Brain Tumor-Related Epilepsy: a Current Review of the Etiologic Basis and Diagnostic and Treatment Approaches

Abstract

Purpose of Review

The relationship of brain tumors and seizures remains poorly understood. This article is an overview of the epidemiology, etiology, and diagnostic and treatment approaches of tumor-related epilepsy primarily with regard to glial-based tumors, the most commonly considered brain tumor in this field.

Recent Findings

Over the past many years, several novel etiologic mechanisms to explain how tumors induce seizures have been developed, which this article reviews, including the roles of glutamate-induced excitotoxicity, matrix metalloproteinases, isocitrate dehydrogenase, methylguanine methyltransferase, and functional network connectivity. As well, diagnostic and treatment approaches vary considerably. This article summarizes the evidence and provides the rationale for a reconsideration of how we deliver pre-operative, peri-operative, and post-operative care to these patients.

Summary

Patients with brain tumors and epilepsy are a very challenging subgroup of patients, which necessitates not just a thorough understanding of the current principles regarding tumor-related epilepsy but also the development of collaborative research to advance our knowledge even further, and a concerted effort to develop a standardized, multi-disciplinary clinical approach to improve the care of these patients.

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CAR T cells targeting solid tumors: carcinoembryonic antigen (CEA) proves to be a safe target

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Dynamics of Templated Assembly of Nanoparticle Filaments within Nanochannels

Nanoparticles (NPs) can self-assemble into complex, organized superstructures on patterned surfaces through fluid-mediated interactions. However, the detailed mechanisms for such NP assemblies are largely unknown. Here, using in situ transmission electron microscopy, the stepwise self-assembly dynamics of hydrophobic gold NPs into long filaments formed on the surfaces of water-filled patterned nanochannel templates is observed. First, the formation of a meniscus between the nanochannel walls, during the slow drying of water, causes accumulation of the NPs in the middle of the nanochannels. Second, owing to the strong van der Waals attraction between the NP ligands, the NPs condense into filaments along the centers of the nanochannels. Filaments with highly fluctuating longitudinal NP densities are also observed to fragment into separated structures. Understanding the intermediate stages of fluid-mediated NP self-assembly on patterned surfaces will have important implications for the controlled formation of templated NP assemblies with numerous applications.

Patterned surfaces can serve as templates that organize nanoparticles into complex structures, but the way such organization occurs is largely unknown. Direct nanoscale imaging reveals the assembly dynamics of robust synthetic filaments from a suspension of hydrophobic nanoparticles inside the patterned nanochannel arrays. The nanoparticles first accumulate in the center of the nanochannel and then condense into a filament through van der Waals interactions.

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Graphene-Contacted Ultrashort Channel Monolayer MoS2 Transistors

2D semiconductors are promising channel materials for field-effect transistors (FETs) with potentially strong immunity to short-channel effects (SCEs). In this paper, a grain boundary widening technique is developed to fabricate graphene electrodes for contacting monolayer MoS₂. FETs with channel lengths scaling down to ≈4 nm can be realized reliably. These graphene-contacted ultrashort channel MoS₂ FETs exhibit superior performances including the nearly Ohmic contacts and excellent immunity to SCEs. This work provides a facile route toward the fabrication of various 2D material-based devices for ultrascaled electronics.

A grain boundary widening technique is developed to fabricate graphene electrodes for contacting monolayer MoS₂ FETs with channel lengths ≈4 nm. These ultrashort channel MoS₂ FETs exhibit superior performances including the nearly Ohmic contacts and excellent immunity to SCEs. This work provides a facile route toward the fabrication of ultrascaled devices based on 2D materials.

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Ultrathin Two-Dimensional Multinary Layered Metal Chalcogenide Nanomaterials

Ultrathin two-dimensional (2D) layered transition metal dichalcogenides (TMDs), such as MoS₂, WS₂, TiS₂, TaS₂, ReS₂, MoSe₂ and WSe₂, have attracted considerable attention over the past six years owing to their unique properties and great potential in a wide range of applications. Aiming to achieve tunable properties and optimal application performances, great effort is devoted to the exploration of 2D multinary layered metal chalcogenide nanomaterials, which include ternary metal chalcogenides with well-defined crystal structures, alloyed TMDs, heteroatom-doped TMDs and 2D metal chalcogenide heteronanostructures. These novel 2D multinary layered metal chalcogenide nanomaterials exhibit some unique properties compared to 2D binary TMD counterparts, thus holding great promise in various potential applications including electronics/optoelectronics, catalysis, sensors, biomedicine, and energy storage and conversion with enhanced performances. This article focuses on the state-of-art progress on the preparation, characterization and applications of ultrathin 2D multinary layered metal chalcogenide nanomaterials.

The exploration of 2D multinary layered metal chalcogenide nanomaterials garners great efforts, aiming to achieve tunable properties and optimal application performances. This Review focuses on the state-of-art progress in the preparation and characterization of ultrathin 2D multinary layered metal chalcogenide nanomaterials, and their potential application in electronics/optoelectronics, catalysis, sensors, biomedicine, and energy storage and conversion.

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Getting Drugs Across Biological Barriers

The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here an overview of approaches that have been taken to crossing biological barriers is presented, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.

Biological barriers throughout the body present challenges for drug delivery. Chemical, physical, and biomolecule-mediated approaches to overcoming biological barriers have been developed for a variety of anatomic locations. The mechanisms and applications of these approaches are reviewed.

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Atomic Force Microscopy as a Tool to Assess the Specificity of Targeted Nanoparticles in Biological Models of High Complexity

The ability to design nanoparticle delivery systems capable of selectively target their payloads to specific cell populations is still a major caveat in nanomedicine. One of the main hurdles is the fact that each nanoparticle formulation needs to be precisely tuned to match the specificities of the target cell and route of administration. In this work, molecular recognition force spectroscopy (MRFS) is presented as a tool to evaluate the specificity of neuron-targeted trimethyl chitosan nanoparticles to neuronal cell populations in biological samples of different complexity. The use of atomic force microscopy tips functionalized with targeted or non-targeted nanoparticles made it possible to assess the specific interaction of each formulation with determined cell surface receptors in a precise fashion. More importantly, the combination of MRFS with fluorescent microscopy allowed to probe the nanoparticles vectoring capacity in models of high complexity, such as primary mixed cultures, as well as specific subcellular regions in histological tissues. Overall, this work contributes for the establishment of MRFS as a powerful alternative technique to animal testing in vector design and opens new avenues for the development of advanced targeted nanomedicines.

Evaluation of neuron-targeted trimethyl-chitosan nanoparticles specificity toward neuronal cell populations in samples of different complexity and biological relevance by molecular recognition force spectroscopy (MRFS). This work puts forward MRFS as a valuable tool for the design and characterization of new targeted formulations that will lead to the development of more robust and advanced nanomedicines.

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Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications

During the past few decades, supercritical fluid (SCF) has emerged as an effective alternative for many traditional pharmaceutical manufacturing processes. Operating active pharmaceutical ingredients (APIs) alone or in combination with various biodegradable polymeric carriers in high-pressure conditions provides enhanced features with respect to their physical properties such as bioavailability enhancement, is of relevance to the application of SCF in the pharmaceutical industry. Herein, recent advances in drug delivery systems manufactured using the SCF technology are reviewed. We provide a brief description of the history, principle, and various preparation methods involved in the SCF technology. Next, we aim to give a brief overview, which provides an emphasis and discussion of recent reports using supercritical carbon dioxide (SC-CO₂) for fabrication of polymeric carriers, for applications in areas related to drug delivery, tissue engineering, bio-imaging, and other biomedical applications. We finally summarize with perspectives.

The supercritical carbon dioxide technology utilizes carbon dioxide in its supercritical state as it is non-toxic, cost-effective, and environmental-friendly. This green technology produces polymeric carriers in various forms by altering critical conditions such as temperature and pressure during the fabrication process. We provide an overview of the history, principle, and preparation methods involving this versatile technology and its use in fabrication of polymeric carriers for applications in drug delivery and related biomedical areas.

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Fine-needle aspiration findings of a rare hematopoietic neoplasm presenting as obstructive jaundice

Abstract

A 51-year-old female who presented with obstructive jaundice was found to have masses in the pancreatic head and tail as well as suspicious liver and periaortic masses on imaging. Aspiration cytology of the pancreatic tail mass showed abundant large single cells with vacuolated eosinophilic cytoplasm, marked nuclear pleomorphism, large bizarre irregular nuclei, binucleation, and prominent nucleoli. Numerous cells also showed intracytoplasmic black to brown pigmentation. A cell block was obtained and extensive immunohistochemical staining was performed. S-100, HMB-45, Sox10, pancytokeratin, CK7, RCC antigen, synaptophysin, HepPar 1, inhibin, CD45, CD21, and CD123 were negative, making melanoma, epithelial malignancies, lymphoma, follicular dendritic and plasmacytoid dendritic cell neoplasms less likely. CD4 and CD56 showed partial positivity, and CD68, CD163, and CD14 were positive, supporting the diagnosis of histiocytic sarcoma. Surgical specimens and immunohistochemistry confirmed the cytologic findings. Histiocytic sarcoma is a rare aggressive malignancy of histiocytic origin with most cases presenting in adults in extranodal sites, most commonly the intestinal tract. Few cases are reported in the literature, presenting diagnostic challenges for cytopathologists when seen on fine-needle aspiration. We present the first reported case of histiocytic sarcoma presenting as a pancreatic mass, diagnosed by endoscopic ultrasound guided fine-needle aspiration (EUS-FNA). This entity is rarely described on cytology and arose in a location in which EUS-FNA is the diagnostic modality of choice. This case study highlights that cytopathologists should be aware of histiocytic sarcoma occurring in extranodal locations accessible by EUS-FNA and be familiar with the cytomorphologic appearance.

