Ca. Fungal communities were considerably correlated with Fe. Interestingly, many dominant bacterial and fungal operational taxonomic units (OTUs) in the investigated rocks from the study area were closely affiliated to those found in other cold regions such as Alpine area, Arctic and Antarctica, suggesting that environmental constraints such as cold temperature may lead to convergence in microbial community composition. These results confirm that rocks in cold environments act as reservoirs of diverse bacteria and fungi, which may improve our understanding of lithic microbial ecology in the cold desert.

https://ift.tt/2HEXLA8

Anaerobic carbon monoxide metabolism by Pleomorphomonas carboxyditropha sp. nov., a new mesophilic hydrogenogenic carboxydotroph

Abstract

CO-metabolism and phenotypic and phylogenetic characterization of a novel anaerobic, mesophilic, and hydrogenogenic carboxydotroph are reported. Strain SVCO-16 was isolated from anaerobic sludge and grows autotrophically and mixotrophically with CO. The genes cooS and cooF, coding for a CO dehydrogenase complex, and genes similar to hycE2, encoding a CO-induced hydrogenase, were present in its genome. The isolate produces H₂ and CO₂ from CO, and acetate and formate from organic substrates. Based on the 16S rRNA sequence, it is an Alphaproteobacterium most closely related to the genus Pleomorphomonas (98.9–99.2% sequence identity). Comparison with other previously characterized Pleomorphomonas showed that P. diazotrophica and P. oryzae do not metabolize CO, and P. diazotrophica does not grow anaerobically with organic substrates. Average nucleotide identity values between strain SVCO-16 and P. diazotrophica, P. oryzae, or P. koreensis were 86.66 ± 0.21%. These values are below the boundary to define species (95–96%). Digital DNA-DNA hybridization estimates between strain SVCO-16 and reference strains were also below the 70% threshold for species delineation: 29.1%–34.5%. Based on the differences in CO metabolism, genome analyses, and cellular fatty acid composition, the isolate should be classified in the genus Pleomorphomonas as a representative of a novel species, Pleomorphomonas carboxyditropha. The type strain of Pleomorphomonas carboxyditropha is SVCO-16^T (strain deposit numbers, DSM 106132^T and TSD-119^T).

https://ift.tt/2JfEJ0p

Clinical Significance of Incidental Prostatic Carcinoma on Radical Cystectomy Histology Specimens: a Clinicopathological and Survival Analysis

Abstract

Incidental prostatic carcinoma on radical cystectomy histology specimens is not an uncommon entity and managing such cases is still controversial. Classification into clinically significant and insignificant cancers by Epstein based on the assumption that one is more likely to affect the survival than the other is not universally accepted. We conducted this retrospective analysis with the aim to find out the role of dichotomization of incidental prostatic cancer into such classification. Patient's data were retrospectively reviewed from January 2013 to December 2014. A total of 175 patients underwent radical cystectomy during the study duration and amongst them, 38 specimens showed incidental prostatic cancer. Their data pertaining to demographic profile, clinicopathological details, treatment received, complications and follow-up data was recorded. On comparative analysis, the disease-free survival in csPCa (clinically significant prostatic cancer) group was 60.82% and cisPCa (clinically insignificant prostatic cancer) 62.68% at 2.3 years (p 0.566), while OS was 55.68% for csPCa and 87.5% for cisPCa respectively (p 0.814). The mean duration to recurrence was also comparable (19.4 months csPCa and 17 months cisPCa). None of the patients developed PSA elevation on follow-up and none of the recurrence or death were attributed to prostatic cancer. The stage of bladder cancer was the only factor, which had a significant impact on overall survival. The distinction between clinically significant and insignificant is not relevant according to our analysis.

https://ift.tt/2HmbM20

CRISPR-Cas9 enabled targeted mutagenesis in the thermotolerant methylotrophic yeast Ogataea thermomethanolica

Abstract

Ogataea thermomethanolica TBRC656 is a thermotolerant methylotrophic yeast suitable for heterologous protein expression at various temperatures. However, the lack of efficient methods for targeted gene mutagenesis limits strain engineering in this yeast. In this study, we applied a CRISPR-Cas9 based-tool for targeted gene mutagenesis in O. thermomethanolica. The putative unfolded protein response (UPR) regulator OtHAC1, and the OtMAL1 (maltase) and OtMAL2 (maltose permease) genes involved with sucrose and maltose utilization were targeted for CRISPR-Cas9 mutagenesis. Plasmids were constructed for integrative and episomal expression of CRISPR-Cas9 elements in O. thermomethanolica in which Cas9 and gRNA are transcribed from the alcohol oxidase (AOX) promoter. The expression of these genome editing elements is controlled by derepression with glycerol and gRNA are flanked by self-cleaving ribozymes. For integrative system, OtHAC1, OtMAL1, and OtMAL2 were disrupted at 63%, 97%, and 93%, respectively. In addition, OtMAL1 was also disrupted with episomal system at 92%. These finding indicate that the CRISPR-Cas9 system described herein are thus applicable for studying gene function and strain engineering in yeast O. thermomethanolica.

