Cancers, Vol. 10, Pages 21: IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Cancers, Vol. 10, Pages 21: IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Cancers doi: 10.3390/cancers10010021

Authors: Cecilia Bandini Aldi Pupuleku Elisa Spaccarotella Elisa Pellegrino Rui Wang Nicoletta Vitale Carlotta Duval Daniela Cantarella Andrea Rinaldi Paolo Provero Ferdinando Di Cunto Enzo Medico Francesco Bertoni Giorgio Inghirami Roberto Piva

Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin's lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.

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Association of conformality index and post-treatment radiation pneumonitis in early-stage non-small cell lung cancer treated with stereotactic body radiotherapy

Abstract

Purpose

Conformality index of the 50% prescription isodose volume (CI50) is an important variable in lung stereotactic body radiotherapy (SBRT) planning but has not been previously correlated to radiation pneumonitis (RP). We hypothesized that adherence to recommended CI50 for patients undergoing lung SBRT would result in decreased incidence and/or severity of RP compared to that for patients with minimal deviations and unacceptable deviations.

Methods and materials

We retrospectively identified patients treated between 2006 and 2016, with > 3 months follow up from lung SBRT treatment. CTCAE v4.0 toxicity grades were used to classify RP. Clinically significant RP was defined as grade ≥ 2 toxicity. Using Radiation Therapy Oncology Group CI50 planning guidelines, patients were separated into three groups: acceptable, minor deviation, and unacceptable deviation. CI25 and CI75 values in patients with and without clinically significant RP were also reported in this study.

Results

One hundred seventy-four patients with a median follow-up time of 26.8 months were included in this analysis. Overall incidence of grade ≥ 2 RP was 12.7%. Thirty-eight (21.8%) patients had acceptable CI50, 100 (57.5%) had minor deviations, and 36 (20.7%) had unacceptable deviations. Incidence of RP did not significantly differ between patients with acceptable, minor deviation, and unacceptable CI50. Additionally, CI25 and CI75 did not significantly differ between patients with and without clinically significant RP.

Conclusions

Adhering to recommended CI50 values does not significantly decrease the incidence of clinically significant RP in patients with NSCLC treated with SBRT. To the authors' knowledge, this observation has not been published previously.

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Issue Information

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Issue Information

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Defining limited stage small cell lung cancer: a radiation oncologists perspective

Description

Small cell lung cancer (SCLC) comprises 13%–15% of all diagnosed lung carcinomas and approximately 30% of those will be defined as limited stage-SCLC (LS-SCLC).1 The definition of LS-SCLC has undergone many modifications and there is no universally accepted definition till date (figure 1).2 It was first defined by the Veteran Affairs Lung cancer study Group (VALG) in 1973 and further redefined by the International Association for the Study of Lung Cancer (IASLC) and American Joint Committee on Cancer (AJCC) in 1989 and 2010, respectively.1 2 Considerable heterogeneity exists pertaining to which definition is used for treating patients in routine practice. As a direct consequence of this, discussions often arise in multidisciplinary tumour board meetings in which different oncologists classify the same patient differently. The subsequent images demonstrate the heterogeneity in subjective classification of patients with SCLC and the role of radiotherapy (RT) in...

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Sarcomatoid carcinoma of the duodenum

Description

A 69-year-old Caucasian man presented to the gastroenterology clinic with complaints of nausea, abdominal pain and more than 100-pound unintentional weight loss over the past 1 year. He had a history of colon polyps and was overdue for surveillance colonoscopy. He was subsequently scheduled for an outpatient oesophagogastroduodenoscopy (EGD) and colonoscopy as initial work-up for his symptoms. One week later, the patient underwent endoscopy. EGD showed an ulcerated mass in the second portion of the duodenum (figure 1). Biopsy of the lesion showed features of pleomorphic cells without glandular differentiation (figures 2 and 3). Immunohistochemical studies revealed pleomorphic cells positive for cytokeratin AE1/AE3 (figure 4), CAM 5.2 and vimentin (figure 5), focally positive for CK7 (figure 6), and weakly for CK20. They were negative for neuroendocrine markers chromogranin, synaptophysin, and CD45 which is a lymphoid marker. Additional...

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Morbid jealousy reactivated by mood episodes

A middle-aged man who has been enduring financial constraint experienced a period of irritability, increased goal-directed activities and insomnia occurring along with extreme jealousy with his current wife. The episode was followed by depressed mood and non-prominent auditory hallucination. His previous history revealed a forensic psychiatry case of a murder he committed 20 years ago.

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Bruns nystagmus: an important clinical clue for cerebellopontine angle tumours

Description

A 24-year-old woman presented with gradual-onset left-sided hearing loss, progressive diminution of vision, headache and unsteadiness of gait. Comprehensive clinical evaluation revealed a left-sided lower motor neuron type of facial nerve palsy (figure 1), bilateral papilloedema, sensory loss in the distribution of ophthalmic branch of the left trigeminal nerve and cerebellar ataxia. Sensorineural hearing loss and absent corneal reflex were also observed on the left side. A coarse, left-beating nystagmus with leftward gaze and a fine primary-position right-beating nystagmus which increased on rightward gaze, consistent with Bruns nystagmus (video 1), were appreciated. In view of the clinical findings, a diagnosis of a space-occupying lesion involving the left cerebellopontine angle was considered. MRI of the brain documented a space-occupying lesion (4x3.5 cm) in the left cerebellopontine angle, most likely a vestibular schwannoma (figures 2 and 3). The condition was explained to...

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An unusual case of basilar artery aneurysm presenting with spastic quadriparesis

Unruptured aneurysm usually presents with headache and neuro-ophthalmic features; when it ruptures, it presents with subarachnoid haemorrhage. Basilar artery aneurysm represents only 3–5% of cerebral aneurysms. Non-haemorrhagic symptoms and the signs of unruptured aneurysms are manifested as mass effect, thromboembolic phenomenon or epileptical attacks. Clinical presentation of unruptured aneurysm depends on structures which are involved. In our case, the patient had insidious onset headache and spastic quadriparesis with sixth cranial nerve palsy, which implicate involvement of corticospinal pathways at the level of pons.

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Urinary Bladder Mass Due To Chronic Lymphocytic Leukaemia

Description

A 66-year-old man was diagnosed with chronic lymphocytic leukaemia (CLL) in November 2014. At diagnosis, his lymphocyte count was 169.66x10⁹/L (table 1). The fluorescent in situ hybridisation (FISH) panel revealed 13q deletion, but there was no evidence of 17p deletion, 11q deletion or t (11;14). He then received four cycles of bendamustine and rituximab, and at the end of the treatment complete blood count showed a lymphocyte count of 1.01x10⁹/L (table 1), and an interval bone marrow biopsy showed only small lymphoid aggregate suggestive of partial response.1 In June 2017, his lymphocyte count was found to be elevated at 14.5x10⁹/L (table 1). An immunophenotypic analysis of the peripheral blood demonstrated approximately 78% lymphocytes and 0.5% mature CD14-positive monocytes. A predominant monoclonal B cell population was identified, comprising approximately 85% of lymphocytes and 67% of the processed specimen. It was...

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Budd-Chiari syndrome: a rare and life-threatening complication of Crohns disease

Budd-Chiari syndrome (BCS) is characterised by obstruction of hepatic venous outflow and may be triggered by the prothrombotic state associated with inflammatory bowel disease (IBD). We reported a case of Crohn's disease (CD) that presented with anasarca, ascites, symptomatic hepatomegaly, elevated liver enzymes, increased prothrombin time and low albumin. Oesophagogastroduodenoscopy and colonoscopy confirmed active CD. Abdominal CT showed hepatic vein thrombosis. Liver biopsy revealed severe perivenular sinusoidal dilation with areas of hepatocyte dropout, bands of hepatocyte atrophy and centrizonal fibrosis, suggestive of BCS. The patient was treated with steroids for CD and systemic anticoagulants for BCS. His liver function and enzymes normalised, and he reported symptomatic improvement. The precise mechanism responsible for increased hypercoagulability in IBD remains unclear. Early recognition and treatment for possible thrombotic complications of CD is critical to prevent potentially fatal events like pulmonary embolism or liver failure.

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Recurrent hiccups may signal brainstem pathology and should be investigated

While occasional hiccups are normal, their persistent recurrence is distressing and may have an underlying aetiology. Patients with recurrent hiccups may undergo a long journey and see many physicians before the diagnosis is finally made. The purpose of this report is to increase awareness of central nervous system lesions as a possible cause for recurrent hiccups and provide an illustrative case of an otherwise fit man presenting with ongoing hiccups caused by a medullary haemangioblastoma.

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Vancomycin-induced coronary artery spasm: a case of Kounis syndrome

Kounis syndrome defined as the appearance of acute coronary syndrome in the context of an allergic reaction is a relatively rare phenomenon. There are three variants of this syndrome in which the patient presents with symptoms of an acute chest. Herein, we describe a case of an 83-year-old woman who demonstrated type I variant of Kounis syndrome in response to vancomycin administration. After initialisation of vancomycin, she became unresponsive and an ECG demonstrated ST changes consistent with inferior-lateral myocardial infarction. Once allergic stimulus was removed, ECG normalised. Differential diagnosis includes, myocardial infarctions, angina as well as intravascular stent thrombosis, which must all be ruled out. The patient was monitored and discharged soon thereafter.

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Early intrauterine pregnancy during major surgery: the importance of preoperative assessment and advice

We present a case of a live birth occurring post radical laparoscopic excision of endometriosis, hysteroscopy, curettage and test of tubal patency in the presence of an early intrauterine gestation.