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Quality assessment and improvement of “Unsatisfactory” liquid-based cervicovaginal papanicolaou smears

Objectives

The quality of cervicovaginal smears determines the success of cytology in screening programs for cervical cancer. Bethesda 2014 revisited the adequacy criteria for atrophic smears and redefined the squamous cell count in the "unsatisfactory" category. In this study, we evaluated the smear quality of Thinprep liquid-based cervicovaginal Papanicolaou cytology slides (TPS) that were previously deemed unsatisfactory, to determine reasons for such categorization. In addition, we attempted to establish the impact of the new adequacy criteria on the rate and management of unsatisfactory diagnosis.

Methods

About 234 unsatisfactory TPS were examined. The reasons for unsatisfactory were noted. The number of squamous cells was recounted, as per the new Bethesda criteria, in borderline adequacy cases that showed an atrophic pattern.

Results

The leading cause for unsatisfactory TPS was lubricating gel, followed by blood, as observed in older and younger age groups, respectively (Figure 1). Eleven borderline cases were reclassified as "satisfactory" using the new Bethesda cell count, with 27% above 60 years of age. About 82% of these borderline cases were negative for intraepithelial lesion or malignancy on repeat testing.

Conclusions

There was no difference of management or change in rate of unsatisfactory when patients above 60 were reclassified into the satisfactory category using the new Bethesda count. However, a larger study is needed to evaluate whether the new recommendation for minimum cellularity can be implemented in patients above a certain age cut-off. The study highlights the need for improvement in collection practices and education of practitioners.

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Anti-TNF treatment in Crohn's disease and risk of bowel resection—a population based cohort study

SUMMARY

Background

TNF inhibitors (TNFi) have been shown to reduce the need for surgery in Crohn's disease, but few studies have examined their effect beyond the first year of treatment.

Aim

To conduct a register-based observational cohort study in Sweden 2006-2014 to investigate the risk of bowel resection in bowel surgery naïve TNFi-treated Crohn's disease patients and whether patients on TNFi ≥12 months are less likely to undergo bowel resection than patients discontinuing treatment before 12 months.

Methods

We identified all individuals in Sweden with Crohn's disease through the Swedish National Patient Register 1987-2014 and evaluated the incidence of bowel resection after first ever dispensation of adalimumab or infliximab from 2006 and up to 7 years follow-up.

Results

We identified 1856 Crohn's disease patients who had received TNFi. Among these patients, 90% treatment retention was observed at 6 months after start of TNFi and 65% remained on the drug after 12 months. The cumulative rates of surgery in Crohn's disease patients exposed to TNFi years 1-7 were 7%, 13%, 17%, 20%, 23%, 25% and 28%. Rates of bowel resection were similar between patients with TNFi survival <12 months and ≥12 months respectively (P=.27). No predictors (eg, sex, age, extension or duration of disease) for bowel resection were identified.

Conclusions

The risk of bowel resection after start of anti-TNF treatment is higher in regular health care than in published RCTs. Patients on sustained TNFi treatment beyond 12 months have bowel resection rates similar to those who discontinue TNFi treatment earlier.

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Fear of childbirth and depressive symptoms among postnatal women: A cross-sectional survey from Chhattisgarh, India

Publication date: Available online 27 July 2017
Source:Women and Birth
Author(s): Paridhi Jha, Margareta Larsson, Kyllike Christensson, Agneta Skoog Svanberg
BackgroundPrevalence rates of Fear of Birth and postnatal depressive symptoms have not been explored in Chhattisgarh, India.ObjectiveTo validate Hindi Wijma Delivery Experience Questionnaire and to study the prevalence of Fear of Birth and depressive symptoms among postnatal women.MethodsA cross-sectional survey at seventeen public health facilities in two districts of Chhattisgarh, India among postnatal women who gave birth vaginally or through C-section to a live neonate. Participants were recruited through consecutive sampling based on health facility records of daily births. Data were collected through one-to-one interviews using the Wijma Delivery Experience Questionnaire Version B and the Edinburgh Postnatal Depression Scale. Non-parametric associations and linear regression data analyses were performed.ResultsThe Hindi Wijma Delivery Experience Questionnaire Version B had reliable psychometric properties. The prevalence of Fear of Birth and depressive symptoms among postnatal women were 13.1% and 17.1%, respectively, and their presence had a strong association (p<0.001). Regression analyses revealed that, among women having vaginal births: coming for institutional births due to health professionals' advice, giving birth in a district hospital and having postnatal depressive symptoms were associated with presence of FoB; while depressive symptoms were associated with having FoB, perineal suturing without pain relief, and giving birth to a low birth-weight neonate in a district hospital.ConclusionThe prevalence of Fear of Birth and depressive symptoms is influenced by pain management during childbirth and care processes between women and providers. These care practices should be improved for better mental health outcomes among postnatal women.



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Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD

Summary

Background

The accuracy of available non-invasive tools for staging severe fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is still limited.

Aim

To assess the diagnostic performance of paired or serial combination of non-invasive tools in NAFLD patients.

Methods

We analysed data from 741 patients with a histological diagnosis of NAFLD. The GGT/PLT, APRI, AST/ALT, BARD, FIB-4, and NAFLD Fibrosis Score (NFS) scores were calculated according to published algorithms. Liver stiffness measurement (LSM) was performed by FibroScan.

Results

LSM, NFS and FIB-4 were the best non-invasive tools for staging F3-F4 fibrosis (AUC 0.863, 0.774, and 0.792, respectively), with LSM having the highest sensitivity (90%), and the highest NPV (94%), and NFS and FIB-4 the highest specificity (97% and 93%, respectively), and the highest PPV (73% and 79%, respectively). The paired combination of LSM or NFS with FIB-4 strongly reduced the likelihood of wrongly classified patients (ranging from 2.7% to 2.6%), at the price of a high uncertainty area (ranging from 54.1% to 58.2%), and of a low overall accuracy (ranging from 43% to 39.1%). The serial combination with the second test used in patients in the grey area of the first test and in those with high LSM values (>9.6 KPa) or low NFS or FIB-4 values (<−1.455 and <1.30, respectively) overall increased the diagnostic performance generating an accuracy ranging from 69.8% to 70.1%, an uncertainty area ranging from 18.9% to 20.4% and a rate of wrong classification ranging from 9.2% to 11.3%.

Conclusion

The serial combination of LSM with FIB-4/NFS has a good diagnostic accuracy for the non-invasive diagnosis of severe fibrosis in NAFLD.

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Acquired pachydermatoglyphia: the cutaneous manifestation of pulmonary tumours

Description

A 74-year-old man with active smoking habits presented to the emergency department with a 2-month history of weight loss (20% of previous body mass), dyspnoea and night sweats. Physical examination showed clinical signs of respiratory distress, significant cachexia and thickened velvety palms with pronounced folds (figure 1). The laboratory results revealed leucocytosis of 15 700 cells/µl, thrombocytosis of 547 000/µl and elevated C reactive protein of 6.65 mg/dL. A posteroanterior chest radiograph showed a right pleural effusion and consolidation suggestive of pneumonia.

Figure 1

Thickened velvety palms with pronounced folds consistent with acquired pachydermatoglyphia.

The patient was given antibiotics and submitted to pleural effusion drainage for symptomatic relief. A skin biopsy of the palms was obtained and the histopathological examination identified signs of hyperkeratosis, acanthosis and papillomatosis consistent with acquired pachydermatoglyphia (figure 2).

Figure 2

Skin biopsy consistent with acquired...

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Bacteraemia and liver abscess due to Fusobacterium necrophorum

Fusobacterium necrophorum is the oropharyngeal pathogen usually associated with Lemierre's syndrome, a pharyngeal infection which evolves to sepsis, septic emboli and thrombophlebitis of the adjacent neck vessels. It is an uncommon causative bacteria of a liver abscess, and an extensive workup should, therefore, be performed in order to rule out potential sources of the infection. This case report describes the workup that led to the diagnosis of a colorectal carcinoma, which was deemed to be the source of the Fusobacterium bacteraemia.

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Hypertrophic olivary degeneration

Description

A 30-year-old man underwent MRI of the internal auditory meatus as a routine follow-up after excision of a large left vestibular schwannoma, 2.5 years previously. MRI images showed an incidental finding of left hypertrophic olivary degeneration (figure 1 and figure 2). This phenomenon occurs as a result of Wallerian degeneration of the olivary nucleus secondary to a lesion in the triangle of Guillain and Mollaret, also known as the dento-rubro-olivary pathway (figure 3). The differential diagnoses of hypertrophic olivary degeneration include infarction, infection, neoplasms and demyelination. Differentials can be excluded by the absence contrast enhancement (figure 2).

