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Issue Information

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Erratum

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World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection

Abstract

The genetic trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [−13910*T (rs4988235), −13907*G (rs41525747), −13915*G (rs41380347), −14009*G (rs869051967) and −14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest. We report here new data on the frequencies of the known LP alleles in the 'Old World' and their haplotype lineages. We examine and confirm EHH of each of the LP alleles in relation to their distinct lineages, but also show marked EHH for one of the older haplotypes that does not carry any of the five LP alleles. The region of EHH of this (B) haplotype exactly coincides with a region of suppressed recombination that is detectable in families as well as in population data, and the results show how such suppression may have exaggerated haplotype-based measures of past selection.

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Lymphatic malformation with acquired Horner syndrome in an infant

An infantpresented with right upper eyelid ptosis and was subsequently diagnosed with acquired Horner syndrome. Further evaluation revealed a right-sided cervicothoracic lymphatic malformation. At 13 weeks of age, the child underwent percutaneous intracystic sclerotherapy with a mixture of sodium tetradecyl sulphate and ethanol. Twenty-one weeks after initial treatment, ophthalmic examination showed complete resolution of the blepharoptosis and pupillary miosis. Percutaneous sclerotherapy not only effectively treated the space-occupying lymphatic malformation but also reversed the Horner syndrome that was presumably induced by neural tension (more likely) or compression.

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Rhomboencephalosynapsis

Description

A baby boy was born to healthy, unrelated parents at 34 weeks gestation by caesarean section in view of an antenatal ultrasound diagnosis of hydrocephalus. Mother had a previous miscarriage at 13 weeks gestation of a twin pregnancy. At birth, the boy weighed 2.47 kg, was well and did not require resuscitation. Pregnancy was unremarkable with no significant events. At birth, a large head circumference was noted, but fontanelles were soft. The Apgar score was 9 at 1 and 10 min, baby had a good cry and was moving all four limbs. A CT scan of brain was done at 1-day old which showed obstructive hydrocephalus at the level of the cerebral aqueduct. A ventriculoperitoneal (VP) shunt was inserted at 1-week old. The boy showed slow development over the subsequent years, he never suffered from seizures, however required growth hormone therapy. A small atrial septal defect was noted on echocardiogram. An...

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Measurement of bone mineral density as an efficacy marker in denosumab treatment of giant cell tumour of bone

Three patients with giant cell tumour of bone (GCTB) in the lower extremity, where the only surgical treatment options were amputation or severe weakening of the bone, were treated with denosumab (D-mab) to strengthen the bone mass in the tumour. In order to quantify changes in bone mineral density (BMD) in the GCTB lesion during D-mab treatment, we did repeated dual-energy X-ray absorptiometry (DXA) scans. The patients underwent operation after 3, 4 and 8 months of D-mab treatment, respectively. The tumours in all three patients responded markedly to D-mab, and up to 50% BMD increase was observed. There was almost no BMD change in the control scans in the hip and spine of the same patients. DXA scans provide no information about local tumour response, but may be of value in evaluation of the time and size of the D-mab response in GCTB, and thereby aid in finding the best timing for surgery.

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Giant mediastinal parathyroid adenoma presenting as bilateral brown tumour of mandible: a rare presentation of primary hyperparathyroidism

Hyperparathyroidism (HPT) is becoming increasingly common endocrinopathy in clinical practice. Nowadays, it is mostly diagnosed in subclinical or early clinical stage. Bony involvement in HPT has seen significant fall in incidence. Brown tumour of bone is exceptionally rare as a first manifestation of primary HPT (PHPT). Its radiological and histopathological features may be mistaken for other bony pathologies. If possibility of underlying HPT is overlooked the disease is bound to recur after surgery adding to morbidity of the patient. Here we present a case of bilateral brown tumour of mandible which was mistakenly treated as giant cell granuloma by surgical curettage. That the patient was harbouring an ectopic parathyroid adenoma with hypercalcemia causing non-specific symptoms was missed by the referring physician. This led to recurrence of the lesion. On subsequent evaluation, a giant mediastinal parathyroid adenoma causing PHPT was detected at our centre and was removed via mini sternotomy approach.

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Transcatheter valve implantation to inferior vena cava to control carcinoid symptoms

Severe carcinoid syndrome and carcinoid heart disease in neuroendocrine tumours can have a significant impact on a patient's quality of life and are a major cause of morbidity and mortality. We present a novel approach to managing a patient with medically uncontrollable carcinoid syndrome. Inferior and superior vena cava placement of transcatheter heart valves has been used to treat patients with right heart failure due to severe tricuspid and pulmonary regurgitation. However, this procedure has not been attempted to specifically reduce hormone secretion, primarily from the liver, in order to control carcinoid syndrome symptoms. We attempted this procedure in a patient with severe carcinoid disease and tricuspid regurgitation as a bridge to later definitive therapy. The procedure was technically successful, but did not improve carcinoid symptoms. The possible reasons for the failure are discussed here.