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Acquired pyloric stenosis resulting in hypokalaemic, hyperchloraemic normal anion gap metabolic acidosis. Persistent vomiting in an adult: cause and effect

A 24-year-old woman presented with a history of persistent vomiting for at least 3 months. This resulted in severe dehydration with risk of acute kidney injury. In addition to volume depletion, loss of gastric fluid resulted in a specific metabolic derangement—hypokalaemic, hypochloraemic normal anion gap metabolic alkalosis with a reduced ionised calcium concentration and paradoxical aciduria. These metabolic changes were reflected in her ECG. Investigation demonstrated acquired gastric outflow tract obstruction secondary to a pyloric peptic ulcer. The patient was resuscitated with intravenous crystalloid and electrolyte supplements. The acquired pyloric stenosis was treated medically with a proton pump inhibitor and Helicobacter pylori eradication therapy with excellent recovery.

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Marked cachexia in probable invasive pulmonary aspergillosis with bronchopleural fistula

A 49-year-old man with a medical history of diabetes and heavy smoking was admitted to intensive care with severe bilateral pneumonia associated with marked cachexia. He developed a complex right-sided bronchopleural fistula and was transferred to our tertiary centre for consideration of surgical intervention.

Despite escalation of antibiotic therapy, he did not improve and further investigations led to a diagnosis of invasive pulmonary aspergillosis. Definitive treatment plans required a right pneumonectomy; however, given the severity of cachexia, he remained unable to undergo such a large operation. This case demonstrates an atypical presentation of invasive pulmonary aspergillosis in a mildly immunodeficient individual. It highlights the challenges in assessment and management of critically ill patients' nutrition as well as optimal timing for surgical intervention.

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Portal vein embolisation in a patient with situs inversus

Portal vein embolisation (PVE) is a well-established technique used for patients who require major hepatic resections without sufficient volume of future remnant liver (FRL). We describe a case of PVE in a patient with situs inversus. Computed Tomography (CT) 4 weeks after the procedure demonstrated significant hypertrophy of the FRL. However, the surgical procedure was aborted due to signs of extrahepatic progression.

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'Clinically suspected myocarditis with pseudoinfarct presentation complicated with left ventricular aneurysm

A 51-year-old man presented with chest pain, high troponin level, inflammatory syndrome and ST-segment elevation in the anterior leads. While the transthoracic echocardiogram (TTE) showed anteroseptal hypokinesis and apical akinesis, the coronary angiogram was normal. Cardiac MR demonstrated a typical aspect of myocarditis (multiple areas of mid-myocardial late gadolinium enhancement, sparing the subendocardial layer, along with oedema). The initial diagnosis was clinically suspected myocarditis with pseudoinfarct presentation. However, the short-term evolution was not typical of this syndrome, since an apical transmural scar with aneurysm developed within 2 weeks. Seven years later, the patient remained asymptomatic, while Q waves persisted in anterior leads along with an apical aneurysm on TTE. A transmural myocardial necrosis with aneurysm is an unusual complication of acute myocarditis. The potential mechanisms accounting for the development of these lesions are reviewed, and the clinical implications for the diagnosis and monitoring of acute myocarditis are discussed.

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A ping-pong ball in left atrium

Description

Rheumatic heart disease (RHD) is much prevalent in low/middle-income  country like India with the prevalence ranging from 0.2 to 1.1/1000 for RHD and from 0.0007 to 0.2/1000 for rheumatic fever.1 Factors that precipitate the formation of clot are atrial fibrillation (AF) rhythm, left atrial (LA) size, duration of symptoms, advanced age and severity of mitral stenosis (MS).2 The prevalence of LA clot in patients with MS is 26% in the AF group and 13.5% in the normal sinus rhythm group.3 The risk of thromboembolism is 9–14% of patients suffering from RHD.4 5 Anticoagulation (vitamin K antagonist or heparin) is indicated in patients with MS with (1) AF (paroxysmal, persistent or permanent) or (2) prior embolic event or (3) a LA thrombus.6

We present a case of a 30-year-old man, a known case of RHD who had balloon mitral valvotomy (BMV) 10 years...

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Chronic strongyloidiasis with recurrent asthma exacerbations and steroid-associated 'hives

A 74-year-old man experienced worsening asthma for several years. Oral steroids were required on multiple occasions for asthma treatment. During his steroid courses, he developed a hive-like rash, which would resolve after completion of each steroid course. He was from Romania, and had lived in the USA for many years. Laboratory testing had shown eosinophilia. He was eventually diagnosed with strongyloidiasis by serology. Treatment with ivermectin led to marked improvement but not resolution of his long-term asthma. His hive-like rash, which was likely larva currens, did not recur with a subsequent steroid course. Improved recognition of strongyloidiasis, particularly in steroid-treated patients, is needed.

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Laryngeal tuberculosis: a rare cause of critical airway obstruction

Laryngeal tuberculosis (TB) is a rare condition, occurring in less than 1% of patients infected with pulmonary TB. We present a case of a 57-year-old male patient, who presented in extremis with audible stridor, increased work of breathing and cyanosis. In addition, the patient had a complex medical history, including a recent diagnosis of congenital malformation of the epiglottis. Emergency intervention was required to secure the airway, and after initial attempts at intubation were unsuccessful, an emergency tracheostomy was performed. Four days after initial presentation, his sputum tested positive for acid-fast bacilli, and a subsequent CT chest revealed pulmonary as well as laryngeal TB, which was confirmed on biopsy of the larynx. The patient was commenced on a 24-week course of anti-tuberculous treatment and was successfully decannulated 6 months after the emergency airway was established.

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Unusual 'feathery cause of a parapharyngeal abscess in an infant

A 7-month-old boy presented to the emergency department with reduced oral intake, neck swelling and fever. Clinical examination revealed a 3 cm left parotid and left level I neck swelling with left medialised tonsil but no trismus. Computed imaging confirmed the presence of an abscess in the peritonsillar area with extension into the parapharyngeal space and deep lobe of the parotid gland. The abscess was incised and drained transorally. Following drainage of the abscess, a small 3 mm suspicious foreign body was seen. After extraction, this was revealed to be a 60 mm feather. We would like to highlight this unusual case in an infant and to ensure that foreign body is considered as aetiology. There are only a handful of cases in the literature involving feathers causing neck abscesses and, to our knowledge, this is the first case where the patient presented with a pharyngeal abscess, which was drained transorally.

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Microangiopathies in pregnancy

Thrombotic thrombocytopenic purpura (TTP) is a potentially reversible, life-threatening medical emergency. We present a case of a 21-year-old female with evidence of haemolytic anaemia based on the presence of positive markers of haemolysis. Negative Coomb's test, thrombocytopenia and placental infarcts raised suspicion for a thrombotic microangiopathy. She was diagnosed with TTP and managed with emergency plasma exchange. Her recovery was immediate.

A presumptive diagnosis of TTP should be based on the presence of microangiopathic haemolytic anaemia with thrombocytopenia and plasma exchange should be initiated while complete work up is pending. Using the regular pentad solely for diagnosis of TTP will lead to underdiagnosis of many cases and should be avoided.

Several microangiopathies can be seen during pregnancy including TTP/atypical haemolytic uraemic syndrome, HELLP syndrome, pre-eclampsia, disseminated intravascular coagulopathy and antiphospholipid antibody syndrome. Distinction between each type will be the focus of our discussion as treatment decisions differ accordingly.

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Sinogenic intracranial complications: is adalimumab a culprit?

We present two 11-year-old girls with chronic recurrent multifocal osteomyelitis, treated with adalimumab. Both developed severe intracranial complications to sinusitis. Patient 1 had been treated with adalimumab for 15 months when she developed acute sinusitis complicated by an orbital abscess, forehead swelling, a subdural empyema and osteomyelitis of the frontal bone. She was treated with a rhinosurgical and neurosurgical approach with intravenous antibiotics.Patient 2 had been in adalimumab treatment for 10 weeks. Adalimumab was discontinued 8 weeks prior to developing subdural empyema and subcortical abscesses in combination with sinusitis. She was treated with endoscopic sinus surgery and intravenous antibiotics. Both patients had developed psoriasis and episodes of infection during treatment. They were non-septic and had low fever on presentation. None of the patients suffered any long-term neurological sequelae. The immunosuppressive treatment with adalimumab is considered to be the cause of the sinogenic intracranial complications in our cases.

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Significance of combined preoperative serum Alb and dNLR for diagnosis of pancreatic cancer

Future Oncology, Ahead of Print.


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Progressive topological disorganization of brain network in focal epilepsy

Objective

Increasing evidence has suggested that epilepsy is a network disease. Graph theory is a mathematical tool that allows for the analysis and quantification of the brain network. We aimed to evaluate the influences of duration of epilepsy on the topological organization of brain network in focal epilepsy patients with normal MRI using the graph theoretical analysis based on diffusion tenor imaging.

Methods

We prospectively enrolled 66 patients with focal epilepsy (18/66 patients were newly diagnosed) and 84 healthy subjects. All of the patients with epilepsy had normal MRI on visual inspection. All of the subjects underwent diffusion tensor imaging that was analyzed using graph theory to obtain network measures.