Figure 1

Axial T2-weighted sequence showing intratumoral haemorrhage within a large left cerebello-pontine angle lesion in keeping with a vestibular schwannoma (panel A). Axial fluid attenuated inversion recovery (FLAIR) image through the posterior fossa after 6 months demonstrating atrophic changes and haemosiderin deposition in the left middle cerebellar peduncle...

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Hiatal hernia mimicking heart problems

Description

A 73-year-old man presented to the emergency department with symptoms of acute coronary syndrome. Findings on examination were dyspnoea, chest tightness and a burning sensation behind the sternum.

On admission, 3 hours after the onset of symptoms, his 12-lead ECG showed a left bundle branch block. Cardiac enzymes revealed only marginally elevated creatine kinase, aspartate transaminase and lactate dehydrogenase levels; however, troponin I (<0.04 ng/mL) was increased to 17 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) to 1472 pg/mL (73 year normal range: 10–220 pg/mL). Though the consulting cardiologist determined coronary angiography to be unnecessary at the time, the patient was promptly sent to the intensive care unit (ICU) for monitoring and for quick intervention, if needed.

At that time, further information was gathered from the patient and his family. Apparently, the symptoms had started during lunch. The patient had experienced these symptoms several times in the preceding months; this time, however, the...

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Postoperative gluteal compartment syndrome following microsurgical free-flap hand reconstruction: the importance of early recognition and treatment

Compartment syndrome, a surgical emergency, is caused by an increase in pressure within a closed osseofascial space, often due to trauma. This causes a decrease in tissue perfusion and ultimately tissue necrosis and multiorgan failure if not treated in a timely fashion. Gluteal compartment syndrome is a rare variant and often caused by a period of immobilisation secondary to intoxication with alcohol or drugs or during long operations, typically in the supine position. We report on a case of gluteal compartment syndrome developing in a patient postoperatively following a long microsurgical procedure to a hand, which has not been documented before. Although rare, we highlight the clinical course and diagnostic criteria, which are essential for early identification and treatment.

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Adjunctive extracorporeal carbon dioxide removal in refractory status asthmaticus

Status asthmaticus (SA) is a life-threatening disorder. Severe respiratory failure may require extracorporeal membrane oxygenation (ECMO). Previous reports have demonstrated utility of ECMO in SA in various patients with varying success. A 25-year-old man was admitted with status asthmatics and severe hypercapnic respiratory failure. Despite tailored ventilator therapies, such as pressure control ventilation and maximal pharmacological therapy, including general anaesthesia, the patientâ™s condition deteriorated rapidly. Veno-venous ECMO (VV-ECMO) was provided for respiratory support. The patientâ™s clinical condition improved over the following 72âhours and was discharged from the intensive care unit on day 3. This case report demonstrates the successful use of VV-ECMO in a patient with severe respiratory failure due to SA, who failed to respond to maximal therapy. This case adds support to a growing body of literature that shows that ECMO can be used with success for refractory status asthmaticus.

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Intraparotid ductal ectasia: rare cause of parotid swelling

A 41-year-old patient was hospitalised for a chronic right parotid mass. A cervical ultrasound revealed a cystic mass of the parotid. Cervical MRI found a ductal ectasia of the parotid and submandibular glands associated with a retention cyst of the right parotid. He had a right total parotidectomy. Histopathological examination of the lesion revealed a multilocular cystic mass with a diffuse glandular ectasia of salivary ducts. The patient had an uneventful postoperative course without any recurrence of symptoms.

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Gamna-Gandy nodules of the spleen and asplenism in SLE: a novel association?

Description

We present a case of a 53-year-old woman who presented to the emergency room with acute abdominal pain, fever and haemodynamic and respiratory instability and was admitted to the intensive care unit with fulminant septic shock with multiorgan failure. CT imaging of the abdomen showed no gross abnormalities, initial laboratory results are presented in table 1.

Table 1

Laboratory test results

ParameterValueReference valueUnitCRP96<10mg/LESR7<20mm/hourHb8.07.0–9.2mmol/LHt0.400.32–0.44L/LMCV9582–89fLWBC6.5

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Reversible Holmesa{euro}™ tremor due to spontaneous intracranial hypotension

Holmes' tremor is a low-frequency hand tremor and has varying amplitude at different phases of motion. It is usually unilateral and does not respond satisfactorily to drugs and thus considered irreversible. Structural lesions in the thalamus and brainstem or cerebellum are usually responsible for Holmes' tremor. We present a 23-year-old woman who presented with unilateral Holmes' tremor. She also had hypersomnolence and headache in the sitting posture. Her brain imaging showed brain sagging and deep brain swelling due to spontaneous intracranial hypotension (SIH). She was managed conservatively and had a total clinical and radiological recovery. The brain sagging with the consequent distortion of the midbrain and diencephalon was responsible for this clinical presentation. SIH may be considered as one of the reversible causes of Holmes' tremor.

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Androgenic alopecia: an entity to consider in adolescence

Description

A 15-year-old healthy adolescent girl went to her physician consultation because she was preoccupied with progressive thinning of her hair since 11 years old. In the last year, she noticed an aggravation, with an excessive hair loss. She does not have hirsutism, acne, asthenia, menstrual irregularities or weight variations. In her family history, she reported that her mother had 'excessive hair loss after pregnancy' and her maternal aunt has alopecia of unknown aetiology. At physical examination it was observed diffuse reduction of capillary thickness and density at the frontal scalp area (figure 1) and vertex (figure 2). Rare black dots were present and the pull test was negative. The analytical study including blood count, iron kinetics, thyroid function and hormonal study had no alterations. The pelvic and adrenal gland's ultrasound were normal. At dermatology consultation, scalp biopsy revealed findings compatible with androgenic alopecia. She started treatment...

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Extramacular dome-shaped elevation: a novel finding in a case of high myopia

Description

Dome-shaped macula (DSM) is an elevation at the macula seen in about 5%–10% cases of high myopia, usually within a posterior staphyloma, caused by localised inward scleral and choroidal convexity.1 It may lead to visual deterioration when associated with serous foveal detachment (44% cases).2 3 Herein, we describe a similar but 'Extramacular dome-shaped elevation (EDSE)' associated with a large retinal hole.

A 23-year-old myopic female patient was referred to our clinic for pre refractive surgery fundus screening. She had a history of diminution of vision in the left eye more than the right eye since childhood and was using myopic glasses for the same. Best-corrected visual acuity on Snellen chart was 20/20 in the right eye and 20/200 in the left eye. Lower acuity in the left eye was attributed to anisometropic amblyopia as her refractive error was –6.75 D sphere...

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Sclerosing lymphangitis of the penis associated with marked penile oedema and skin erosions

Sclerosing lymphangitis of the penis is a benign, under-reported condition consisting of a asymptomatic firm cord-like swelling around the coronal sulcus of the penis usually affecting men in the second or third decade of life. Penile oedema and erosions are rarely reported. Clinical signs may be remarkable contrasting with the self-limited character of the disease. We report a new case of sclerosing lymphangitis of the penis occurring in a 59-year-old patient marked by penile swelling and several overlying skin erosions, and discuss the clinical features and the pathogenesis aspects of the disease.

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Directly observed therapy for clozapine with concomitant methadone prescription: a method for improving adherence and outcome

A young male presented with many years of delusions and hallucinations, with concurrent heroin use and subsequent amphetamine uses. There were no depressive or manic symptoms and psychotic symptoms prior to the amphetamine use. After the trials of two atypical antipsychotics and later clozapine due to treatment resistance, adherence and functionality were poor and there was still persistent drug use. As a result, a long acting injectable adjunct was commenced, but only minimal effects were observed. However after initiation of directly observed treatment of clozapine with methadone, there has been functional and clinical response and drug use has ceased.

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Accidental hypothermic cardiac arrest and rapid mediastinal warming with pleural lavage: a survivor after 3.5 hours of manual CPR

A 30-year-old man suffered post-traumatic hypothermic cardiac arrest. On arrival in the emergency department, rectal core temperature was 23°C. Manual cardiopulmonary resuscitation (CPR) was continued as no mechanical chest compression device was available, and active and passive rewarming was undertaken. Bilateral thoracostomies confirmed good lung inflation. Defibrillation and intravenous epinephrine were discontinued until core temperature was elevated above 30°C. Extracorporeal rewarming was unavailable. When no increase in rectal temperature was achieved after 90 min, an alternative oesophageal probe confirmed mediastinal temperature as 23°C. Bilateral chest drain insertion, followed by microwave-heated saline pleural lavage, rapidly raised the oesophageal temperature above 30°C with subsequent successful defibrillation, initially to pulseless electrical activity and finally return of spontaneous circulation 3.5 hours after the commencement of CPR. The patient recovered fully and was discharged without neurological deficit. Rapid mediastinal warming with pleural lavage should be considered in units with no access to extracorporeal rewarming service.