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Birt-Hogg-Dube syndrome: awareness is important!

Birt-Hogg-Dubé (BHD) is a rare syndrome of inherited renal cell carcinomas, characterised by cutaneous lesions and pulmonary cysts and pneumothorax in a vast majority of the patients. Awareness of this syndrome is important in order to refer patients for genetic counselling and personalised follow-up as soon as possible. We describe a case of a 30-year-old female referred to our institution due to incidental discovery of solid bilateral renal masses. Renal biopsies were consistent with chromophobe tumour, and bilateral nephrectomy was performed. Gross examination revealed deformed kidneys with 28 brown and solid lesions, size variable between 0.1 and 6 cm, histologically corresponding to renal cell carcinomas, chromophobe type. Genetic test was required that showed a c.573delGAinsT frameshift mutation in heterozigosity at the folliculin gene, consistent with BHD diagnosis.

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Idiopathic catastrophic thrombosis with happy ending

A 59-year-old male patient suffered three life-threatening instent thromboses after an initial resuscitation due to an ST-segment elevation myocardial infarction of the anterior cardiac wall. With a high-risk profile for heparin-induced thrombocytopenia (HIT), he was placed on argatroban after the second reinfarction. Under this apparently appropriate treatment, a third reinfarction occurred, and the patient had to undergo high-risk cardiac bypass surgery. Later on, a deep vein thrombosis and an intracardiac thrombus formed. Despite a positive screening test for HIT and a single positive result in the heparin-induced platelet aggregation test, we are not convinced that HIT was the only underlying cause for this 'catastrophic thrombotic syndrome'. We speculate that a massive generation of thrombin, reflected in consistently high D dimers and the need of copious amounts of a direct thrombin inhibitor, triggered the set of events. With this case report, we want to raise awareness for cardiac complications in patients with complex clotting disorders and share our experience in the diagnostic and therapeutic management of such an unusual scenario.

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Neuroendocrine tumour in pancreatic dorsal agenesis: a rare association

Pancreatic dorsal agenesis (PDA) is a rare congenital anomaly, usually asymptomatic, that can present with abdominal pain, pancreatitis, diabetes mellitus and jaundice. Pancreatic tumours in PDA background are extremely rare, and when they occur are mainly pancreatic ductal adenocarcinoma. We present a case of a 48-year-old female patient with incidental detection of a 26x20 mm nodular lesion of the cephalic pancreas on ultrasound. Surgery was performed and gross examination revealed PDA with a tumour developed around the Wirsung duct. Histology showed a neuroendocrine tumour G1 with neural and vascular invasion. Two and half years later, the patient is alive and without tumour relapse. Awareness of the association of PDA and pancreatic tumours is fundamental in order to develop personalised follow-up programmes.

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Adverse reaction with suvorexant for insomnia: acute worsening of depression with emergence of suicidal thoughts

A 59-year-old woman on daily peritoneal dialysis for end-stage renal failure received care at an outpatient psychiatric clinic for her diagnoses that include major depressive disorder, generalised anxiety disorder and insomnia disorder. Although there was partial improvement in the patient's mood and anxiety symptoms with antidepressant treatment, insomnia remained a persistent complaint despite adequate trials of different sleep medications. The novel hypnotic, suvorexant (Belsomra, Merck & Co.) was then initiated at the recommended bedtime dose of 10 mg and was followed by a 15 mg dose the following night. Within an hour after taking her second suvorexant dose, the severity of patient's depression symptoms worsened and was accompanied by new onset of suicidal thoughts.

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Metastatic meningioma: a rare cause of mediastinal lymphadenopathy.

Description

A 69-year-old man with known, stable atypical meningioma of the brain diagnosed 5 years previously presented with severe shortness of breath. The patient had previously been treated with surgery and radiotherapy to the brain. Chest X-ray revealed bulky mediastinal lymphadenopathy (figure 1). CT (figure 2) confirmed mediastinal and upper abdominal lymphadenopathy in addition to multiple pulmonary emboli. The patient underwent an endoscopic ultrasound and fine-needle aspiration (EUS-FNA), an established technique that enables prompt cytological sampling and assessment.1

Figure 1

Chest X-ray.

Figure 2

Contrast-enhanced CT image showing adenopathy at the level of the aortic arch.

The EUS-FNA preparations showed sheets and clusters of bland, polygonal epithelioid cells (figure 3). These demonstrated strong immunohistochemical positivity (figure 4) for epithelial membrane antigen. The final immunopanel was strongly supportive...

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Olfactory nerve hypertrophy: a clue to the presence of ipsilateral megalencephaly

Description

A boy aged 4 years presented with refractory focal seizures since 9 months of age. The seizures involved the left side of the body and consisted of clonic movements with frequent generalisation. MRI brain showed abnormal area with poor grey-white differentiation involving the right frontal lobe, especially the basifrontal region and the temporal lobe (figure 1A,B) suggesting the presence of a frontotemporal developmental malformation. Interestingly olfactory nerve hypertrophy was also noted on the same side (figure 1C,D). Video-electroencephalogram study demonstrated concurrence of the interictal (figure 2A) and ictal data (figure 2B) with the MRI defined abnormality. An 18-fluoro-2-deoxy-D-glucose positron emission tomography/CT of the brain showed severe right frontotemporal hypometabolism. The boy underwent a disconnection procedure involving the right frontal lobe sparing the motor cortex and the temporal lobe. Histopathology of the abnormal brain obtained during the surgery showed large...