Results

The measures of characteristic path length and small-worldness in the patients with focal epilepsy were significantly decreased, even after multiple corrections (P < .01). Moreover, the measures including mean clustering coefficient and global efficiency in the patients with epilepsy had strong tendency to decrease compared to those in healthy subjects (P = .0153 and P = .0138, respectively). When comparing the measures among the patients with newly diagnosed/chronic epilepsy and healthy subjects using ANOVA, the characteristic path length (P = .006), small-worldness (P = .032), and global efficiency (P = .004) were significantly different. In addition, the duration of epilepsy was negatively correlated with global efficiency (r = −.249, P = .0454).

Conclusions

We newly found a progressive topological disorganization of the brain network in focal epilepsy. In addition, we demonstrated disrupted topological organization in focal epilepsy, shifting toward a more random state.

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Ticagrelor for Secondary Prevention of Atherothrombotic Events After Myocardial Infarction: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Abstract

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique^®), to submit evidence on the clinical and cost effectiveness of ticagrelor 60 mg twice daily (BID) in combination with low-dose aspirin [acetylsalicylic acid (ASA)] compared with ASA only for secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (MI) and who are at increased risk of atherothrombotic events. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Centre+, was commissioned as the evidence review group (ERG). This paper summarises the company submission (CS), the ERG report and the NICE guidance produced by the appraisal committee (AC) for the use of ticagrelor in England and Wales. The ERG critically reviewed the clinical- and cost-effectiveness evidence in the CS. The systematic review conducted as part of the CS identified one randomised controlled trial (RCT), PEGASUS-TIMI 54. This trial reported the time to first occurrence of any event from the composite of cardiovascular death, MI and stroke as the primary outcome (hazard ratio 0.84 ticagrelor 60 mg BID vs. placebo, 95% confidence interval 0.74–0.95). The population addressed in the CS was a subgroup of the PEGASUS-TIMI 54 trial population, i.e. the 'base-case' population, which comprised patients who had experienced an MI between 1 and 2 years ago, whereas the full trial population included patients who had experienced an MI between 1 and 3 years ago. While the ERG believed the findings of this RCT to be robust, doubts concerning the applicability of the trial to UK patients were raised. The company submitted an individual patient simulation model to estimate the cost-effectiveness of ticagrelor 60 mg BID + ASA versus ASA only. Parametric time-to-event models were used to estimate the time to first and subsequent (cardiovascular) events, time to treatment discontinuation and time to adverse events. The company's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £20,098 per quality-adjusted life-year (QALY) gained. The main issues surrounding the cost effectiveness of ticagrelor 60 mg BID + ASA were the use of parametric time-to-event models estimated based on the full trial population instead of being fitted to the 'label' population (the 'label' population comprised the 'base-case' population and patients who started ticagrelor 60 mg BID within 1 year of previous adenosine diphosphate inhibitor treatment), the incorrect implementation of the probabilistic sensitivity analysis (PSA) of the individual patient simulation, and simplifications of the model structure that may have biased the health benefits and costs estimations of the intervention and comparator. The ERG believed the use of the full trial population to inform the parametric time-to-event models was not appropriate because the 'label' population was the main focus of the scope and CS. The ERG could not investigate the magnitude of the bias introduced by this assumption. The PSA of the individual patient simulation provided unreliable probabilistic results and underestimated the uncertainty surrounding the results because it was based on a single patient. The ERG used the cohort simulation presented in the cost-effectiveness model to perform its base-case and additional analyses and to obtain probabilistic results. The ERG amended the company cost-effectiveness model, which resulted in an ERG base-case ICER of £24,711 per QALY gained. In its final guidance, the AC recommended treatment with ticagrelor 60 mg BID + low-dose ASA for secondary prevention of atherothrombotic events in adults who have had an MI and are at increased risk of atherothrombotic events.

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Letter to the Editor

Volume 34, Issue 4, October 2017, Page 157-157
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Response to Klorer's Letter to the Editor (Hamrick and Byma)

Volume 34, Issue 4, October 2017, Page 158-158
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Response to Klorer's Letter to the Editor (Talwar)

Volume 34, Issue 4, October 2017, Page 158-158
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What Do Structural Racism and Oppression Have to Do With Scholarship, Research, and Practice in Art Therapy?

Volume 34, Issue 4, October 2017, Page 154-156
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Cytotoxic T lymphocytes from cattle sharing the same MHC class I haplotype and immunized with live Theileria parva sporozoites differ in antigenic specificity

The objective of this study was to assess whether cytotoxic T cells (CTL) generated by the live vaccine, known as "ITM Muguga cocktail", which is used for the cattle disease East Cost fever (ECF) in Sub-Sahara...

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Association between sickle cell and β-thalassemia genes and hemoglobin concentration and anemia in children and non-pregnant women in Sierra Leone: ancillary analysis of data from Sierra Leone’s 2013 National Micronutrient Survey

By measuring the associations between the presence of sickle cell and β-thalassemia genes, we assessed the extent to which these hemoglobinopathies contribute to the high prevalence of anemia observed in presc...

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Lipoblastoma: a clinicopathologic review of 23 cases from a major tertiary care center plus detailed review of literature

Lipoblastoma is a rare neoplasm that occurs mostly in infants and children. Although benign, it has a tendency for local recurrence.

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Uncovering Genomic Regions Associated with Trypanosoma Infections in Wild Populations of the Tsetse Fly Glossina fuscipes

Vector-borne diseases are responsible for more than one million deaths every year but genomic resources for most species responsible for their transmission are limited. This is true for neglected diseases such as sleeping sickness (Human African Trypanosomiasis), a disease caused by Trypanosoma parasites vectored by several species of tseste flies within the genus Glossina.  We describe an integrative approach that identifies statistical associations between trypanosome infection status of Glossina fuscipes fuscipes (Gff) flies from Uganda, for which functional studies are complicated because the species cannot be easily maintained in laboratory colonies, and ~73,000 polymorphic sites distributed across the genome. Then, we identify candidate genes involved in Gff trypanosome susceptibility by taking advantage of genomic resources from a closely related species, Glossina morsitans (Gmm). We compiled a comprehensive transcript library from 72 published and unpublished RNAseq experiments of trypanosome infected and uninfected Gmm flies and improved the current Gmm transcriptome assembly. This new assembly was then used to enhance the functional annotations on the  Gff genome. As a consequence, we identified 56 candidate genes in the vicinity of the 18 regions associated with Trypanosoma infection status in Gff. Twenty-nine  of these genes were differentially expressed among parasite-infected and uninfected Gmm, suggesting that their orthologs in Gff may correlate with disease transmission. These genes were involved in DNA regulation, neurophysiological functions, and immune responses. We highlight the power of integrating population and functional genomics from related species to enhance our understanding of the genetic basis of physiological traits, particularly in non-model organisms.

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Effects of temperature, pH, and bile salt on antimicrobial activity of bacteriocin-like substances obtained from barley sourdough LAB

Abstract

This study aimed to investigate the effects of temperature (4, 85, 121 °C), pH (2, 4, 11), and bile salt (0.3, 0.6, 1%)—as common conditions of gastrointestinal tract or thermal food processing—on antimicrobial activity of bacteriocin-like substances (BLS) obtained from barley sourdough lactic acid bacteria (LAB) against some of food-borne pathogens. In addition, the safety of LAB isolates was also evaluated. The isolates were identified by sequencing of PCR products as Lactobacillus brevis, Lactobacillus curieae, Pediococcus stilesii and Weissella cibaria. At low and high temperatures and pH values and at the presence of bile salt, BLS of the LAB isolates showed remarkable antimicrobial activity against studied indicator bacteria. Furthermore, BLS of L. curieae treated in pH 4 among all pH treatments, BLS of L. brevis and P. stilesii in 1% bile salt among all bile salt treatments, and finally BLS of L. curieae and P. stilesii treated at 4 °C among all temperature treatments were the most effective, respectively, against Aspergillus niger and A. flavus. The safety results demonstrated that consumption of LAB isolates had no adverse effects on general health of mice. Body weight of mice was increased by administration of LAB during 3 weeks, such as control group. Liver enzyme activities of mice treated with the LAB isolates had also insignificant difference with control mice.

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RASA1/NF1 mutant lung cancer: Racing to the clinic?

Although mutation of NF1 has been described in non-small cell lung cancer (NSCLC), co-mutation with RASA1, another Ras-GTPase activating protein (RasGAP), defines a novel genetically defined subclass of NSCLC. RASA1/NF1 mutant cell lines are highly sensitive to MEK inhibitors, warranting clinical evaluation of MAPK inhibition in this subclass of patients.

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DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing, surveillance and treatment recommendations. Attendees from North America, Europe and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology and clinical research. Recommendations are provided for genetic testing, prenatal management, and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated.

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A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T and B cell acute lymphoblastic leukemias in vivo

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug L-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine-dependency of ALL cells. In addition to hydrolyzing the amino acid L-asparagine, all FDA-approved L-asparaginases also have significant L-glutaminase coactivity. Since several reports suggest that L-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced L-glutaminase coactivity might be clinically beneficial if their anti-leukemic activity would be preserved. Here we show that novel low L-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi L-asparaginase were highly efficacious against both T and B cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer L-asparaginases without L-glutaminase activity for the treatment of human ALL.

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Antitumor properties of RAF709, a highly selective and potent inhibitor of RAF kinase dimers, in tumors driven by mutant RAS or BRAF

Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared to cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Further, RAF709 elicited regression of primary human tumor derived xenograft models with BRAF, NRAS or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS mutant tumors.

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Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGF-β signature genes. Excess glucose was found to promote EMT through autocrine TGF-β stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.