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Disseminated tuberculosis in relatively asymptomatic young woman

Description

A previously healthy 20-year-old woman presented to the emergency department with a history of one episode of generalised tonic–clonic seizure. No history of fever or constitutional symptoms. At admission, she was haemodynamically stable and Glasgow Coma Scale was 8, with no focal neurological deficits. For the workup of seizures, MRI brain (figure 1) was done which revealed multiple ring-enhancing lesions in bilateral temporal, frontal and right parietal lobes. Cerebrospinal fluid examination showed normal cell count with high protein (84 mg/dL) and normal glucose levels (43 mg/dL), and high adenosine deaminase (9.3 U/L) level. Chest X-ray showed (figure 2A) miliary mottling which was confirmed by contrast-enhanced CT (CECT) chest (figure 2B and C). CECT abdomen (figure 3A and B) revealed thick-walled multiloculated collection (7.3x8.4x14.2 cm) with thick internal septations in the left lumbar and iliac fossa region. Pelvic collections were drained with an image-guided pig tail insertion and...

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A perforated caecal volvulus in the foramen of Winslow

The aim of this report is to discuss with high-quality images, a case of a caecal volvulus herniating through the foramen of Winslow with signs of perforation.

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Comparison between mineralized cancellous bone allograft and an alloplast material for sinus augmentation: A split mouth histomorphometric study

Abstract

Background

Several grafting materials have been used in sinus augmentation procedures including autogenous bone, demineralized freeze-dried bone, hydroxyapatite, β-tricalcium phosphate, anorganic deproteinized bovine bone, and combination of these and others. Yet, the issue of the optimal graft material for sinus floor augmentation is controversial.

Purpose

This prospective, randomized split-mouth study was undertaken to histomorphometrically compare a biphasic calcium phosphate (BCP) alloplastic bone substitute and a human bone mineral allograft (freeze-dried bone allograft, FDBA) in patients undergoing bilateral maxillary lateral sinus floor augmentation.

Material and methods

Apico-coronal core biopsies were harvested at 9 months from 26 bilateral sites in 13 treated patients. Specimens were processed for histological and histomorphometrical analyses.

Results

Newly formed bone (NB) was evident in all specimens with values of 27.5% and 24.0% at the FDBA and BCP sites, respectively (P = .331). The residual graft particle values were 12.5% and 25.4% (P = .001), and the connective tissue values were 60.0% and 50.6%, respectively. The osteoconductive value was 52.6% for the FDBA and 26.7% for the alloplast (P = .001). The values for the measured residual graft particles, connective tissue, and osteoconductivity, but not for NB, showed highly significant differences between the two groups. All sections in the alloplast material showed evidence of a light chronic inflammatory infiltrate, mainly comprising lymphocytes and multinucleated giant cells.

Conclusions

Both graft materials are suitable for sinus floor augmentation, with the allograft material being more osteoconductive.

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Ipsilateral radial and ulnar artery cannulation during the same coronary catheterization procedure

CASE SERIES

Hippokratia 2016, 20(3):249-251

Koutouzis M¹, Ziakas A², Didagelos M², Maniotis C¹, Kyriakides Z^1
1Cardiology Department, Red Cross General Hospital, Athens, ²1^st Cardiology Department, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Left atrial appendage pericardial fluid: contrast-enhanced transesophageal echocardiography makes it visible

CASE REPORT

Hippokratia 2016, 20(3):235-237

Kamperidis V¹, Michou E¹, Kouskouras K², Nikolaidou O², Karvounis H^1
11^st Cardiology Department, ²Radiology Department, AHEPA Hospital, Medical Faculty, Aristotle University of Thessaloniki, Thessaloniki, Greece

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The results of molecular genetic testing for RET proto-oncogene mutations in patients with medullary thyroid carcinoma in a referral center after the two decade period

RESEARCH ARTICLE

Hippokratia 2016, 20(3):187-191

Rovcanin B¹, Damjanovic S², Zivaljevic V¹, Diklic A¹, Jovanovic M¹, Paunovic I^1
1Center for Endocrine Surgery , ²Institute of Endocrinology, Diabetes and Metabolic Disease, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

http://ift.tt/2tHyLhj

The effect of thoracic aortic balloon occlusion during hemorrhagic shock on spinal cord and visceral organ damage

LETTER

Hippokratia 2016, 20(3):255

Demiropoulos F¹, Papazoglou K¹, Miliaras D^2
15^th Department of Surgery, ²Laboratory of Histology and Embryology, Medical Faculty, Aristotle University of Thessaloniki, Thessaloniki, Greece

http://ift.tt/2tI7mM9

Diffusion weighted MRI and spectroscopy in invasive carcinoma of the breast at 3Tesla. Correlation with dynamic contrast enhancement and pathologic findings.

RESEARCH ARTICLE

Hippokratia 2016, 20(3):192-197

Boulogianni G¹, Chryssogonidis I², Drevelegas A^1
1Diagnostic Radiology Department, Interbalkan Medical Center, ²Diagnostic Radiology Department, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

http://ift.tt/2v4htyu

Extranodal marginal zone B-cell lymphoma arising in chronic myeloid leukaemia successfully treated with tyrosine kinase inhibitor: a case report

CASE REPORT

Hippokratia 2016, 20(3):241-243

Mihaylov G¹, Varbanova V¹, Stoeva V¹, Dikov T^2
1Clinical Hematology Department, ²Hematopathology and Immunohematology Department, National Hematological Disease Hospital, Sofia, Bulgaria

http://ift.tt/2v4p5kw

Increased oxidative stress in diabetic nephropathy and its relationship with soluble Klotho levels

RESEARCH ARTICLE

Hippokratia 2016, 20(3):198-203

Inci A¹, Olmaz R¹, Sarı F², Coban M¹, Ellidag HY³, Sarıkaya M^1
1Division of Nephrology, Internal Medicine, Antalya Training and Research Hospital, ²Division of Nephrology, Internal Medicine, Akdeniz University, Faculty of Medicine, ³Division of Biochemistry, Internal Medicine, Antalya Training and Research Hospital, Antalya, Turkey

http://ift.tt/2tIiN6s

Metastatic tumors to the head and neck region: a fifteen-year-long retrospective study

LETTER

Hippokratia 2016, 20(3):253

Krasic D¹, Trajkovic M¹, Zivkovic N^2
1Department of Maxillofacial Surgery, ²Department of Pathology, Faculty of Medicine, University of Niš, Niš, Serbia

http://ift.tt/2v4GOZf

Long-term mortality and follow-up after carotid artery stenting

RESEARCH ARTICLE

Hippokratia 2016, 20(3):204-208

Arif S, Wojtasik J, Dziewierz A, Bartuś K, Dudek D, Bartuś S
2^nd Department of Cardiology and Cardiovascular Interventions, University Hospital, Krakow, Poland

http://ift.tt/2tIbM5D

Massive bleeding in cardiac surgery. Definitions, predictors and challenges

REVIEW ARTICLE

Hippokratia 2016, 20(3):179-186

Petrou A¹, Tzimas P¹, Siminelakis S^2
1Department of Anesthesiology and Postoperative Intensive Care, ²Department of Cardiothoracic Surgery, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Hellas

http://ift.tt/2v4vRGT

Hemodynamic and respiratory factors that influence the opening of patent foramen ovale in mechanically ventilated patients

RESEARCH ARTICLE

Hippokratia 2016, 20(3):209-213

Vavlitou A¹, Minas G², Zannetos S^3, Kyprianou T¹, Tsagourias M⁴, Matamis D^4
1Intensive Care Unit, Nicosia's General Hospital, Nicosia, ²Intensive Care Unit, Limassol's General Hospital, Limassol, ³Healthcare Management Department, Faculty of Economics and Management, Open University Cyprus, Nicosia Cyprus, ⁴Intensive Care Unit, "George Papageorgiou" General Hospital, Thessaloniki, Greece

http://ift.tt/2tI3YkB

Parachute-like mitral valve as a cause of mitral regurgitation

CASE REPORT

Hippokratia 2016, 20(3):238-240

Rouskas P¹, Giannakoulas G¹, Kallifatidis A², Karvounis H^1
1Cardiology Department, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, ²Department of Radiology, St. Luke's Hospital, Thessaloniki, Greece

http://ift.tt/2v4s8sR

Association of antiviral therapy with reduced disease progression in chronic Hepatitis B patients: Results from a nation-wide cohort study