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Necrotising pneumonia following influenza due to PVL-negative Staphylococcus aureus in a 64-year-old woman

Description

A 64-year-old immunocompetent woman presented to our institution during the 2016–2017 influenza A(H3N2) epidemic for cough and fever. She presented 10 days ago with an influenza syndrome, treated with ibuprofen 400 mg/day for 7 days. As the fever continued, with blood-streaked sputum, amoxicillin with clavulanic acid was prescribed for 3 days and then ceftriaxone (1 g/day). She had elevated transaminases and C reactive protein (184 mg/L). A chest X-ray was performed, showing a left pneumonia (figure 1A), and the patient was admitted in the infectious disease unit. There was no respiratory failure. Amphoric breath sound was heard at the top of the right lung. Antibiotics were modified, as levofloxacine (500 mg twice daily) was added to cefotaxime (1 g/8 hours). A CT scan of the chest was performed (figure 1B,C), showing a bifocal pneumonia involving the upper right and lower left lobes, and excavated bilateral nodules. The bronchoalveolar lavage showed a positive influenza...

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An update of pitfalls in prostate mpMRI: a practical approach through the lens of PI-RADS v. 2 guidelines

Abstract

Objectives

The aim of the current report is to provide an update in the imaging interpretation of prostate cancer on multiparametric magnetic resonance imaging (mpMRI), with a special focus on how to discriminate pathological tissue from the most common pitfalls that may be encountered during daily clinical practice using the Prostate Imaging Reporting and Data System (PI-RADS) version 2 guidelines.

Methods

All the cases that are shown in this pictorial review comply with the European Society of Urogenital Radiology (ESUR) guidelines for technical mpMRI requirements.

Results

Despite the standardised manner to report mpMRI (PI-RADS v. 2), some para-physiologic appearances of the prostate can mimic cancer. As such, it is crucial to be aware of these pitfalls, in order to avoid the under/overestimation of prostate cancer.

Conclusions

A detailed knowledge of normal and abnormal findings in mpMRI of the prostate is pivotal for an accurate management of the wide spectrum of clinical scenarios that radiologists may encounter during their daily practice.

Teaching Points

• Some para-physiologic appearances of the prostate may mimic cancer.

• Knowledge of normal and abnormal findings in prostate mpMRI is pivotal.

• Any radiologist involved in prostate mpMRI reporting should be aware of pitfalls.

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Body composition determinants of radiation dose during abdominopelvic CT

Abstract

Objectives

We designed a prospective study to investigate the in-vivo relationship between abdominal body composition and radiation exposure to determine the strongest body composition predictor of dose length product (DLP) at CT.

Methods

Following institutional review board approval, quantitative analysis was performed prospectively on 239 consecutive patients who underwent abdominopelvic CT. DLP, BMI, volumes of abdominal adipose tissue, muscle, bone and solid organs were recorded.

Results

All measured body composition parameters correlated positively with DLP. Linear regression (R² = 0.77) revealed that total adipose volume was the strongest predictor of radiation exposure [B (95% CI) = 0.027(0.024–0.030), t=23.068, p < 0.001]. Stepwise linear regression using DLP as the dependent and BMI and total adipose tissue as independent variables demonstrated that total adipose tissue is more predictive of DLP than BMI [B (95% CI) = 16.045 (11.337-20.752), t=6.681, p < 0.001].

Conclusions

The volume of adipose tissue was the strongest predictor of radiation exposure in our cohort.

Main message

• Individual body composition variables correlate with DLP at abdominopelvic CT.

• Total abdominal adipose tissue is the strongest predictor of radiation exposure.

• Muscle volume is also a significant but weaker predictor of DLP.

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Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies

Abstract

Background

Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection.

Methods

A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy.

Results

Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56–4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23–6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242).

Conclusion

Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.

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Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism

Abstract

Background

In recent years, four-dimensional computed tomography (4DCT) has emerged as a new localization study for primary hyperparathyroidism (pHPT).

Objective

We aimed to assess the added value of 4DCT in our institution in the first 4 years of use.

Methods

A retrospective cohort study was conducted from February 2004 to June 2015. Since 2011, patients over 50 years of age without concordant sestamibi-SPECT (SeS) and ultrasound (US) findings underwent 4DCT. Imaging results, surgical findings, histopathology, and postoperative biochemistry were collected.