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T-type Ca2+ Channels: T for Targetable

In the past decade, T-type Ca2+ channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, in vitro and in vivo studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug–drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells in vitro and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer. Cancer Res; 78(3); 1–7. ©2018 AACR.

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Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target. USP18 is the major DUB that removes IFN-stimulated gene 15 (ISG15) from conjugated proteins. Prior work discovered that engineered loss of USP18 increases ISGylation and in contrast to its gain decreases cancer growth by destabilizing growth-regulatory proteins. Loss of USP18 reduced cancer cell growth by triggering apoptosis. Genetic loss of USP18 repressed cancer formation in engineered murine lung cancer models. The translational relevance of USP18 was confirmed by finding its expression was deregulated in malignant versus normal tissues. Notably, the recent elucidation of the USP18 crystal structure offers a framework for developing an inhibitor to this DUB. This review summarizes strong evidence for USP18 as a previously unrecognized pharmacologic target in oncology. Cancer Res; 78(3); 1–6. ©2018 AACR.

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The effects of green cardamom supplementation on blood glucose, lipids profile, oxidative stress, sirtuin-1 and irisin in type 2 diabetic patients: a study protocol for a randomized placebo-controlled clinical trial

It has been suggested that the antioxidant, anti-inflammatory and hypolipidemic activities of cardamom may improve diabetes. However, the effect of this spice has not been investigated in diabetic subjects. Th...

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Epidermal permeability barrier function and sphingolipid content in the skin of sphingomyelin synthase 2 deficient mice

Abstract

Background

Sphingomyelin synthase (SMS) is an enzyme that generates sphingomyelin (SM) from ceramide (CER) and phosphatidylcholine. SM in the epidermis is a precursor of CER, an important lipid for epidermal permeability barrier function. However, the physiological role of SMS in skin is unclear.

Objectives

To uncover the function of SMS in skin, we investigated sphingolipid metabolism enzyme activity in skin, SM content in the epidermis, CER content in the stratum corneum (SC) and transepidermal water loss (TEWL) as an indicator of barrier function in SMS2-knockout (KO) mice.

Methods

The activities of sphingolipid metabolism enzymes in skin homogenates were measured using a fluorescently labeled substrate. Enzymatic reaction products were detected by high performance liquid chromatography (HPLC). Lipids in the epidermis or SC were extracted and quantified by high performance thin layer chromatography (HPTLC). TEWL was measured using a Tewameter TM300.

Results

In SMS2-KO mice, SMS activity in skin homogenates, epidermal SM content and SC CER content were significantly decreased relative to wild type (WT) mice. The TEWL of SMS2-KO mice was significantly increased compared to WT mice.

Conclusion

Our data indicate that SMS2 generate SM in the epidermis and contribute to epidermal permeability barrier function and will support understanding of SM related metabolic disorders.

This article is protected by copyright. All rights reserved.

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Boost Irradiation Integrated to Whole Brain Radiotherapy in the Management of Brain Metastases

Abstract

Our retrospective analysis aimed to evaluate the clinical value of dose intensification schemes: WBRT and consecutive, delayed, or simultaneous integrated boost (SIB) in brain metastasis (BM) management. Clinical data and overall survival (OS) of 468 patients with BM from various primaries treated with 10 × 3 Gy WBRT (n = 195), WBRT+ 10 × 2 Gy boost (n = 125), or simultaneously 15 × 2.2 Gy WBRT+0.7 Gy boost (n = 148) during a 6-year period were statistically analysed. Significant difference in OS could be detected with additional boost to WBRT (3.3 versus 6.5 months) and this difference was confirmed for BMs of lung cancer and melanoma and both for oligo- and multiplex lesions. The OS was prolonged for the RPA 2 and RPA3 categories, if patients received escalated dose, 4.0 vs. 7.7 months; (p = 0.002) in class RPA2 and 2.6 vs. 4.2 months; (p < 0.0001) in the class RPA 3 respectively. The significant difference in OS was also achieved with SIB. The shortened overall treatment time of SIB with lower WBRT fraction dose exhibited survival benefit over WBRT alone, and could be applied for patients developing BM even with unfavourable prognostic factors. These results warrant for further study of this approach with dose escalation using the lately available solutions for hippocampus sparing and fractionated stereotactic irradiation. The simultaneous delivery of WBRT with reduced fraction dose and boost proved to be advantageous prolonging the OS with shortened treatment time and reduced probability for cognitive decline development even for patients with poor performance status and progressing extracranial disease.

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NDUFAF3 Variants that Disrupt Mitochondrial Complex I Assembly may associate with Cavitating Leukoencephalopathy

Abstract

Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a one-year-old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17–21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C>A:p.Pro169Thr). Two-dimensional blue native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate-PAGE revealed reductions in Q-module (NDUFS2, NDUFS3, and NDUFA9) and P-module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3.

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The Effects of Folate Supplementation on Diabetes Biomarkers Among Patients with Metabolic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Horm Metab Res
DOI: 10.1055/s-0043-125148

Although several studies have evaluated the effect of folate supplementation on diabetes biomarkers among patients with metabolic diseases, findings are inconsistent. This review of randomized controlled trials (RCTs) was performed to summarize the evidence on the effects of folate supplementation on diabetes biomarkers among patients with metabolic diseases. Randomized-controlled trials (RCTs) published in PubMed, EMBASE, Web of Science and Cochrane Library databases up to 1 September 2017 were searched. Two review authors independently assessed study eligibility, extracted data, and evaluated risk of bias of included studies. Heterogeneity was measured with a Q-test and with I2 statistics. Data were pooled by using the fix or random-effect model based on the heterogeneity test results and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). A total of sixteen randomized controlled trials involving 763 participants were included in the final analysis. The current meta-analysis showed folate supplementation among patients with metabolic diseases significantly decreased insulin (SMD –1.28; 95% CI, –1.99, –0.56) and homeostasis model assessment of insulin resistance (HOMA-IR) (SMD –1.28; 95% CI, –1.99, –0.56). However, folate supplementation did not affect fasting plasma glucose (FPG) (SMD –0.30; 95% CI, –0.63, 0.02) and hemoglobin A1C (HbA1c) (SMD –0.29; 95% CI, –0.61, 0.03). The results of this meta-analysis study demonstrated that folate supplementation may result in significant decreases in insulin levels and HOMA-IR score, but does not affect FPG and HbA1c levels among patients with metabolic diseases.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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Redefining Hypertension — Assessing the New Blood-Pressure Guidelines

Like physical guidelines designed to ensure that hikers stay on the safest path through tricky terrain, expert medical guidelines aim to steer clinicians toward best practices. The new Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults issued by the…

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Suprapedicular Circumferential Opening Technique of Percutaneous Endoscopic Transforaminal Lumbar Discectomy for High Grade Inferiorly Migrated Lumbar Disc Herniation

Purpose. To evaluate the efficacy of suprapedicular circumferential opening technique (SCOT) of percutaneous endoscopic transforaminal lumbar discectomy (PETLD) for high grade inferiorly migrated lumbar disc herniation. Material and Methods. Eighteen consecutive patients who presented with back and leg pain with a single-level high grade inferiorly migrated lumbar disc herniation were included. High grade inferiorly migrated disc was removed by the SCOT through PETLD approach. Outcome evaluation was done with visual analog scale (VAS) and Mac Nab's criteria. Result. There were 14 males and 4 females. The mean age of patients was years. One, 4, and 13 patients had disc herniation at L1-2, L3-4, and L4-5 levels, respectively, on MRI, which correlated with clinical findings. The mean follow-up duration was months. According to Mac Nab's criteria, 9 patients (50%) reported excellent and the remaining 9 patients (50%) reported good outcomes. The mean preoperative and postoperative VAS for leg pain were and , respectively (). Improvement in outcomes was maintained even at final follow-up. There was no complication. Conclusion. In this preliminary study we achieved good to excellent clinical results using the SCOT of PETLD for high grade inferiorly migrated lumbar disc herniation.

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Lifetime Traumatic Experiences and Disordered Eating among University Students: The Role of Posttraumatic Stress Symptoms

The associations between lifetime traumatic events (TEs), posttraumatic stress (PTS) symptoms, and disordered eating (DE) were studied in a sample of 614 university students (mean age 20 years). An anonymous questionnaire included 32 lifetime TEs, IES-revised measured PTS symptoms, and EAT-26 evaluated DE symptoms. Statistical analyses included Pearson correlations and structural equation models (SEM) with bootstrapping method. Findings reveal the prevalence of DE in 8.1% of participants, while 73.9% of students experienced at least one lifetime TE. 52.0% of students with DE had PTS symptoms () and 30.8% of students with lifetime TEs had PTS symptoms (). In SEM, direct paths from lifetime TEs to PTS symptoms (0.38, ) and from PTS symptoms to DE (0.40, ) were observed. The final SEM confirmed the mediating role of PTS symptoms in the path between some TEs (traffic accident and seriously injured) and DE among the university students. If PTS symptoms are associated with DE, then addressing PTS symptoms in the context of DE treatment may improve treatment efficacy.

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Response to different furosemide doses predicts AKI progression in ICU patients with elevated plasma NGAL levels

Furosemide responsiveness (FR) is determined by urine output after furosemide administration and has recently been evaluated as a furosemide stress test (FST) for predicting severe acute kidney injury (AKI) pr...

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An appraisal: how notifiable infectious diseases are reported by Hungarian family physicians

Within the frame of National Epidemiological Surveillance System, family physicians have an obligation to report infections and suspicions cases.