https://ift.tt/2JZ5hEl

Identification of a contact-dependent growth inhibition system in the probiotic Escherichia coli Nissle 1917

Abstract

Contact-dependent growth inhibition (CDI) is a type of competitive mechanisms, and has been identified in various strains including Burkholderia, Dickeya, E. coli, and Yersinia. Classical CDI systems contain three genes, cdiB, cdiA and cdiI. CdiB encoded by cdiB gene is a conserved β-barrel protein and required for export of CdiA. CdiA protein encoded by cdiA gene includes a conserved N-terminal domain, and variable C-terminal toxic domain (CdiA-CT). Immunity protein CdiI binds and inactivates toxin protein CdiA-CT. Here we identified two CDI systems, an intact cdiBAI operon with a truncated CdiB due to an unexpected mutation, and an 'orphan' cdiA-CT/cdiI module in the probiotic Escherichia coli Nissle 1917 (EcN) genome. Both CdiA-CTs from EcN showed auto-inhibition activity when transferring into E. coli DH5α, as well the sequential deletion of amino acid residues resulted in generation of the most potent mutant of CdiA-CT. CdiI neutralized the toxicity activity of CdiA and was immunity protein as previous report. In conclusion, this is the first report that functional CDI system is in probiotic EcN and might provide a potential competitive mechanism for probiotic EcN in intestinal microenvironment.

https://ift.tt/2JdtghE

YidC-mediated Membrane Insertion

Abstract

The most simple membrane protein insertion catalyst known so far is the universal YidC/Oxa/Alb insertase that is composed of a single multi-spanning protein present in archaea, bacteria and in eukaryotic organelles. In bacteria, YidC is known to integrate small membrane proteins on its own and more complex proteins in conjunction with the SecYEG translocase. In mitochondria, the YidC homologue Oxa is responsible for the insertion of all membrane proteins synthesized in the matrix since no Sec homologues are present in the mitochondrial inner membrane. This is tantamount to the observation that YidC is able to operate also independently of SecYEG in bacteria. Reconstituted into liposomes, YidC rapidly and efficiently binds to substrate proteins and leads to their integration into the bilayer. Additionally, single molecule force spectroscopy experiments show that YidC binds to unfolded membrane proteins and promotes their folding into the membrane bilayer. To achieve membrane insertion and the correct folding, the periplasmic regions of the substrate have to cross the membrane with the help of YidC by a mechanism that is presently explored.

https://ift.tt/2JZu6zP

A town on fire! Integrating 16S rRNA gene amplicon analyses into an undergraduate microbiology lecture class

Abstract

Microbiology increasingly relies upon bioinformatics to understand complex microbial interactions. Nevertheless, biology undergraduates often lack the basic quantitative and computer-based skills required for bioinformatics analyses. To address these issues, the course module 'A Town on Fire! 16S rRNA Gene Amplicon Analysis of Microbial Communities Overlying the Centralia, PA Mine Fire' was developed for an undergraduate microbiology lecture course. In this module, microbiology students used Quantitative Insights into Microbial Ecology (QIIME) to perform taxonomic, phylogenetic and statistical analyses on bacterial communities from three hot mine fire-impacted surface soils using 16S rRNA gene amplicon sequences. Pre- and post-module assessment data for each of two years was compiled, and indirect assessment indicated that students' confidence regarding their ability to perform bioinformatics analyses, as well as their ability to interpret bioinformatics data both increased, as did their enthusiasm for bioinformatics. Direct assessment demonstrated that students' understanding of topics that they actually used in the module, such as the statistical analyses that underlie bioinformatics investigations and the ability to infer phylogenetic relationships, improved during the module, but that their underlying understanding of techniques that they did not directly perform, such as sequencing and library construction, did not.

https://ift.tt/2F4ti9r

Cancers, Vol. 10, Pages 126: Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

Cancers, Vol. 10, Pages 126: Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

Cancers doi: 10.3390/cancers10040126

Authors: Christophe Deben Vanessa Deschoolmeester Jorrit De Waele Julie Jacobs Jolien Van den Bossche An Wouters Marc Peeters Christian Rolfo Evelien Smits Filip Lardon Patrick Pauwels

The compound APR-246 (PRIMA-1MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1&alpha; (HIF-1&alpha;) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1&alpha; protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1&alpha;-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

https://ift.tt/2qQz1KR