Results

A total of 536 parathyroid operations in 510 patients were performed during the study period. The overall cure rate was 99.2% after reoperation in some patients, and the overall sensitivity for SeS was 76.0%, and 74.8% for US. Since 2011, 100 patients without concordant SeS/US findings have undergone 4DCT, with a sensitivity of 72.9%. This is in comparison to the sensitivities for SeS (48.3%) and US (52.3%). 4DCT was more sensitive in patients with persistent/recurrent disease (60.0% compared with SeS 43.8% and US 36.4%) and patients with multigland disease (67.4% compared with SeS 40.9% and US 42.1%). Comparison between outcomes in the pre- versus post-CT era demonstrated no difference in the initial cure rate (95.4 vs. 95.9%, p = 0.85) or the rate of minimally invasive parathyroidectomies (74.5 vs. 79.9%, p = 0.22).

Conclusion

Parathyroid 4DCT can aid surgical planning in cases without concordant SeS/US findings; however, the introduction of 4DCT as a second-line test did not change our overall cure rate or rate of minimally invasive parathyroidectomy. The role of 4DCT as the primary localization study for pHPT merits further investigation.

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Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy

Abstract

Background

Pre-operative ultrasound-guided needle sampling (UNS) of abnormal axillary lymph nodes in breast cancer can identify patients with axillary metastases and therefore rationalize patient care and inform decision-making. To obtain tissue diagnosis, UNS can be performed by either fine needle aspiration (FNA) or core needle biopsy (CNB). However, few studies have compared the sensitivity of these techniques and the majority show no difference.

Methods

All node-positive patients (those with micro- and macrometastases but not isolated tumor cells) treated at a tertiary referral center between January 2012 and December 2015 were retrospectively identified from pathology records. The result of the first axillary UNS performed on each patient was compared with postoperative histopathology results. The UNS method used was according to individual radiologist preference.

Results

A total of 215 patients underwent FNA (1 patient had bilateral breast cancer and underwent bilateral FNA), and 92 underwent CNB. Sensitivity of CNB was significantly higher than FNA (83.7 vs. 69.0%, P = 0.008). The false-negative rate in the FNA group was therefore higher than in the CNB group by a factor of 2.5. There was no difference in inadequacy rate between the two techniques. There were no complications in the FNA group, and only one hematoma (which did not require operative intervention) in the CNB group.

Conclusions

CNB is safe and should be the preferred technique for UNS to improve sensitivity.

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Long-Term Outcomes After R0 Resection of Synchronous Peritoneal Metastasis from Colorectal Cancer Without Cytoreductive Surgery or Hyperthermic Intraperitoneal Chemotherapy

Abstract

Background

The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: "If R0 resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers." This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods

This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance.

Results

No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis.

Conclusions

From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.

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Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Surgical Resection of Pancreatic Ductal Adenocarcinoma Appears to be Safe and Effective

Abstract

Background

A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT).

Methods

The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed.

Results

The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity.

Conclusions

Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.

http://ift.tt/2gElEwi

Disturbance of verticality perception and postural dysfunction in Parkinson's disease

Objectives

Verticality perception is known to be abnormal in Parkinson's disease (PD), but in which stage respective dysfunctions arise and how they relate to postural disorders remains to be settled. These issues were studied with respect to different dimensions of the subjective visual vertical (SVV) in relation to clinical parameters of postural control.

Materials & Methods

All participants had to orientate a luminous line at random planar orientations to a strictly vertical position using an automated operator system. The SVV was analyzed in 58 PD patients and 28 control subjects with respect to (i) the angle between true and subjective vertical (deviation) and (ii) the variability of this across five measurements (variability). Results were referred to the subjective upright head position (SUH), the disease stage, and clinical gait/balance features assessed by the MDS-UPDRS and the Tinetti test.

Results

Parkinson's disease patients had significantly higher SVV deviation and variability than controls. With respect to disease stage, deviation developed before abnormal variability. SVV variability was associated with poor balance and gait performance, as well as postural instability. Deficits in SUH and SVV deviation were correlated and mostly unidirectional, but did not correspond to the side of motor symptom dominance.

Conclusions

Visual verticality perception in PD is deviated already in early stages, conceivably as a relatively static internal misrepresentation of object orientation. Variability about verticality perception emerges in more advanced stages and is associated with postural and balance abnormalities.

http://ift.tt/2z39Viv

Integrative cancer pharmacogenomics to establish drug mechanism of action: drug repurposing

Pharmacogenomics, Ahead of Print.


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HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer

Future Oncology, Ahead of Print.