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Antimicrobial resistance of Neisseria gonorrhoeae in Germany: low levels of cephalosporin resistance, but high azithromycin resistance

The widespread antimicrobial resistance of Neisseria gonorrhoeae is a serious problem for the treatment and control of gonorrhoea. Many of the previously effective therapeutic agents are no longer viable. Because...

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World Health Organization (WHO) guidelines on use of medically important antimicrobials in food-producing animals

Antimicrobial use in food-producing animals selects for antimicrobial resistance that can be transmitted to humans via food or other transmission routes. The World Health Organization (WHO) in 2005 ranked the ...

http://ift.tt/2EQGIpG

Clinical features and dysfunctions of iron metabolism in Parkinson disease patients with hyper echogenicity in substantia nigra: a cross-sectional study

Transcranial ultrasound is a useful tool for providing the evidences for the early diagnosis and differential diagnosis of Parkinson disease (PD). However, the relationship between hyper echogenicity in substa...

http://ift.tt/2DqcKeV

Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers

Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers

Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers, Published online: 17 January 2018; doi:10.1038/s41419-017-0072-x

Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers

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Notices

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Cover Image

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Retraction

HLA-A2-/HLA-DR1-transgeneic H-2 class I-/class II-knockout mouse is an ideal animal model for study of chronic HBV infection. Ding-Qiang Chen, Ling Yang, Jie Zhou, Liwei Lu, Yu-Chun Lone, Kwok-Yung Yuen, and Bo-Jian Zheng. Hepatology 2010; doi: 10.1002/hep.23932.

The above article, published online on August 23, 2010, in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors and Wiley Periodicals, Inc. The withdrawal has been agreed due to the fact that the authors found that the reagents used for studying hepatic dendritic cell populations reported on in the article were faulty, which made their results inaccurate.

REFERENCE

Chen D-Q, Yang L, Zhou J, Lu L, Lone Y-C, Yuen K-Y, Zheng B-J. HLA-A2-/HLADR1-transgeneic H-2 class I-/class II-knockout mouse is an ideal animal model for study of chronic HBV infection. Hepatology 2010; doi: 10.1002/hep.23932.

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Table of contents

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Hepatology Highlights

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Masthead

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Correction

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Correction

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Instructions to authors and Information for readers

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Compressive Temporal Summation in Human Visual Cortex

Combining sensory inputs over space and time is fundamental to vision. Population receptive field models have been successful in characterizing spatial encoding throughout the human visual pathways. A parallel question, how visual areas in the human brain process information distributed over time, has received less attention. One challenge is that the most widely used neuroimaging method, fMRI, has coarse temporal resolution compared with the time-scale of neural dynamics. Here, via carefully controlled temporally modulated stimuli, we show that information about temporal processing can be readily derived from fMRI signal amplitudes in male and female subjects. We find that all visual areas exhibit subadditive summation, whereby responses to longer stimuli are less than the linear prediction from briefer stimuli. We also find fMRI evidence that the neural response to two stimuli is reduced for brief interstimulus intervals (indicating adaptation). These effects are more pronounced in visual areas anterior to V1-V3. Finally, we develop a general model that shows how these effects can be captured with two simple operations: temporal summation followed by a compressive nonlinearity. This model operates for arbitrary temporal stimulation patterns and provides a simple and interpretable set of computations that can be used to characterize neural response properties across the visual hierarchy. Importantly, compressive temporal summation directly parallels earlier findings of compressive spatial summation in visual cortex describing responses to stimuli distributed across space. This indicates that, for space and time, cortex uses a similar processing strategy to achieve higher-level and increasingly invariant representations of the visual world.

SIGNIFICANCE STATEMENT Combining sensory inputs over time is fundamental to seeing. Two important temporal phenomena are summation, the accumulation of sensory inputs over time, and adaptation, a response reduction for repeated or sustained stimuli. We investigated these phenomena in the human visual system using fMRI. We built predictive models that operate on arbitrary temporal patterns of stimulation using two simple computations: temporal summation followed by a compressive nonlinearity. Our new temporal compressive summation model captures (1) subadditive temporal summation, and (2) adaptation. We show that the model accounts for systematic differences in these phenomena across visual areas. Finally, we show that for space and time, the visual system uses a similar strategy to achieve increasingly invariant representations of the visual world.

http://ift.tt/2FIY3Ca

Role of the Axon Initial Segment in the Control of Spontaneous Frequency of Nigral Dopaminergic Neurons In Vivo

The spontaneous tonic discharge activity of nigral dopamine neurons plays a fundamental role in dopaminergic signaling. To investigate the role of neuronal morphology and architecture with respect to spontaneous activity in this population, we visualized the 3D structure of the axon initial segment (AIS) along with the entire somatodendritic domain of adult male mouse dopaminergic neurons, previously recorded in vivo. We observed a positive correlation of the firing rate with both proximity and size of the AIS. Computational modeling showed that the size of the AIS, but not its position within the somatodendritic domain, is the major causal determinant of the tonic firing rate in the intact model, by virtue of the higher intrinsic frequency of the isolated AIS. Further mechanistic analysis of the relationship between neuronal morphology and firing rate showed that dopaminergic neurons function as a coupled oscillator whose frequency of discharge results from a compromise between AIS and somatodendritic oscillators. Thus, morphology plays a critical role in setting the basal tonic firing rate, which in turn could control striatal dopaminergic signaling that mediates motivation and movement.

SIGNIFICANCE STATEMENT The frequency at which nigral dopamine neurons discharge action potentials sets baseline dopamine levels in the brain, which enables activity in motor, cognitive, and motivational systems. Here, we demonstrate that the size of the axon initial segment, a subcellular compartment responsible for initiating action potentials, is a key determinant of the firing rate in these neurons. The axon initial segment and all the molecular components that underlie its critical function may provide a novel target for the regulation of dopamine levels in the brain.

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Inhibition in Simple Cell Receptive Fields Is Broad and OFF-Subregion Biased

Inhibition in thalamorecipient layer 4 simple cells of primary visual cortex is believed to play important roles in establishing visual response properties and integrating visual inputs across their receptive fields (RFs). Simple cell RFs are characterized by nonoverlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the firing rate of the cell, depending on contrast. Inhibition is believed to be triggered exclusively from visual stimulation of individual RF subregions. However, this view is at odds with the known anatomy of layer 4 interneurons in visual cortex and differs from recent findings in mouse visual cortex. Here we show with in vivo intracellular recordings in cats that while excitation is restricted to RF subregions, inhibition spans the width of simple cell RFs. Consequently, excitatory stimuli within a subregion concomitantly drive excitation and inhibition. Furthermore, we found that the distribution of inhibition across the RF is stronger toward OFF subregions. This inhibitory OFF-subregion bias has a functional consequence on spatial integration of inputs across the RF. A model based on the known anatomy of layer 4 demonstrates that the known proportion and connectivity of inhibitory neurons in layer 4 of primary visual cortex is sufficient to explain broad inhibition with an OFF-subregion bias while generating a variety of phase relations, including antiphase, between excitation and inhibition in response to drifting gratings.

SIGNIFICANCE STATEMENT The wiring of excitatory and inhibitory neurons in cortical circuits is key to determining the response properties in sensory cortex. In the visual cortex, the first cells that receive visual input are simple cells in layer 4. The underlying circuitry responsible for the response properties of simple cells is not yet known. In this study, we challenge a long-held view concerning the pattern of inhibitory input and provide results that agree with current known anatomy. We show here that inhibition is evoked broadly across the receptive fields of simple cells, and we identify a surprising bias in inhibition within the receptive field. Our findings represent a step toward a unified view of inhibition across different species and sensory systems.

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A New, High-Efficacy, Noninvasive Transcranial Electric Stimulation Tuned to Local Neurodynamics

In this paper, we pose the following working hypothesis: in humans, transcranial electric stimulation (tES) with a time course that mimics the endogenous activity of its target is capable of altering the target's excitability. In our case, the target was the primary motor cortex (M1). We identified the endogenous neurodynamics of hand M1's subgroups of pyramidal neuronal pools in each of our subjects by applying Functional Source Separation (FSS) to their EEG recordings. We then tested whether the corticospinal excitability of the hand representation under the above described stimulation, which we named transcranial individual neurodynamics stimulation (tIDS), was higher than in the absence of stimulation (baseline). As a check, we compared tIDS with the most efficient noninvasive facilitatory corticospinal tES known so far, which is 20 Hz transcranial alternating current stimulation (tACS). The control conditions were as follows: (1) sham, (2) transcranial random noise stimulation (tRNS) in the same frequency range as tIDS (1–250 Hz), and (3) a low current tIDS (tIDS_low). Corticospinal excitability was measured with motor-evoked potentials under transcranial magnetic stimulation. The mean motor-evoked potential amplitude increase was 31% of the baseline during tIDS (p < 0.001), and it was 15% during tACS (p = 0.096). tRNS, tIDS_low, and sham induced no effects. Whereas tACS did not produce an enhancement in any subject at the individual level, tIDS was successful in producing an enhancement in 8 of the 16 subjects. The results of the present proof-of-principle study showed that proper exploitation of local neurodynamics can enhance the efficacy of personalized tES.

SIGNIFICANCE STATEMENT This study demonstrated that, in humans, transcranial individual neurodynamics stimulation (tIDS), which mimics the endogenous dynamics of the target neuronal pools, effectively changes the excitability of these pools. tIDS holds promise for high-efficacy personalized neuromodulations based on individual local neurodynamics.