RESEARCH ARTICLE

Hippokratia 2016, 20(3):214-221

Vourli G¹, Papatheodoridis G², Raptopoulou M³, Dalekos GN⁴, Hounta A⁵, Nikolopoulou G⁶, Zouboulis-Vafeiadis I⁷, Manesis E⁸, Kitis G⁹, Gogos C¹⁰, Ketikoglou I¹¹, Hatzis G¹², Vasilialdis T¹³, Karatapanis S¹⁴, Mimidis K¹⁵, Drakoulis C¹⁶, Touloumi G¹, The HEPNET-Greece study
¹Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, Athens, ²Department of Gastroenterology, Athens University Medical School, "Laiko" General Hospital of Athens, Athens, ³4^th Medical Department, Aristotle University of Thessaloniki, Thessaloniki, ⁴Department of Medicine & Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, 4^th Department of Internal Medicine, General University Hospital "Attikon", Athens, ⁶Viral Hepatitis Committee, KEELPNO, Athens, ⁷First Department of Propaedeutic Medicine, Athens University Medical School "Laiko" General Hospital of Athens, Athens, ⁸Division of Internal Medicine, Athens University Medical School, Athens, ⁹Gastroenterology Clinic, General Hospital "G. Papanikolaou", Thessaloniki, ¹⁰Department of Infectious Diseases, Patras University Hospital, Patras, ¹¹Department of Internal Medicine, "Hippocration" General Hospital, Athens, ¹²Department of Pathophysiology, University of Athens, Athens, ¹³3^rd Department of Internal Medicine, Aristotle University of Thessaloniki, "Papageorgiou" Hospital, Thessaloniki, ¹⁴Department of Internal Medicine, General Hospital of Rhodes, Rhodes, ¹⁵Department of Medicine, Democritus University of Thrace, Alexandroupolis, ¹⁶2^nd Department of Internal Medicine, General Hospital of Nikaia, Athens, Greece

http://ift.tt/2tI7xXM

Arachnoid cysts: the role of the BLADE technique

CASE SERIES

Hippokratia 2016, 20(3):244-248

Mavroidis P^1,2, Roka V³, Kostopoulos S⁴, Batsikas G⁵, Lavdas E^6,7
1Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA, ²Department of Medical Physics, Karolinska Institutet & Stockholm University, Stockholm, Sweden, ³Health Center of Farkadona, Trikala, Greece, ⁴Department of Medical Instruments Technology, Technological Education Institute of Athens, Athens, Greece, ⁵Department of Medical Imaging, IASO Thessalias Hospital, Larissa, Greece, ⁶Department of Medical Radiological Technologists, Technological Education Institute of Athens, Athens, Greece, ⁷Department of Medical Imaging, Animus kyanoys Larissa Hospital, Larissa, Larissa, Greece

http://ift.tt/2v4fla6

Interobserver and intraobserver reliability of Salter-Harris classification of physeal injuries

RESEARCH ARTICLE

Hippokratia 2016, 20(3):222-226

Tzavellas AN, Kenanidis E, Potoupnis M, Pellios S, Tsiridis E, Sayegh F
3^rd Academic Orthopaedic Unit, Medical School, Aristotle University of Thessaloniki, "Papageorgiou" General Hospital, Thessaloniki, Greece

http://ift.tt/2tI7rPU

Maximizing native arteriovenous fistulae rates in patients with diabetes mellitus. Is routine color Doppler vascular mapping in preoperative planning of value?

LETTER

Hippokratia 2016, 20(3):252

Giannikouris IE^1,2, Bacchini GM^1
1Department of Nephrology, Dialysis and Transplantation, Alessandro Manzoni Hospital, Lecco, Italy, ²Medifil AE, Hemodialysis Center, Peristeri, Attiki, Greece

 

http://ift.tt/2v44Jrw

Bone involvement at diagnosis as a predictive factor in children with acute lymphoblastic leukemia

RESEARCH ARTICLE

Hippokratia 2016, 20(3):227-230

Tragiannidis A, Vasileiou E, Papageorgiou M, Damianidou L, Hatzipantelis E, Gombakis N, Giannopoulos A
2^nd Pediatric Department, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

http://ift.tt/2tHGSdJ

Double valvular dysfunction in a 4-year-old girl with tuberous sclerosis

LETTER

Hippokratia 2016, 20(3):254

Gogou M,  Keivanidou A, Giannopoulos A
2^nd Department of Pediatrics, AHEPA General Hospital, Medical Faculty, Aristotle University of Thessaloniki, Greece

http://ift.tt/2v4iWF9

Unusual case of stroke related to Kocuria Kristinae endocarditis treated with surgical procedure

CASE REPORT

Hippokratia 2016, 20(3):231-234

Aleksic D, Miletic-Drakulic S, Boskovic-Matic T, Simovic S, Toncev G
Department of Neurology, Faculty of Medical Science, University of Kragujevac, Kragujevac, Serbia

http://ift.tt/2tHQp4z

Aberrant right hepatic artery originating from the superior mesenteric artery discovered incidentally during Longmire-Traverso operation

LETTER

Hippokratia 2016, 20(3):256

Papaziogas B¹, Kapoulas S¹, Christoforidis E^1
12^nd Surgical Clinic, Aristotle University of Thessaloniki, G.Gennimatas Hospital, Greece

http://ift.tt/2tI3niP

131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment

Purpose: <p>Camelid single-domain antibody-fragments (sdAbs) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here we describe the generation of a ¹³¹I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.</p> <br />Experimental Design: <p>Anti-HER2 sdAb 2Rs15d was labeled with ¹³¹I using [¹³¹I]SGMIB and evaluated in vitro. Biodistribution was evaluated in two HER2⁺ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [¹³¹I]SGMIB-2Rs15d  was investigated in two HER2⁺  tumor  mouse models. A single-dose toxicity study was performed in mice using unlabeled [¹²⁷I]SGMIB-sdAb at 1.4mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography.</p> <br />Results: <br /> <p>[¹³¹I]SGMIB-2Rs15d bound specifically to HER2⁺ cells (K_D=4.74±0.39nM). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3h. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo. [¹³¹I]SGMIB-2Rs15d alone, or in combination with trastuzumab extended median survival significantly. No toxicity was observed after injecting [¹²⁷I]SGMIB-2Rs15d.</p> <br />Conclusions: <br />These findings demonstrate the theranostic potential of [¹³¹I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [¹³¹I]SGMIB-2Rs15d, and could thereby impact therapy outcome on HER2⁺ BC patients.

http://ift.tt/2vOI8gz

Head and Neck Carcinoma Immunotherapy: Facts and Hopes

Cancer of the head and neck (HNC) is a heterogeneous disease of the upper aerodigestive tract, encompassing distinct histological types, different anatomical sites and HPV+ as well as HPV^neg cancers. Advanced/recurrent HNCs have poor prognosis with low survival rates. Tumor-mediated inhibition of anti-tumor immune responses and a high mutational burden are common features of HNCs. Both are responsible for the successful escape of these tumors from the host immune system. HNCs evolve numerous mechanisms of evasion from immune destruction. These mechanisms are linked to genetic aberrations, so that HNCs with a high mutational load are also highly immunosuppressive. The tumor microenvironment of these cancers is populated by immune cells that are dysfunctional, inhibitory cytokines and exosomes carrying suppressive ligands. Dysfunctional immune cells in patients with recurrent/metastatic HNC can be made effective by the delivery of immunotherapies in combination with conventional treatments. With many promising immune-based strategies available, the future of immune therapies in HNC is encouraging, especially since methods for genetic profiling and mapping the immune landscape of the tumor are being integrated into a personalized approach. Efficiency of immune therapies is expected to rapidly improve with the possibility for patients' selection based on personal immunogenomic profiles. Non-invasive biomarkers of response to therapy will be emerging as a better understanding of the various molecular signals coopted by the tumors is gained. The emerging role of immunotherapy as a potentially beneficial addition to standard treatments for recurrent/metastatic HNC offers hope to the patients for whom no other therapeutic options exist.

http://ift.tt/2uDgLHT

Association of FGFR1 with ER{alpha} maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer

Purpose: FGFR1 amplification occurs in ~15% of ER+ human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.<br /><br />Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 immunohistochemistry, FGFR1 FISH, and RNA-sequencing. ER+/FGFR1 amplified breast cancer cells and patient-derived xenografts (PDXs) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by co-immunoprecipitation and proximity ligation, ER genomic activity by ChIP-sequencing, and gene expression by RT-PCR.<br /><br />Results: ER+/FGFR1 amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER+/FGFR1 amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from FGFR1-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.<br /><br />Conclusions: These data suggest the ERα pathway remains active in estrogen-deprived ER+/FGFR1-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists.

http://ift.tt/2vOnnS6

Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient survival

Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.<br /><br />Experimental Design: Patient-resected GBM, the cancer genome atlas, human T cell:GBM co-cultures, as well as nu/nu, NOD-scid and humanized (NSG-SGM3-BLT) mice engrafted human GBM, form the basis of our investigation.<br /><br />Results: In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P=0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially-engrafted human GBM revealed an IFNg-associated T cell-mediated increase of intratumoral IDO1. <br /><br />Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T cell-mediated effects against GBM, should consider combinatorial approaches that co-inhibit potential T cell-mediated IDO1 enhancement during therapy.

http://ift.tt/2uDHB2F

T2-FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower Grade Gliomas: A TCGA/TCIA Project

Purpose: Lower grade gliomas (WHO grade II/III) have been classified into clinically-relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower grade glioma molecular subtypes.<br /><br />Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n=125) were evaluated by 2 independent neuroradiologists to assess: 1) presence/absence of homogenous signal on T2WI; 2) presence/absence of "T2-FLAIR mismatch" sign; 3) sharp or indistinct lesion margins; 4) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review, and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort (n=82) was analyzed to validate the T2-FLAIR mismatch sign. <br /><br />Results: Among TCGA/TCIA cases, inter-reader agreement was calculated for lesion homogeneity (ĸ=0.234 [0.111-0.358]), T2-FLAIR mismatch sign (ĸ=0.728 [0.538-0.918]), lesion margins (ĸ=0.292 [0.135-0.449]), and peritumoral edema (ĸ=0.173 [0.096-0.250]). All 15 cases that were positive for the T2-FLAIR mismatch sign were IDH-mutant, 1p/19q-non-codeleted tumors (p<0.0001; PPV=100%, NPV=54%). Analysis of the validation cohort demonstrated substantial inter-reader agreement for the T2-FLAIR mismatch sign (ĸ=0.747 [0.536 - 0.958]); all 10 cases positive for the T2-FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (p<0.00001; PPV=100%, NPV=76%). <br /><br />Conclusion: Among lower grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q-non-codeleted molecular subtype.

http://ift.tt/2vOvBKi

Gene Copy Number Estimation From Targeted Next Generation Sequencing Of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification.