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An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms

Future Oncology, Ahead of Print.


http://ift.tt/2yDOrbd

Prenatal methamphetamine exposure is associated with corticostriatal white matter changes in neonates

Abstract

Diffusion tensor imaging (DTI) studies have shown that prenatal exposure to methamphetamine is associated with alterations in white matter microstructure, but to date no tractography studies have been performed in neonates. The striato-thalamo-orbitofrontal circuit and its associated limbic-striatal areas, the primary circuit responsible for reinforcement, has been postulated to be dysfunctional in drug addiction. This study investigated potential white matter changes in the striatal-orbitofrontal circuit in neonates with prenatal methamphetamine exposure. Mothers were recruited antenatally and interviewed regarding methamphetamine use during pregnancy, and DTI sequences were acquired in the first postnatal month. Target regions of interest were manually delineated, white matter bundles connecting pairs of targets were determined using probabilistic tractography in AFNI-FATCAT, and fractional anisotropy (FA) and diffusion measures were determined in white matter connections. Regression analysis showed that increasing methamphetamine exposure was associated with reduced FA in several connections between the striatum and midbrain, orbitofrontal cortex, and associated limbic structures, following adjustment for potential confounding variables. Our results are consistent with previous findings in older children and extend them to show that these changes are already evident in neonates. The observed alterations are likely to play a role in the deficits in attention and inhibitory control frequently seen in children with prenatal methamphetamine exposure.

http://ift.tt/2zKSqjO

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Abstract

Background

The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types.

Methods

The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded.

Results

The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods).

Conclusion

We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.

http://ift.tt/2xjMUDc

Modeling of Lymphogenous and Hematogenous Metastasizing from Murine В16 Melanoma in Rats

We developed a model of experimental melanoma. Intralienal xenogeneic transplantation of a suspension of melanoma cells B16 in physiological saline (0.1 ml; 1:10) was conducted to outbred male rats. In 6 months, histologically confirmed melanoma B16 in the spleen and its metastases in the liver, intestine, pancreas, adrenal glands, and lungs (hematogenous metastasis), as well as in the thymus and lymph nodes (lymphogenous metastasis) were revealed in rats. The proposed rat model of melanoma B16 metastasizes by the hematogenous and lymphogenous pathways, develops over 6 months, and allows receiving sufficient volume of material for analysis.

http://ift.tt/2hZWNiV

Physiopathology of Migraine: What Have We Learned from Functional Imaging?

Abstract

Purpose of Review

This review aims to provide an overview of the most recent and significant functional neuroimaging studies which have clarified the complex mechanisms underlying migraine pathophysiology.

Recent Findings

The recent data allow us to overcome the concept of a migraine generator suggesting that functional networks abnormalities may lead to changes in different brain area activities and consequent reduced migraine thresholds susceptibility, likely associated with higher migraine severity and burden.

Summary

Although functional magnetic resonance imaging studies have allowed recognition of several migraine mechanisms, its pathophysiology is not completely understood and is still a matter of research. Nevertheless, in recent years, functional magnetic resonance imaging studies have allowed us to implement our knowledge of migraine pathophysiology. The pivotal role of both the brainstem and the hippocampus in the first phase of a migraine attack, the involvement of limbic pathway in the constitution of a migrainous pain network, the disrupted functional connectivity in cognitive brain networks, as well as the abnormal function of the visual network in patients with migraine with aura are the main milestones in migraine imaging achieved through functional imaging advances. We believe that further studies based on combined functional and structural techniques and the investigation of the different phases of migraine cycle may represent an efficient methodological approach for comprehensively looking into the migrainous brain secrets.

http://ift.tt/2y1Fioo

Cellular subtype may predict survival outcomes in salivary adenoid cystic carcinoma patients—a single-institution experience

http://ift.tt/2lboiLp

Diffuse midline gliomas with subclonal H3F3A K27M mutation and mosaic H3.3 K27M mutant protein expression

http://ift.tt/2zxPzd8

Coping and adjustment in men with prostate cancer: a systematic review of qualitative studies

Abstract

Purpose

Prostate cancer (PCa) is one of the most common forms of cancer amongst males. Men's coping responses are an important determinant of functioning and adjustment to this disease. Previous qualitative research exists in this area, but the current review sought to systematically review and summarise these studies.

Methods

A systematic review was conducted to identify studies concerned with men's coping strategies in their attempts to live with PCa. A search of relevant electronic databases was conducted to identify studies that met inclusion criteria for this review. Methodological quality assessment was also undertaken for each included study.

Results

One hundred twenty-one publications were identified for initial screening, and 18 studies were included in the review. A total of five coping strategy categories or 'meta-themes' were identified across included studies. These categories were labelled 'avoidance, minimisation, and withdrawal', 'directing cognition and attention', 'reframing masculinity and seeking support', 'retain pre-illness identity and lifestyle', and 'symptom/side-effect management'.

Conclusions

A range of coping strategies were reported by men with PCa. Some of these strategies appear to be partially influenced by gender roles and masculinities. Coping meta-themes reported in this review have also been found in other research on men's coping. Strategies relating to flexible interpretation of gender roles/masculinities may be a particularly relevant category of coping responses due to the hypothesised beneficial impact of flexibility on psychological well-being.

Implications for cancer survivors

PCa survivors utilise a range of coping strategies, and the types of strategies used may have implications for men's well-being. The ability to be flexible in both coping responses used, and in the view of oneself as a man may be particularly important skills in meeting the challenges associated with this disease.