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Dopamine-Dependent Sensitization of Rod Bipolar Cells by GABA Is Conveyed through Wide-Field Amacrine Cells

The vertebrate retina has the remarkable ability to support visual function under conditions of limited illumination, including the processing of signals evoked by single photons. Dim-light vision is regulated by several adaptive mechanisms. The mechanism explored in this study is responsible for increasing the light sensitivity and operational range of rod bipolar cells, the retinal neurons operating immediately downstream of rod photoreceptors. This sensitization is achieved through the sustained dopamine-dependent GABA release from other retinal neurons. Our goals were to identify the cell type responsible for the GABA release and the site of its modulation by dopamine. Previous studies have suggested the involvement of amacrine and/or horizontal cells. We now demonstrate, using mice of both sexes, that horizontal cells do not participate in this mechanism. Instead, sustained GABA input is provided by a subpopulation of wide-field amacrine cells, which stimulate the GABA_C receptors at rod bipolar cell axons. We also found that dopamine does not act directly on either of these cells. Rather, it suppresses inhibition imposed on these wide-field cells by another subpopulation of upstream GABAergic amacrine cells, thereby sustaining the GABA_C receptor activation required for rod bipolar cell sensitization.

SIGNIFICANCE STATEMENT The vertebrate retina has an exquisite ability to adjust information processing to ever-changing conditions of ambient illumination, from bright sunlight to single-photon counting under dim starlight. Operation under each of these functional regimes requires an engagement of specific adaptation mechanisms. Here, we describe a mechanism optimizing the performance of the dim-light channel of vision, which consists of sensitizing rod bipolar cells by a sustained GABAergic input originating from a population of wide-field amacrine cells. Wide-field amacrine cells span large segments of the retina, making them uniquely equipped to normalize and optimize response sensitivity across distant receptive fields and preclude any bias toward local light-intensity fluctuations.

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Phosphorylated CCAAT/Enhancer Binding Protein {beta} Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies

Chronic pain is increasingly recognized as an important comorbidity of HIV-infected patients, however, the exact molecular mechanisms of HIV-related pain are still elusive. CCAAT/enhancer binding proteins (C/EBPs) are expressed in various tissues, including the CNS. C/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO₂^·–), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNFα bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO₂^·–, pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targeted O₂^·–scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBPβ. Knockdown of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBPβ. These results suggested that the pathway of TNFα/TNFRI–mtO₂^·––pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα in vitro and repeated intrathecal injection of recombinant TNFα in naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment.

SIGNIFICANCE STATEMENT Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPβ (pC/EBPβ) influences AIDS progression, but it is still not clear about the exact role of pC/EBPβ and the detailed upstream factors of pC/EBPβ in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPβ was triggered by TNFα/TNFRI–mtO₂^·––pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα in vitro, and by repeated intrathecal injection of recombinant TNFα in naive rats. The present results revealed the functional significance of TNFα/TNFRI–mtO₂^·––pCREB–pC/EBPβ signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.

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MT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding

Cell-surface molecules are dynamically regulated at the synapse to assemble and disassemble adhesive contacts that are important for synaptogenesis and for tuning synaptic transmission. Metalloproteinases dynamically regulate cellular behaviors through the processing of cell surface molecules. In the present study, we evaluated the role of membrane-type metalloproteinases (MT-MMPs) in excitatory synaptogenesis. We find that MT3-MMP and MT5-MMP are broadly expressed in the mouse cerebral cortex and that MT3-MMP loss-of-function interferes with excitatory synapse development in dissociated cortical neurons and in vivo. We identify Nogo-66 receptor (NgR1) as an MT3-MMP substrate that is required for MT3-MMP-dependent synapse formation. Introduction of the shed ectodomain of NgR1 is sufficient to accelerate excitatory synapse formation in dissociated cortical neurons and in vivo. Together, our findings support a role for MT3-MMP-dependent shedding of NgR1 in regulating excitatory synapse development.

SIGNIFICANCE STATEMENT In this study, we identify MT3-MMP, a membrane-bound zinc protease, to be necessary for the development of excitatory synapses in cortical neurons. We identify Nogo-66 receptors (NgR1) as a downstream target of MT3-MMP proteolytic activity. Furthermore, processing of surface NgR1 by MT3-MMP generates a soluble ectodomain fragment that accelerates the formation of excitatory synapses. We propose that MT3-MMP activity and NgR1 shedding could stimulate circuitry remodeling in the adult brain and enhance functional connectivity after brain injury.

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Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in Drosophila axon guidance [RESEARCH ARTICLE]

Ramakrishnan Kannan, Eric Cox, Lei Wang, Irina Kuzina, Qun Gu, and Edward Giniger

Notch signaling is required for the development and physiology of nearly every tissue in metazoans. Much of Notch signaling is mediated by transcriptional regulation of downstream target genes, but Notch controls axon patterning in Drosophila by local modulation of Abl tyrosine kinase signaling, via direct interactions with the Abl co-factors Disabled and Trio. Here, we show that Notch-Abl axonal signaling requires both of the proteolytic cleavage events that initiate canonical Notch signaling. We further show that some Notch protein is tyrosine phosphorylated in Drosophila, that this form of the protein is selectively associated with Disabled and Trio, and that relevant tyrosines are essential for Notch-dependent axon patterning but not for canonical Notch-dependent regulation of cell fate. Based on these data, we propose a model for the molecular mechanism by which Notch controls Abl signaling in Drosophila axons.

http://ift.tt/2FJdl9X

Non-cell autonomous control of precerebellar neuron migration by Slit and Robo proteins [RESEARCH ARTICLE]

Chloe Dominici, Quentin Rappeneau, Pavol Zelina, Stephane Fouquet, and Alain Chedotal

During development, precerebellar neurons migrate tangentially from the dorsal hindbrain to the floor plate. Their axons cross it but their cell bodies stop their ventral migration upon reaching the midline. It has previously been shown that Slit chemorepellents and their receptors, Robo1 and Robo2, might control the migration of precerebellar neurons in a repulsive manner. Here, we have used a conditional knockout strategy in mice to test this hypothesis. We show that the targeted inactivation of the expression of Robo1 and Robo2 receptors in precerebellar neurons does not perturb their migration and that they still stop at the midline. The selective ablation of the expression of all three Slit proteins in floor-plate cells has no effect on pontine neurons and only induces the migration of a small subset of inferior olivary neurons across the floor plate. Likewise, we show that the expression of Slit proteins in the facial nucleus is dispensable for pontine neuron migration. Together, these results show that Robo1 and Robo2 receptors act non-cell autonomously in migrating precerebellar neurons and that floor-plate signals, other than Slit proteins, must exist to prevent midline crossing.

http://ift.tt/2FL8m8N

NFIA and GATA3 are crucial regulators of embryonic articular cartilage differentiation [RESEARCH ARTICLE]

Pratik Narendra Pratap Singh, Upendra Singh Yadav, Kimi Azad, Pooja Goswami, Veena Kinare, and Amitabha Bandyopadhyay

During appendicular skeletal development, the bi-potential cartilage anlagen gives rise to transient cartilage, which is eventually replaced by bone, and to articular cartilage that caps the ends of individual skeletal elements. While the molecular mechanism that regulates transient cartilage differentiation is relatively well understood, the mechanism of articular cartilage differentiation has only begun to be unraveled. Furthermore, the molecules that coordinate the articular and transient cartilage differentiation processes are poorly understood. Here, we have characterized in chick the regulatory roles of two transcription factors, NFIA and GATA3, in articular cartilage differentiation, maintenance and the coordinated differentiation of articular and transient cartilage. Both NFIA and GATA3 block hypertrophic differentiation. Our results suggest that NFIA is not sufficient but necessary for articular cartilage differentiation. Ectopic activation of GATA3 promotes articular cartilage differentiation, whereas inhibition of GATA3 activity promotes transient cartilage differentiation at the expense of articular cartilage. We propose a novel transcriptional circuitry involved in embryonic articular cartilage differentiation, maintenance and its crosstalk with the transient cartilage differentiation program.

http://ift.tt/2ENUvxm

Distinct subsets of Eve-positive pericardial cells stabilise cardiac outflow and contribute to Hox gene-triggered heart morphogenesis in Drosophila [RESEARCH REPORT]

Monika Zmojdzian, Svetlana de Joussineau, Jean Philippe Da Ponte, and Krzysztof Jagla

The Drosophila heart, composed of discrete subsets of cardioblasts and pericardial cells, undergoes Hox-triggered anterior-posterior morphogenesis, leading to a functional subdivision into heart proper and aorta, with its most anterior part forming a funnel-shaped cardiac outflow. Cardioblasts differentiate into Tin-positive 'working myocytes' and Svp-expressing ostial cells. However, developmental fates and functions of heart-associated pericardial cells remain elusive. Here, we show that the pericardial cells that express the transcription factor Even Skipped adopt distinct fates along the anterior-posterior axis. Among them, the most anterior Antp-Ubx-AbdA-negative cells form a novel cardiac outflow component we call the outflow hanging structure, whereas the Antp-expressing cells differentiate into wing heart precursors. Interestingly, Hox gene expression in the Even Skipped-positive cells not only underlies their antero-posterior diversification, but also influences heart morphogenesis in a non-cell-autonomous way. In brief, we identify a new cardiac outflow component derived from a subset of Even Skipped-expressing cells that stabilises the anterior heart tip, and demonstrate non-cell-autonomous effects of Hox gene expression in the Even Skipped-positive cells on heart morphogenesis.