Abstract <p>Purpose</p> <p>Precise detection of copy number aberrations (CNAs) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next generation sequencing (NGS) is inexpensive, high throughput and easily feasible, allowing single nucleotide variant calls, but CNA estimation from this remains challenging..</p> <p>Experimental Design</p> <p>We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration resistant prostate cancer biopsies, and used capture based whole exome sequencing (WES), array comparative genomic hybridization (aCGH), and fluorescent in situ hybridization (FISH) to explore the viability of this approach.</p> <p>Results</p> <p>We showed that this method produced highly reproducible CNA results (r=0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted next generation sequencing were comparable with WES (r=0.86) and aCGH (r=0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN and RB1) CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results.</p> <p>The frequency of CNAs in our population was comparable to that previously described (ie. deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intra-tumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.</p> <p>Conclusion</p> <p>Targeted NGS and CNVkit based analyses provide a robust, precise, high throughput and cost effective method for CNA estimation for the delivery of more precise patient care.  

http://ift.tt/2uDgUv1

Exposure-Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies

Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure-response analysis to inform the phase II trial design. <p>Experimental Design: Pharmacokinetic, efficacy and safety data from 95 patients, who were administered 10 to 100 mg BID doses of veliparib for either 8, 14 or 21 days with T+C, were utilized for exposure-efficacy (objective response and overall survival) and exposure-safety (≥Grade 3  mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment and number of prior therapies.</p> <p>Results: The odds of having objective response were 1.08-fold with 1000 ng.hr/mL increase in AUC, 1.8-fold with >8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN) and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1000 ng.hr/mL increase in AUC, 39% with >8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥Grade 3 mucositis increased by 29% with 1000 ng.hr/mL increase in AUC.</p> Conclusions: Despite shallow exposure-efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC₅₀. Shallow exposure-mucositis relationship also supports the 80 mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg BID for at least 14 days in combination with T+C is recommended to be studied in MPN patients.

http://ift.tt/2vOjf4U

Numb-/low enriches a castration resistant prostate cancer cell subpopulation associated with enhanced Notch and Hedgehog signaling

Purpose: To elucidate the role and molecular mechanism of Numb in prostate cancer (PCa) and the functional contribution of Numb^-/low PCa cells in castration resistance.<br /><br />Experimental Design: The expression of Numb was assessed using multiple Oncomine datasets and PCa tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human PCa cell lines were investigated in vitro and in vivo. In addition, we developed a reliable approach to distinguish between PCa cell populations with a high or low endogenous expression of Numb protein using a Numb promoter based lentiviral reporter system. The difference between Numb^-/low and Numb^high PCa cells in the response to androgen deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting and quantitative real-time PCR.<br /><br />Results: We show here that Numb was down-regulated and negatively correlated with PCa advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and CRPC development by suppressing Notch and Hedgehog signaling. Using a Numb promoter based lentiviral reporter system, we were able to distinguish Numb^-/low PCa cells from Numb^high cells. Numb^-/low PCa cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell-associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb^-/low cells in response to ADT.<br /><br />Conclusions:Numb^-/low enriches a castration resistant PCa cell subpopulation that is associated with unregulated Notch and Hedgehog signaling.

http://ift.tt/2uCJcpg

Towards precision radiotherapy for use with immune checkpoint blockers

The first evidence that radiation therapy (RT) enhances the efficacy of immune checkpoint blockers (ICBs) was obtained a dozen years ago in a mouse model of metastatic carcinoma refractory to anti-CTLA-4 treatment. At the time, ICBs had just entered clinical testing, an endeavor that culminated in 2011 with the approval of the first anti-CTLA-4 antibody for use in metastatic melanoma patients (ipilimumab). Thereafter, some patients progressing on ipilimumab showed systemic responses only upon receiving radiation to one lesion, confirming clinically the pro-immunogenic effects of radiation. Preclinical data demonstrate that multiple immunomodulators synergize with RT to cause the regression of irradiated tumors and, less often, non-irradiated metastases. However, the impact of dose and fractionation on the immunostimulatory potential of RT has not been thoroughly investigated. This issue is extremely relevant given the growing number of clinical trials testing the ability of RT to increase the efficacy of ICBs. Recent data demonstrate that the recruitment of dendritic cells to neoplastic lesions (and hence the priming of tumor-specific CD8⁺ T cells) is highly dependent on RT dose and fractionation through a mechanism that involves the accumulation of double stranded DNA in the cytoplasm of cancer cells and consequent type I interferon release. The molecular links between the cellular response to RT and type I interferon secretion are just being uncovered. Here, we discuss the rationale for an optimized use of RT, as well as candidate biomarkers that may predict clinical responses to RT combined with ICBs.

http://ift.tt/2tO3s8M

miRomics and proteomics reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc feedback loop modulated by HDGF/DDX5/{beta}-catenin complex in lung adenocarcinoma

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.<br /><br />Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EDU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance, western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The  miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and Co-immunoprecipitation combined with mass spectrometry and  GST pull-down were respectively designed to analyze the DNA-protein complex and HDGF/DDX5/β-catenin complex.<br /><br />Results:We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to Cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK-Ras-c-Myc signaling thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF-β-catenin-c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA-FAK-Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin-c-Myc, which suppresses miR-296-3p and further activates PRKCA-FAK-Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with  HDGF/DDX5, but not PRKCA. <br /><br />Conclusions:Our study provides a novel mechanism that the miR-296-3p-PRKCA-FAK-Ras-c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC.

http://ift.tt/2vOnjBQ

Pediatric phase 1 trial and pharmacokinetic study of trebananib in relapsed solid tumors ADVL1115: A Children's Oncology Group phase 1 consortium report

Purpose: Trebananib is a first-in-class anti-angiogenic peptibody (peptide-Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose limiting toxicities (DLT), recommended phase 2 dose (RP2D) and pharmacokinetics (PK).<br /><br />Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI.<br /><br />Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n=4), anemia, thrombocytopenia, neutropenia, vomiting and hypertension (n=1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI.<br /><br />Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg.

http://ift.tt/2uDgnsS

FDA Approval Summary: Rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer

On December 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to rucaparib (RUBRACA, Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. FDA also approved the FoundationFocus™ CDx_BRCA test (Foundation Medicine Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 ovarian cancer patients, treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% (57/106; 95% CI: 44-64%), and median duration of response was 9.2 months (95% CI: 6.6, 11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval.

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Genome-Wide SNP Discovery and Analysis of Genetic Diversity in Farmed Sika Deer (Cervus nippon) in Northeast China Using Double-Digest Restriction-Site Associated DNA Sequencing

Sika deer are an economically valuable species for their use in traditional Chinese medicine, particularly velvet antlers. Sika deer in northeast China are mostly farmed in enclosure. Therefore, genetic management of farmed sika deer would benefit from detailed knowledge of their genetic diversity. In this study, we generated over 1.45 billion high-quality paired-end reads (288 Gbp) across 42 unrelated individuals using double-digest restriction-site associated DNA sequencing (ddRAD-seq). A total of 96,188 (29.63%) putative bi-allelic SNP loci were identified with an average sequencing depth of 23x. Based on the analysis, we found that majority of the loci had a deficit of heterozygotes (F_IS> 0) and low values of H_obs, which could be due to inbreeding and Wahlund effects. We also developed a collection of high-quality SNP probes that would likely be useful in a variety of applications in genotyping for cervid species in the future.

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The Integrated Genomic Architecture and Evolution of Dental Divergence in East African Cichlid Fishes (Haplochromis chilotes x H. nyererei)

The independent evolution of the two toothed jaws of cichlid fishes is thought to have promoted their unparalleled ecological divergence and species richness. However, dental divergence in cichlids could exhibit substantial genetic covariance and this could dictate how traits like tooth numbers evolve in different African Lakes and on their two jaws. To test this hypothesis, we used a hybrid mapping cross of two trophically divergent Lake Victoria species (Haplochromis chilotes x Haplochromis nyererei) to examine genomic regions associated with cichlid tooth diversity. Surprisingly, a similar genomic region was found to be associated with oral jaw tooth numbers in cichlids from both Lake Malawi and Lake Victoria. Likewise, this same genomic location was associated with variation in pharyngeal jaw tooth numbers. Similar relationships between tooth numbers on the two jaws in both our Victoria hybrid population and across the phylogenetic diversity of Malawi cichlids additionally suggests that tooth numbers on the two jaws of haplochromine cichlids might generally coevolve due to shared genetic underpinnings. Integrated, rather than independent, genomic architectures could be key to the incomparable evolutionary divergence and convergence in cichlid tooth numbers.