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Isolation and characterization of three new anti-proliferative Sesquiterpenes from Polygonum barbatum and their mechanism via apoptotic pathway

Abstract

Background

The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential.

Methods

The structural elucidation and characterization of the isolated compounds 1–3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D–NMR spectroscopy. Furthermore, the compounds 1–3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line.

Results

All the compounds 1–3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mouse fibroblast (NIH-3 T3) cell lines. Among these, compound 3 was found to be more cytotoxic against NCI-H460 and MCF-7 cells (IC₅₀ = 17.86 ± 0.72 and 11.86 ± 0.46 μM respectively). When compared with the standard drug cisplatin compound 3 was found to have more potent activity against NCI-H460 (IC_{50 =} 19 ± 1.24 μM) as compared to MCF-7 cell lines (IC_{50 =} 9.62 ± 0.5 μM). Compound 3 induced apoptosis in NCI-H460 cells in a dose dependent manner. It significantly downregulated, the expression of anti-apoptotic (BCL-2 L1 and p53) and increased the expression of pro-apoptotic (BAK and BAX) genes. Besides apoptosis, it also significantly reduced the cell migration and downregulated the angiogenic genes (i.e. VEGF and COX-2), thereby, inhibiting angiogenesis in NCI-H460 cells.

Conclusion

Compound 3 possesses potent anti-proliferative potential as well as induced apoptosis and inhibited the cell migration of the cancerous cells by altering the gene expression, responsible for it.

http://ift.tt/2iv0mBO

Whether intermediate-risk stage 1A, grade 1/2, endometrioid endometrial cancer patients with lesions larger than 2 cm warrant lymph node dissection?

Abstract

Background

Our research aimed to investigate whether lymphadenectomy was required in patients with intermediate-risk endometrioid endometrial cancer (EEC).

Methods

Between 1989 and 2015, 1009 patients with intermediate-risk EEC: grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter ≥ 2 cm and 818 low-risk patients with grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter < 2 cm were enrolled in this study. The rate and risk factors of node metastasis were evaluated and compared between the two risk groups. Survival data were analyzed in patients with intermediate-risk EEC with or without lymphadenectomy.

Results

In all, 624 of 1009 (61.8%) patients with intermediate-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 1.9% (12/624), whereas 394 of 818 (48.2%) patients with low-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 0.3% (1/394) (p = 0.021). Notably, intermediate-risk EEC patients with a microcystic, elongated and fragmented (MELF) pattern of invasion, lymphatic vascular space invasion (LVSI), diffuse lesions, or lesions located in the cornua were more likely to have node metastasis. The 5-year overall cancer-related survival and the recurrence-free survival rates of the 742 intermediate-risk EEC patients who were followed for more than 3 years were 99.4% and 94.7%, respectively. In intermediate-risk group, 6 patients (6/443, 1.4%) with lymphadenectomy and 9 patients (9/299, 3.0%) without lymphadenectomy recurred, with a mean recurrence time of 38.3 and 18.7 months respectively. The five-year overall and recurrence-free survival rates of intermediate-risk patients with and without lymphadenectomy were similar (100% vs 98.9%, p = 0.351; 95.2% vs 93.3%, p = 0.464).

Conclusion

Patients with intermediate-risk EEC have low nodal metastasis rate and a favorable outcome whether lymphadenectomy is performed or not. Omission of lymphadenectomy may be a reasonable option in the surgical management of patients with intermediate-risk EEC.

http://ift.tt/2z2XtPv

18 F- FDG PET/CT helps differentiate autoimmune pancreatitis from pancreatic cancer

Abstract

Background

¹⁸F-FDG PET/CT could satisfactorily show pancreatic and extra-pancreatic lesions in AIP, which can be mistaken for pancreatic cancer (PC). This study aimed to identify ¹⁸F-FDG PET/CT findings that might differentiate AIP from PC.

Methods

FDG-PET/CT findings of 26 AIP and 40 PC patients were reviewed. Pancreatic and extra-pancreatic lesions related findings, including maximum standardized uptake values (SUVmax) and patterns of FDG uptake, were identified and compared.

Results

All 26 patients with AIP had increased pancreatic FDG uptake. Focal abnormal pancreatic FDG activities were found in 38/40 (95.00%) PC patients, while longitudinal were found in 18/26 (69.23%) AIP patients. SUVmax was significantly different between AIP and PC, both in early and delayed PET/CT scans (p < 0.05). AUCs were 0.700 (early SUVmax), 0.687 (delayed SUVmax), 0.683 (early lesions/liver SUVmax), and 0.715 (delayed lesion/liver SUVmax). Bile duct related abnormalities were found in 12/26 (46.15%) AIP and 10/40 (25.00%) PC patients, respectively. Incidentally, salivary and prostate gland SUVmax in AIP patients were higher compared with those of PC patients (p < 0.05). In males,an inverted "V" shaped high FDG uptake in the prostate was more frequent in AIP than PC patients (56.00%, 14/25 vs. 5.71%, 2/35). Increased FDG activity in extra-pancreatic bile duct was present in 4/26 of AIP patients, while was observed in none of the PC patients. Only in AIP patients, both diffuse pancreatic FDG accumulation and increased inverted "V" shaped FDG uptake in the prostate could be found simultaneously.