http://ift.tt/2ERRFXQ

Commissural neurons transgress the CNS/PNS boundary in absence of ventricular zone-derived netrin 1 [RESEARCH REPORT]

Juan Antonio Moreno-Bravo, Sergi Roig Puiggros, Heike Blockus, Chloe Dominici, Pavol Zelina, Patrick Mehlen, and Alain Chedotal

During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.

http://ift.tt/2ERRThE

Neural migration: re-evaluating Slit and Robo [RESEARCH HIGHLIGHT]

http://ift.tt/2FKzxR0

Neural migration: re-evaluating Slit and Robo [RESEARCH HIGHLIGHT]

http://ift.tt/2FKzxR0

Non-cell autonomous control of precerebellar neuron migration by Slit and Robo proteins [RESEARCH ARTICLE]

Chloe Dominici, Quentin Rappeneau, Pavol Zelina, Stephane Fouquet, and Alain Chedotal

During development, precerebellar neurons migrate tangentially from the dorsal hindbrain to the floor plate. Their axons cross it but their cell bodies stop their ventral migration upon reaching the midline. It has previously been shown that Slit chemorepellents and their receptors, Robo1 and Robo2, might control the migration of precerebellar neurons in a repulsive manner. Here, we have used a conditional knockout strategy in mice to test this hypothesis. We show that the targeted inactivation of the expression of Robo1 and Robo2 receptors in precerebellar neurons does not perturb their migration and that they still stop at the midline. The selective ablation of the expression of all three Slit proteins in floor-plate cells has no effect on pontine neurons and only induces the migration of a small subset of inferior olivary neurons across the floor plate. Likewise, we show that the expression of Slit proteins in the facial nucleus is dispensable for pontine neuron migration. Together, these results show that Robo1 and Robo2 receptors act non-cell autonomously in migrating precerebellar neurons and that floor-plate signals, other than Slit proteins, must exist to prevent midline crossing.

http://ift.tt/2FL8m8N

Commissural neurons transgress the CNS/PNS boundary in absence of ventricular zone-derived netrin 1 [RESEARCH REPORT]

Juan Antonio Moreno-Bravo, Sergi Roig Puiggros, Heike Blockus, Chloe Dominici, Pavol Zelina, Patrick Mehlen, and Alain Chedotal

During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.

http://ift.tt/2ERRThE

Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in Drosophila axon guidance [RESEARCH ARTICLE]

Ramakrishnan Kannan, Eric Cox, Lei Wang, Irina Kuzina, Qun Gu, and Edward Giniger

Notch signaling is required for the development and physiology of nearly every tissue in metazoans. Much of Notch signaling is mediated by transcriptional regulation of downstream target genes, but Notch controls axon patterning in Drosophila by local modulation of Abl tyrosine kinase signaling, via direct interactions with the Abl co-factors Disabled and Trio. Here, we show that Notch-Abl axonal signaling requires both of the proteolytic cleavage events that initiate canonical Notch signaling. We further show that some Notch protein is tyrosine phosphorylated in Drosophila, that this form of the protein is selectively associated with Disabled and Trio, and that relevant tyrosines are essential for Notch-dependent axon patterning but not for canonical Notch-dependent regulation of cell fate. Based on these data, we propose a model for the molecular mechanism by which Notch controls Abl signaling in Drosophila axons.

http://ift.tt/2FJdl9X

Distinct subsets of Eve-positive pericardial cells stabilise cardiac outflow and contribute to Hox gene-triggered heart morphogenesis in Drosophila [RESEARCH REPORT]

Monika Zmojdzian, Svetlana de Joussineau, Jean Philippe Da Ponte, and Krzysztof Jagla

The Drosophila heart, composed of discrete subsets of cardioblasts and pericardial cells, undergoes Hox-triggered anterior-posterior morphogenesis, leading to a functional subdivision into heart proper and aorta, with its most anterior part forming a funnel-shaped cardiac outflow. Cardioblasts differentiate into Tin-positive 'working myocytes' and Svp-expressing ostial cells. However, developmental fates and functions of heart-associated pericardial cells remain elusive. Here, we show that the pericardial cells that express the transcription factor Even Skipped adopt distinct fates along the anterior-posterior axis. Among them, the most anterior Antp-Ubx-AbdA-negative cells form a novel cardiac outflow component we call the outflow hanging structure, whereas the Antp-expressing cells differentiate into wing heart precursors. Interestingly, Hox gene expression in the Even Skipped-positive cells not only underlies their antero-posterior diversification, but also influences heart morphogenesis in a non-cell-autonomous way. In brief, we identify a new cardiac outflow component derived from a subset of Even Skipped-expressing cells that stabilises the anterior heart tip, and demonstrate non-cell-autonomous effects of Hox gene expression in the Even Skipped-positive cells on heart morphogenesis.

http://ift.tt/2ERRFXQ

Zoll LifeVest 4000 Wearable Cardioverter Defibrillator: FDA Safety Communication - Potential Lack of Treatment (Shock) Delivery Due to Device Failure

Audience: Risk Manager, Cardiology, Nursing [Posted 01/17/2018] ISSUE: FDA is providing information and recommendations regarding the Zoll LifeVest 4000 due to concerns that the device may fail to deliver treatment to the patient if the device is...

http://ift.tt/2rc0V7k

AI technology helping dispatchers detect cardiac arrest

Corti, an AI assistant, uses speech recognition software to analyze the conversation and alert dispatchers if the caller is experiencing sudden cardiac arrest

http://ift.tt/2EPHjb5

microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11

Abstract

Background

Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.

Methods

In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.

Results

Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.

Conclusions

Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.

http://ift.tt/2mCYVj0

Liquid biomarkers in melanoma: detection and discovery

Abstract

A vast array of tumor-derived genetic, proteomic and cellular components are constantly released into the circulation of cancer patients. These molecules including circulating tumor DNA and RNA, proteins, tumor and immune cells are emerging as convenient and accurate liquid biomarkers of cancer. Circulating cancer biomarkers provide invaluable information on cancer detection and diagnosis, prognosticate patient outcomes, and predict treatment response. In this era of effective molecular targeted treatments and immunotherapies, there is now an urgent need to implement use of these circulating biomarkers in the clinic to facilitate personalized therapy. In this review, we present recent findings in circulating melanoma biomarkers, examine the challenges and promise of evolving technologies used for liquid biomarker discovery, and discuss future directions and perspectives in melanoma biomarker research.

http://ift.tt/2DnYa7L

Periorbital Necrobiotic Xanthogranuloma Successfully Treated with Intravenous Immunoglobulin

Background: Necrobiotic xanthogranuloma (NXG) is a rare non-Langerhans histiocytosis with cutaneous manifestations, most commonly of the periorbital skin, and is often associated with hematologic disorders such as monoclonal gammopathy. Treatment of NXG is notoriously difficult, and fraught with recurrence and progression. Case Presentation: The authors describe a case of NXG with periorbital involvement in a patient with a complex autoimmune and hematologic medical history. The biopsy of this rare lesion prompted subsequent evaluation for an underlying disorder, which led to the diagnosis of multiple myeloma. Her NXG lesions demonstrated remarkable clinical improvement after treatment with intravenous immunoglobulin (IVIG). Conclusions: This case demonstrates the ophthalmologist's critical role in the diagnosis and management of NXG, as early detection cannot only prevent ophthalmic consequences such as ocular perforation and blindness, but also prompt further investigation that may reveal an underlying disorder or systemic involvement, including hematologic malignancy as in this case. NXG has been effectively treated with IVIG in a handful of reported cases. To the author's knowledge, this is the third case of periorbital NXG successfully treated with IVIG, and the first in the ophthalmic literature.
Case Rep Ophthalmol 2018;9:70–75

http://ift.tt/2DKsFTm

Repair of Traumatic Rhegmatogenous Retinal Detachment Combined with Congenital Falciform Retinal Detachment

Purpose: To report a case of surgical repair of traumatic rhegmatogenous retinal detachment combined with congenital falciform retinal detachment (FRD). Methods: A retrospective case report. Results: A 36-year-old man with traumatic rhegmatogenous retinal detachment complicating a previously known FRD was successfully treated despite residual FRD following pars plana lensectomy, vitrectomy, and encircling scleral buckling. His best corrected visual acuity improved from hand motion at 50 cm to 20/1,000. Conclusion: We concluded that the root of the FRD is susceptible to trauma because of the contraction of fibrovascular tissue. The early intervention of modern vitrectomy to traumatic rhegmatogenous retinal detachment complicating a previously known FRD is an important consideration for enhanced quality of care and optimal patient outcomes.
Case Rep Ophthalmol 2018;9:49–53

http://ift.tt/2DHf7YE

Two Cases of Rhegmatogenous Retinal Detachment Associated with Asteroid Hyalosis

Background: To report two cases of rhegmatogenous retinal detachment (RRD) associated with asteroid hyalosis (AH). Case Presentation: Two patients presented with RRD originating from a flap tear. Case 1 involved a 62-year-old male who was found to have bullous RRD in his left eye originating from a flap tear. During vitreous surgery, a thick vitreous cortex was found to have strongly adhered to the entire retinal surface, from the center to the periphery. A bimanual method was then used in conjunction with the vitrectomy to create an artificial posterior vitreous detachment. After surgery, the retina was successfully reattached, and his corrected visual acuity (VA) improved. Case 2 involved a 70-year-old male who was found to have localized RRD in his left eye originating from a flap tear. During vitreous surgery, a thick vitreous cortex was found to have strongly adhered to the entire retinal surface. After surgery, the retina was successfully reattached, and his corrected VA improved. Conclusions: RRD associated with AH presents with stronger vitreoretinal adhesion compared to typical RRD, thus requiring a more complicated surgical technique to properly treat the patient.
Case Rep Ophthalmol 2018;9:43–48

http://ift.tt/2Ddsa2N

Human papillomavirus genotype distribution in cervical cancer biopsies from Nepalese women

Abstract

Background

Cervical cancer (CC) is the leading cause of morbidity and mortality from cancer in Nepalese women. Nearly all cases of CC are caused by infection with certain genotypes of human papillomavirus (HPV). Data on HPV genotype distribution in Nepalese CC patients is sparse. We aimed to determine the distribution of HPV genotypes in biopsies of CC tissue from Nepalese women.