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Ras/MAPK Modifier Loci Revealed by eQTL in Caenorhabditis elegans

The oncogenic Ras/MAPK pathway is evolutionarily conserved across metazoans. Yet, almost all our knowledge on this pathway comes from studies using single genetic backgrounds, whereas mutational effects can be highly background dependent. Therefore, we lack insight in the interplay between genetic backgrounds and the Ras/MAPK-signaling pathway. Here, we used a Caenorhabditis elegans RIL population containing a gain-of-function mutation in the Ras/MAPK pathway gene let-60 and measured how gene expression regulation is affected by this mutation. We mapped eQTL and found that the majority (~73%) of the 1516 detected cis-eQTL were not specific for the let-60 mutation, whereas most (~76%) of the 898 detected trans-eQTL were associated with the let-60 mutation. We detected 6 eQTL trans-bands specific for the interaction between the genetic background and the mutation, one of which co-localized with the polymorphic Ras/MAPK modifier amx-2. Comparison between transgenic lines expressing allelic variants of amx-2 showed the involvement of amx-2 in 79% of the trans-eQTL for genes mapping to this trans-band. Together, our results have revealed loci hidden loci affecting Ras/MAPK signaling using sensitized backgrounds in C. elegans. These loci harbor putative polymorphic modifier genes that would not have been detected using mutant screens in single genetic backgrounds.

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The Caenorhabditis elegans Female State: Decoupling theTranscriptomic Effects of Aging and Sperm-Status

Understanding genome and gene function in a whole organism requires us to fully comprehend the life cycle and the physiology of the organism in question. Caenorhabditis elegans XX animals are hermaphrodites that exhaust their sperm after 3 days of egg-laying. Even though C. elegans can live for many days after cessation of egg-laying, the molecular physiology of this state has not been as intensely studied as other parts of the life cycle, despite documented changes in behavior and metabolism. To study the effects of sperm depletion and aging of C. elegans during the first 6 days of adulthood, we measured the transcriptomes of 1st day adult hermaphrodites; 6th day sperm-depleted adults; and at the same time points, mutant fog-2(lf) worms that have a feminized germline phenotype. We found that we could separate the effects of biological aging from sperm depletion. For a large subset of genes, young adult fog-2(lf) animals had the same gene expression changes as sperm-depleted 6th day wild-type hermaphrodites, and these genes did not change expression when fog-2(lf) females reached the 6th day of adulthood. Taken together, this indicates that changing sperm status causes a change in the internal state of the worm, which we call the female-like state. Our data provide a high-quality picture of the changes that happen in global gene expression throughout the period of early aging in the worm.

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The Douglas-Fir Genome Sequence Reveals Specialization of the Photosynthetic Apparatus in Pinaceae

A reference genome sequence for Pseudotsuga menziesii var. menziesii (Mirb.) Franco (Coastal Douglas-fir) is reported, thus providing a reference sequence for a third genus of the family Pinaceae. The contiguity and quality of the genome assembly far exceeds that of other conifer reference genome sequences (contig N50 = 44,136 bp and scaffold N50 = 340,704 bp). Incremental improvements in sequencing and assembly technologies are in part responsible for the higher quality reference genome, but it may also be due to a slightly lower exact repeat content in Douglas-fir versus pine and spruce. Comparative genome annotation with angiosperm species reveals gene-family expansion and contraction in Douglas-fir and other conifers which may account for some of the major morphological and physiological differences between the two major plant groups. Notable differences in the size of the NDH-complex gene family and genes underlying the functional basis of shade tolerance/intolerance were observed. This reference genome sequence not only provides an important resource for Douglas-fir breeders and geneticists but also sheds additional light on the evolutionary processes that have led to the divergence of modern angiosperms from the more ancient gymnosperms.

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Ankyrin-1 Gene Exhibits Allelic Heterogeneity in Conferring Protection Against Malaria

Allelic heterogeneity is a common phenomenon where a gene exhibit different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulted in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1^(MRI96570) mutation was found to inhibit intra-erythrocytic parasite maturation, whereas Ank-1^(MRI95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomenon to achieve a better understanding of host-parasite interactions, which could be the basis of future studies.

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Panel OKs CAR T Therapy for Leukemia [News in Brief]

Novartis's tisagenlecleucel could become the first FDA-approved genetically modified T-cell therapy for cancer.

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Introduction to the Symposium: Integrative Life-History of Whole-Organism Performance

Abstract

A strong case can be made for whole-organism performance traits (i.e., dynamic, ecologically relevant traits whose expression is shaped by underlying morphological factors) as being the ultimate integrative traits. This is not only because they capture the output of multiple lower levels of biological organization, but also because they are directly relevant to individual fitness in multiple ecological contexts, and are in many cases important proximate determinants of survival and/or reproductive success. But although many ecological and evolutionary phenomena can be examined through the lens of performance (and vice-versa), performance research has been surprisingly slow to incorporate concepts from the large and important field of life-history evolution. Such a synthesis is necessary, because shifts in resource allocation strategies can have implications for these highly ecologically relevant, functional traits, whose expression may trade-off against fecundity, immune function, or longevity, among other key life-history traits. The papers in this symposium showcase many of the ways in which life-history strategies can have direct consequences for the expression, maintenance, and evolution of whole-organism performance (and at least one case where they may not). By approaching the issue of life-history trade-offs from a number of diverse perspectives, this symposium reveals the scope for future explicit integration of life-history techniques with those of whole-organism performance studies for a more complete understanding of multivariate phenotypic evolution.

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RFamide-related Peptide-3 and the Trade-off between Reproductive and Ingestive Behavior

Abstract

Ingestive and sex behaviors are important for individual survival and reproductive success, but when environmental energy availability is limited, individuals of many different species make a trade-off, forfeiting sex for ingestive behavior. For example, food-deprived female Syrian hamsters (Mesocricetus auratus) forego vaginal scent marking and lordosis (sex behaviors) in favor of foraging, hoarding, and eating food (ingestive behavior). Reproductive processes tend to be energetically costly, and individual survival requires homeostasis in metabolic energy. Thus, during energetic challenges, the chances of survival are enhanced by decreasing the energy expended on reproductive processes. The entire hypothalamic-pituitary-gonadal (HPG) system is inhibited by severe energetic challenges, but comparatively little is known about the effects of mild energetic challenges. We hypothesized that (1) a trade-off is made between sex and ingestive behavior even when the level of food restriction is insufficient to inhibit the HPG system; (2) mild energetic challenges force a trade-off between appetitive ingestive and sex behaviors, but not consummatory versions of the same behaviors; and (3) the trade-off is orchestrated by ovarian steroid modulation of RFamide-related peptide 3 (RFRP-3). In other species, RFRP-3, an ortholog of avian gonadotropin-inhibitory hormone, is implicated in control of behavior in response to energetic challenges and stressful stimuli. In support of our three hypotheses, there is a "dose-response" effect of food restriction and re-feeding on the activation of RFRP-3-immunoreactive cells in the dorsomedial hypothalamus and on appetitive behaviors (food hoarding and sexual motivation), but not on consummatory behaviors (food intake and lordosis), with no significant effect on circulating levels of estradiol or progesterone. The effect of food restriction on the activation of RFRP-3 cells is modulated at the time of estrus in gonadally-intact females and in ovariectomized females treated with progesterone alone or with estradiol plus progesterone. Intracerebral treatment with RFRP-3 results in significant decreases in sexual motivation and results in significant but small increases in food hoarding in hamsters fed ad libitum. These and other results are consistent with the idea that ovarian steroids and RFRP-3 are part of a system that orchestrates trade-offs in appetitive behaviors in environments where energy availability fluctuates.

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Putting it in Context: Linking Auditory Processing with Social Behavior Circuits in the Vertebrate Brain

Abstract

Context is critical to the adaptive value of communication. Sensory systems such as the auditory system represent an important juncture at which information on physiological state or social valence can be added to communicative information. However, the neural pathways that convey context to the auditory system are not well understood. The serotonergic system offers an excellent model to address these types of questions. Serotonin fluctuates in the mouse inferior colliculus (IC), an auditory midbrain region important for species-specific vocalizations, during specific social and non-social contexts. Furthermore, serotonin is an indicator of the valence of event-based changes within individual social interactions. We propose a model in which the brain's social behavior network serves as an afferent effector of the serotonergic dorsal raphe nucleus in order to gate contextual release of serotonin in the IC. Specifically, discrete vasopressinergic nuclei within the hypothalamus and extended amygdala that project to the dorsal raphe are functionally engaged during contexts in which serotonin fluctuates in the IC. Since serotonin strongly influences the responses of IC neurons to social vocalizations, this pathway could serve as a feedback loop whereby integrative social centers modulate their own sources of input. The end result of this feedback would be to produce a process that is geared, from sensory input to motor output, toward responding appropriately to a dynamic external world.

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Does the Treadmill Support Valid Energetics Estimates of Field Locomotion?