Conclusions

¹⁸F-FDG PET/CT findings might help differentiate AIP from PC.

http://ift.tt/2iw91E5

Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer

http://ift.tt/2xhIvAL

A case of sudden death due to spontaneous right subclavian artery dissection

Abstract

Acute subclavian artery dissection (SAD) is a rare entity which is usually associated with several vascular abnormalities and traumatic events. Spontaneous SAD remains exceptional and often affects the left artery. We report the autopsy case of a 29-year-old female who died suddenly following a spontaneous dissection of the right subclavian artery.

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Chemical meningitis related to intra-CSF liposomal cytarabine

CNS Oncology, Ahead of Print.


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Assessing non-inferiority in treatment trials regarding severe infectious diseases: An extension to the entire follow-up period using a cure-death multistate model [PublishAheadOfPrint]

Background: In current and former clinical trials for the development of antibacterial drugs, various primary endpoints have been used and treatment effects are mostly evaluated in non-inferiority analyses at the end of follow-up which varies between studies. A more convincing and highly patient-relevant statement would be a non-inferiority assessment over the entire follow-up period with cure and death as co-primary endpoints, while preserving the desired alpha level for statistical testing.

Materials and Methods: To account for the time-dynamic pattern of cure and death, we apply a cure-death multistate model. The endpoint of interest is "get cured and stay alive over time". Non-inferiority between treatments over the entire follow-up period is studied by means of one-sided confidence bands provided by a flexible resampling technique.

Results: We illustrate the technique on a recently published study and establish non-inferiority in being cured and alive over a time frame of interest for the entire population, patients with hospital-acquired pneumonia, but not for the subset of patients with ventilator-associated pneumonia. Our analysis improves the original results in the sense that our endpoint is more patient-benefiting, a stronger non-inferiority statement is demonstrated, and the time-dependency of cure and death, competing events, and different follow-up times is captured.

Summary: Multistate methodology combined with confidence bands add a valuable statistical tool for clinical trials in the context of infection control. The framework is not restricted to the cure-death model, but can be adapted to more complex multistate endpoints and equivalence or superiority analyses.

http://ift.tt/2yI8RgH

Antileishmanial Efficacy and Pharmacokinetics of DB766-azole Combinations [PublishAheadOfPrint]

Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular L. donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for five days were more effective than DB766 or posaconazole alone. For example, 81 ± 1% (mean ± standard error) inhibition of liver parasite burden was observed for 37.5 mg/kg DB766 + 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40 ± 5% and 21 ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

http://ift.tt/2yLTSEF

Intrapulmonary Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Nebulized Administration of Laninamivir Octanoate in Healthy Japanese Subjects [PublishAheadOfPrint]

A single inhaled dose of laninamivir octanoate (LO) using a dry powder inhaler (DPI) is effective for the treatment and prophylaxis of influenza. Nebulizers are an option for pediatric and elderly patients who may have difficulty in using a DPI. A single-center, open-label study was conducted to evaluate the plasma and intrapulmonary pharmacokinetics (PK) of laninamivir after a single nebulized administration of LO in healthy male Japanese subjects for identifying a safe and effective dosage regimen for a nebulizer. A single dose of LO (40–320 mg) was administered using a nebulizer and plasma concentrations of LO and laninamivir were analyzed up to 168 h after inhalation by validated liquid chromatography-tandem mass spectrometry methods. Subgroups of 6 subjects each underwent bronchoalveolar lavage at specified time intervals over 4–168 h following a single nebulized administration of LO (160 mg) and the concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. PK parameters were determined by non-compartment analysis. Inhaled nebulized LO was found to be safe and well-tolerated up to the highest dose evaluated (320 mg). Plasma laninamivir concentrations increased almost dose-proportionally. Laninamivir concentrations in ELF exceeded the 50% inhibitory concentrations for viral neuraminidase up to 168 h after the nebulized inhalation of 160 mg LO. Thus, similar to the DPI, ELF concentration profiles of laninamivir after a single nebulized administration supports its long lasting effect against influenza virus infection.

http://ift.tt/2yJtNUI

In vitro evaluation of Povidone-Iodine and Chlorhexidine against Outbreak and Non-outbreak strains of Mycobacterium abscessus using Standard Quantitative Suspension and Carrier Testing [PublishAheadOfPrint]

Background

Povidone-iodine (PI) and chlorhexidine (CHX) are widely used antiseptics active against conventional Staphylococcus aureus, Enterobacteriaceae, Candida species and viruses but their efficacy against Mycobacterium abscessus remain unproven.

Methods

We determined the in vitro potency of alcoholic PI and CHX against M. abscessus subspecies abscessus (ATCC 19977), M. abscessus subspecies bolletii (BCRC 16915), our outbreak strain of M. abscessus subspecies massiliense (TPE 101) in reference to Staphylococcus aureus (ATCC 29213) by standard quantitative suspension and carrier methods (EN 14563).