Methods

This study examined 248 archived paraffin-embedded tissue specimens from CC cases from patients of B.P. Koirala Memorial Cancer Hospital, Bharatpur, Chitwan, Nepal. DNA was extracted from the biopsies and HPV detection performed by PCR. HPV genotyping was then carried out by a reverse line hybridization technique capable of identifying 36 distinct HPV genotypes.

Results

Most of the samples were from tumors that had been designated by hospital pathologists as squamous cell carcinoma (77.6%). 165 of the 248 samples contained DNA of sufficient quality for rigorous PCR testing. All the analyzable specimens were positive for HPV. The most common HPV genotypes, in decreasing order of frequency were 16, 18, 45, 33, 52, 56 and 31; most were found as single infections (94.5%). Together, HPV types 16, 18, and 45 were found in 92% of the tumor samples.

Conclusion

This study strengthens the knowledge-base of HPV genotype distribution in CC cases in Nepal. Hopefully, this information will be useful to the medical community and public health policy-makers in generating improved HPV-surveillance, −prevention and -treatment strategies in Nepal.

http://ift.tt/2FJ094V

Reactive Vapor Deposition of Conjugated Polymer Films on Arbitrary Substrates

This paper presents a protocol for reactive vapor deposition of poly(3,4-ethylenedioxythiophene), poly(3,4-propylenedioxythiophene), and poly(thieno[3,2-b]thiophene) films on glass slides and rough substrates, such as textiles and paper.

http://ift.tt/2DJ1ic2

A Facile Method to Fabricate Anisotropic Hydrogels with Perfectly Aligned Hierarchical Fibrous Structures

Abstract

Natural structural materials (such as tendons and ligaments) are comprised of multiscale hierarchical architectures, with dimensions ranging from nano- to macroscale, which are difficult to mimic synthetically. Here a bioinspired, facile method to fabricate anisotropic hydrogels with perfectly aligned multiscale hierarchical fibrous structures similar to those of tendons and ligaments is reported. The method includes drying a diluted physical hydrogel in air by confining its length direction. During this process, sufficiently high tensile stress is built along the length direction to align the polymer chains and multiscale fibrous structures (from nano- to submicro- to microscale) are spontaneously formed in the bulk material, which are well-retained in the reswollen gel. The method is useful for relatively rigid polymers (such as alginate and cellulose), which are susceptible to mechanical signal. By controlling the drying with or without prestretching, the degree of alignment, size of superstructures, and the strength of supramolecular interactions can be tuned, which sensitively influence the strength and toughness of the hydrogels. The mechanical properties are comparable with those of natural ligaments. This study provides a general strategy for designing hydrogels with highly ordered hierarchical structures, which opens routes for the development of many functional biomimetic materials for biomedical applications.

Anisotropic hydrogels with perfectly aligned hierarchical fibrous structures are fabricated by a simple method. Drying a physical hydrogel by confining its length direction generates a 1D tensile force that controls polymeric alignment and supramolecular interactions. A tunable structure and mechanical properties are realized in different types of rigid polymeric hydrogels and the properties are comparable with those of natural ligaments.

http://ift.tt/2Dc2TWN

Lipid and Nucleic Acid Chemistries: Combining the Best of Both Worlds to Construct Advanced Biomaterials

Abstract

Hybrid synthetic amphiphilic biomolecules are emerging as promising supramolecular materials for biomedical and technological applications. Herein, recent progress in the field of nucleic acid based lipids is highlighted with an emphasis on their molecular design, synthesis, supramolecular properties, physicochemical behaviors, and applications in the field of health science and technology. In the first section, the design and the study of nucleolipids are in focus and then the glyconucleolipid family is discussed. In the last section, recent contributions of responsive materials involving nucleolipids and their use as smart drug delivery systems are discussed. The supramolecular materials generated by nucleic acid based lipids open new challenges for biomedical applications, including the fields of medicinal chemistry, biosensors, biomaterials for tissue engineering, drug delivery, and the decontamination of nanoparticles.

Hybrid molecules combining nucleic acid structures with lipids have recently received increasing attention as a new class of supramolecular biomaterials. An overview of the latest studies on their chemical and biological properties is presented, including several biomedical applications ranging from medicinal chemistry to biomaterials. Some suggestions for developing these types of soft materials in the near future are also proposed.

http://ift.tt/2DGlj34

Zoll LifeVest 4000 Wearable Cardioverter Defibrillator: FDA Safety Communication - Potential Lack of Treatment (Shock) Delivery Due to Device Failure

Audience: Risk Manager, Cardiology, Nursing [Posted 01/17/2018] ISSUE: FDA is providing information and recommendations regarding the Zoll LifeVest 4000 due to concerns that the device may fail to deliver treatment to the patient if the device is...

http://ift.tt/2rc0V7k

Eliminating Alcohol-Impaired Driving Fatalities: What Can Be Done?

Despite decades of progress, more than 10 000 alcohol-related driving fatalities occur each year. To identify ways of reinvigorating efforts to stem these tragic events, the National Highway Traffic Safety Administration asked the National Academies of Sciences, Engineering, and Medicine to form a committee to do a rigorous study of the problem and make recommendations. This commentary highlights the recommendations.

http://ift.tt/2FMFi0E

Simultaneous Distinction of Monospecific and Mixed DFS70 Patterns During ANA Screening with a Novel HEp-2 ELITE/DFS70 Knockout Substrate

DFS70 autoantibodies mimic common disease-associated antinuclear antibody patterns making accurate interpretation challenging when using conventional HEp-2 substrates. The protocol describes advantages of novel engineered HEp-2 substrate over conventional HEp-2 in ANA screening and distinguishing DFS70 patterns with high confidence in both monospecific and mixed ANA positive cases.

http://ift.tt/2Bam2qf

A Method for Obtaining Serial Ultrathin Sections of Microorganisms in Transmission Electron Microscopy

This study presents reliable and easy procedures for obtaining serial ultrathin sections of a microorganism without expensive equipment in transmission electron microscopy.

http://ift.tt/2B9MdNV

Endoscopic Endonasal Trans-sphenoidal Approach: Minimally Invasive Surgery for Pituitary Adenomas

The aim of this paper is to describe the different steps of the endoscopic endonasal approach to the sella turcica.

http://ift.tt/2B9M8tB

Osteogenic efficacy of BMP-2 mixed with hydrogel and bone substitute in peri-implant dehiscence defects in dogs: 16 weeks of healing

Abstract

Objectives

The objective of this study was to determine the effect of bone morphogenetic protein-2 (BMP-2) mixed with either polyethylene glycol hydrogel or synthetic bone substitute (SBS) on new bone formation in peri-implant dehiscence defects after 16 weeks of healing.

Materials and methods

A guided bone regeneration procedure was performed in box-type peri-implant defects that were surgically prepared in six beagle dogs. The following four experimental groups were used (i) control (no graft), (ii) SBS+hydrogel, (iii) SBS+BMP-2/hydrogel and (iv) BMP-2/SBS+hydrogel. Volumetric analysis using micro-computed tomography and histomorphometric analysis was performed at 16 weeks post-operatively.

Results

The amount of new bone and the total augmented volume did not differ significantly between both BMP-treated groups and the SBS+hydrogel group (p > .05). Likewise, no histometric differences were observed in the values of new bone area and bone-to-implant contact ratio among the three augmentation groups (new bone area: 0.06 ± 0.08, 0.19 ± 0.20, 0.48 ± 0.37 and 0.56 ± 0.60 mm² [mean ± standard deviation] in groups 1–4, respectively; bone-to-implant contact: 9.44 ± 11.51%, 19.91 ± 15.19%, 46.31 ± 29.82% and 42.58 ± 26.27% in groups 1–4, respectively).

Conclusion

The osteogenic efficacy of BMP-2 on the regeneration of peri-implant bone defects was not detectable after 16 weeks regardless of the carrier materials.

http://ift.tt/2Dix2YK

ZOLL 2018 PULSE Awards open for nominations

CHELMSFORD, Mass. — ZOLL® Medical Corporation, an Asahi Kasei Group Company that manufactures medical devices and related software solutions, today announced that the 2018 ZOLL PULSE Awards is now open for nominations. Nominations can be submitted online between now and March 16. The winners will be announced at SUMMIT, ZOLL's annual user conference held May 8-10 in Denver. The intent ...

http://ift.tt/2B7yiIm

Quick take: Quality and safety gain prominence at NAEMSP

SAN DIEGO — The National Association of EMS Physicians started its 2018 Annual Meeting with a day-long session aimed at introducing EMS medical directors to some fundamental quality and safety concepts. The course was designed to be an interactive application of these concepts to a crowd that is not traditionally well-versed on the topics. The instructors used the System of Profound Knowledge ...

http://ift.tt/2mOvHP2