Abstract

Quantifying animal energy expenditure during locomotion in the field is generally based either on treadmill measurements or on estimates derived from a measured proxy. Two common proxies are heart rate (ƒ_H) and dynamic body acceleration (accelerometry). Both ƒ_H and accelerometry have been calibrated extensively under laboratory conditions, which typically involve prompting the animal to locomote on a treadmill at different speeds while simultaneously recording its rate of oxygen uptake (V˙;o₂) and the proxy. Field estimates of V˙;o₂ during locomotion obtained directly from treadmill running or from treadmill-calibrated proxies make assumptions about similarities between running in the field and in the laboratory. The present study investigated these assumptions, focusing on humans as a tractable species. First we investigated experimentally if and how the rate of energy expenditure during treadmill locomotion differs to that during field locomotion at the same speeds, with participants walking and running on a treadmill, on tarmac, and on grass, while wearing a mobile respirometry system. V˙;o₂ was substantially higher during locomotion in both of the field conditions compared with on a level treadmill: 9.1% on tarmac and 17.7% on grass. Second, we included these data in a meta-analysis of previous, related studies. The results were influenced by the studies excluded due to particulars of the experiment design, suggesting that participant age, the surface type, and the degree of turning during field locomotion may influence by how much treadmill and field locomotion V˙;o₂ differ. Third, based on our experiments described earlier, we investigated the accuracy of treadmill-calibrated accelerometry and ƒ_H for estimating V˙;o₂ in the field. The mean algebraic estimate errors varied between 10% and 35%, with the ƒ_H associated errors being larger than those derived from accelerometry. The mean algebraic errors were all underestimates of field V˙;o₂, by around 10% for f_H and varying between 0% and 15% for accelerometry. Researchers should question and consider how accurately a treadmill-derived proxy calibration of V˙;o₂ will estimate V˙;o₂ during terrestrial locomotion in free-living animals.

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Dramatic Differences in Gut Bacterial Densities Correlate with Diet and Habitat in Rainforest Ants

Abstract

Abundance is a key parameter in microbial ecology, and important to estimates of potential metabolite flux, impacts of dispersal, and sensitivity of samples to technical biases such as laboratory contamination. However, modern amplicon-based sequencing techniques by themselves typically provide no information about the absolute abundance of microbes. Here, we use fluorescence microscopy and quantitative polymerase chain reaction as independent estimates of microbial abundance to test the hypothesis that microbial symbionts have enabled ants to dominate tropical rainforest canopies by facilitating herbivorous diets, and compare these methods to microbial diversity profiles from 16S rRNA amplicon sequencing. Through a systematic survey of ants from a lowland tropical forest, we show that the density of gut microbiota varies across several orders of magnitude among ant lineages, with median individuals from many genera only marginally above detection limits. Supporting the hypothesis that microbial symbiosis is important to dominance in the canopy, we find that the abundance of gut bacteria is positively correlated with stable isotope proxies of herbivory among canopy-dwelling ants, but not among ground-dwelling ants. Notably, these broad findings are much more evident in the quantitative data than in the 16S rRNA sequencing data. Our results provide quantitative context to the potential role of bacteria in facilitating the ants' dominance of the tropical rainforest canopy, and have broad implications for the interpretation of sequence-based surveys of microbial diversity.

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ESO names Tad Druart as VP of Marketing

Leading healthcare Software-As-A-Service (SaaS) and data provider taps marketing veteran to support its rapid growth AUSTIN, Texas — ESO Solutions, Inc., a leading provider of healthcare software and data interoperability solutions to emergency medical services (EMS) and hospitals, announced that Tad Druart has joined the company as Vice President of Marketing. "We're pleased to have ...

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Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients

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A comparative study of germline BRCA1 and BRCA2 mutation screening methods in use in 20 European clinical diagnostic laboratories

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Knowledge or noise? Making sense of General Practitioners’ and Consultant use of 2-week-wait referrals for suspected cancer

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TCTP as a therapeutic target in melanoma treatment

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Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis

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Epstein-Barr virus-positive ileal carcinomas associated with Crohn’s disease

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Risk Stratification in Pediatric Acute Respiratory Distress Syndrome: A Multicenter Observational Study.

Objectives: The Pediatric Acute Lung Injury Consensus Conference developed a pediatric specific definition for acute respiratory distress syndrome (PARDS). In this definition, severity of lung disease is stratified into mild, moderate, and severe groups. We aim to describe the epidemiology of patients with PARDS across Asia and evaluate whether the Pediatric Acute Lung Injury Consensus Conference risk stratification accurately predicts outcome in PARDS. Design: A multicenter, retrospective, descriptive cohort study. Setting: Ten multidisciplinary PICUs in Asia. Patients: All mechanically ventilated children meeting the Pediatric Acute Lung Injury Consensus Conference criteria for PARDS between 2009 and 2015. Interventions: None. Measurements and Main Results: Data on epidemiology, ventilation, adjunct therapies, and clinical outcomes were collected. Patients were followed for 100 days post diagnosis of PARDS. A total of 373 patients were included. There were 89 (23.9%), 149 (39.9%), and 135 (36.2%) patients with mild, moderate, and severe PARDS, respectively. The most common risk factor for PARDS was pneumonia/lower respiratory tract infection (309 [82.8%]). Higher category of severity of PARDS was associated with lower ventilator-free days (22 [17-25], 16 [0-23], 6 [0-19]; p

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The ICU Is Becoming a Main Battlefield for Severe Maternal Rescue in China: An 8-Year Single-Center Clinical Experience.

Objectives: To review the characteristics of and to identify the reasons for severe maternal admissions to the ICU. Design: This was an analytical, observational, open, and retrospective study. Setting: In our ICU. Patients: A total of 487 severe maternal cases were reviewed during the 8-year study period of January 2009 to December 2016. Intervention: None. Measurements and Main Results: A total of 487 severe maternal cases (12.6%) among the 3,867 patients admitted to ICU were reviewed. Of these, 361 patients were admitted for obstetric reasons, mainly pregnancy-induced hypertension (58.7%) and postpartum hemorrhage (36.8%). The remaining 126 patients were admitted for nonobstetric reasons, including cardiac-related disease (31.0%), immune-related disease (24.6%), and sepsis (20.6%). A total of 249 patients experienced combined comorbidities: the most common was a scarred uterus (100 patients; 40.2%), followed by endocrine-related disease (25.3%), immune-related disease (21.3%), and cardiac-related disease (18.1%). Central venous insertion (90.6%) was the most common intervention, followed by arterial catheter insertion (33.7%), mechanical ventilation (11.7%), blood purification (5.7%), and invasive hemodynamic monitoring (3.7%). Nine patients died during the study period, of which the death of four could have been avoided. Conclusions: The number of severe maternal cases has increased annually in our ICU. Although obstetric causes remained the most common reason for admission, the nonobstetric causes and basic complications were too complex, dangerous, and beyond the reach of the obstetrician with regard to monitoring and treatment. We call for a multidisciplinary team mainly composed of ICU staff to improve severe maternal outcomes. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Composite Agency: Semiotics of Modularity and Guiding Interactions

Abstract

Principles of constructivism are used here to explore how organisms develop tools, subagents, scaffolds, signs, and adaptations. Here I discuss reasons why organisms have composite nature and include diverse subagents that interact in partially cooperating and partially conflicting ways. Such modularity is necessary for efficient and robust functionality, including mutual construction and adaptability at various time scales. Subagents interact via material and semiotic relations, some of which force or prescribe actions of partners. Other interactions, which I call "guiding", do not have immediate effects and do not disrupt the evolution and learning capacity of partner agents. However, they modify the extent of learning and evolutionary possibilities of partners via establishment of scaffolds and constraints. As a result, subagents construct reciprocal scaffolding for each other to rebalance their communal evolution and learning. As an example, I discuss guiding interactions between the body and mind of animals, where the pain system adjusts mind-based learning to the physical and physiological constraints of the body. Reciprocal effects of mind and behaviors on the development and evolution of the body includes the effects of Lamarck and Baldwin.

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Engraftment and Repopulation Potential of Late Gestation Fetal Rat Hepatocytes.

Background: The limited availability of donor organs has led to a search for alternatives to liver transplantation to restore liver function and bridge patients to transplantation. We have shown that the proliferation of late gestation (embryonic day 19; ED19) fetal rat hepatocytes is mitogen-independent, and that mechanisms regulating of mRNA translation, cell cycle progression and gene expression differ from those of adult rat hepatocytes. In the present study, we investigated whether E19 fetal hepatocytes can engraft and repopulate an injured adult liver. Methods: Fetal hepatocytes were isolated using a monoclonal antibody against a hepatic surface protein, leucine amino peptidase (LAP). LAP+ and LAP- fractions were analyzed by immunofluorescence and microarray. Immunopurified E19 liver cells from DPPIV+ rats were transplanted via splenic injection into partial hepatectomized DPPIV- rats that had been pretreated with mitomycin C. Results: More than a third of LAP+ fetal hepatocytes expressed ductal markers. Transcriptomic analysis revealed that these dual expressing cells represent a population of less well differentiated hepatocytes. Upon transplantation, LAP+ late gestation fetal hepatocytes formed hepatic, endothelial and ductal colonies within 1 month. By 10 months, colonies derived from LAP+ cells increased so that up to 35% of the liver was repopulated by donor-derived cells. Conclusions: Late gestation fetal hepatocytes, despite being far along in the differentiation process, possess the capacity for extensive liver repopulation. This is likely related to the unexpected presence of a significant proportion of hepatocyte marker-positive cells maintaining a less well differentiated phenotype. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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