Results

By suspension, all mycobacterial strains compared to S. aureus were significantly more resistant to CHX but not PI. By carrier, the mean logarithmic reductions (LR) achieved by PI under clean (dirty) conditions were 6.575 (2.482), 5.540 (2.298), 4.595 (1.967), 1.173 (0.889) while that achieved by CHX under clean (dirty) conditions were 3.164 (5.445), 5.307 (2.564), 3.844 (2.232), 0.863 (0.389) for S. aureus, M. abscessus subspecies bolletii, M. abscessus subspecies abscessus, and M. abscessus subspecies massiliense, respectively. M. abscessus subspecies massiliense (outbreak strain) was significantly more resistant than the other tested strains to PI and CHX. By both methods, the mean LR achieved by PI was higher than for CHX for all mycobacterial strains, but under dirty conditions neither antiseptic was effectively mycobactericidal (LR<5).

Conclusions

These preliminary findings caution against the universal replacement of PI with CHX as the first-line skin antiseptic since all M. abscessus isolates were resistant to CHX. More studies are needed to establish the best practice for skin antisepsis if mycobacterial infections are also to be prevented.

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Dissemination and Characteristics of a Novel Plasmid-Encoded Carbapenem-Hydrolyzing Class D {beta}-Lactamase, OXA-436 from Four Patients Involving Six Different Hospitals in Denmark [PublishAheadOfPrint]

The diversity of OXA-48-like carbapenemases is continually expanding. In this study, we describe the dissemination and characteristics of a novel carbapenem-hydrolyzing class D carbapenemase (CHDL) named OXA-436. In total, six OXA-436-producing Enterobacteriaceae isolates including Enterobacter asburiae (n=3), Citrobacter freundii (n=2) and Klebsiella pneumoniae (n=1) were identified in four patients in the period between September 2013 and April 2015. All three species of OXA-436-producing Enterobacteriaceae were found in one patient. The amino acid sequence of OXA-436 showed 90.4-92.8% identity to other acquired OXA-48-like variants. Expression of OXA-436 in Escherichia coli and kinetic analysis of purified OXA-436 revealed an activity profile similar to OXA-48 and OXA-181 with activity against penicillins including temocillin, limited or no activity against extended-spectrum cephalosporins and activity against carbapenems. The bla_OXA-436 gene was located on a conjugative ~314 kb IncHI2/IncHI2A plasmid belonging to pMLST ST1, in a region surrounded by chromosomal genes previously identified adjacent to bla_OXA-genes in Shewanella spp. In conclusion, OXA-436 is a novel CHDL with similar functional properties as OXA-48-like CHDLs. The described geographical spread among different Enterobacteriaceae and plasmid location of bla_OXA-436 illustrates its potential for further dissemination.

http://ift.tt/2yJkwvC

In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria [PublishAheadOfPrint]

Cefiderocol (CFDC, S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species including carbapenem-resistant strains of Enterobacteriaceae and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP 3) of Enterobacteriaceae and non-fermenting bacteria similar to ceftazidime. Deficiency of iron-transporter of PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across outer membrane. Deficiency of OmpK35/36 in Klebsiella pneumoniae and overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.

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The antifungal activity of oleylphosphocholine (OlPC) on in vitro and in vivo Candida albicans biofilms [PublishAheadOfPrint]

In this study, we investigated the potential antifungal activity of the alkylphospholipid - oleylphosphocholine (OlPC), a structural analogue of miltefosine, on in vitro and in vivo Candida albicans biofilm formation. The effect of OlPC on in vitro and in vivo C. albicans biofilms was studied inside triple-lumen polyurethane catheters. In vivo biofilms were developed subcutaneously after catheter implant on the lower back of Sprague Dawley rats. Animals were treated orally with OlPC (20 mg/kg of body weight/day) for 7 days. The effect of OlPC on biofilms developed on mucosal surface was studied in an ex vivo model of oral candidiasis. The role of OlPC on C. albicans morphogenesis was investigated in hyphae-inducing media namely, Lee, Spider and RPMI 1640. OlPC displayed activity against both planktonic cells and in vitro C. albicans biofilms. To completely abolish preformed, 24 h old biofilms, higher concentrations (8, 10 and 13 mg/L) were needed. Moreover, OlPC was able to reduce C. albicans biofilms formed by caspofungin-resistant clinical isolates and acted synergistically when combined with caspofungin. Daily administration of OlPC orally, significantly reduced in vivo C. albicans biofilms developed subcutaneously. In addition, OlPC decreased biofilm formation on mucosal surfaces. Interestingly, application of sub-inhibitory concentrations of OlPC already inhibited the yeast-to-hyphae transition, a crucial virulence factor of C. albicans. We document, for the first time, the effects of OlPC on C. albicans cells and suggest the potential use of OlPC in the treatment of C. albicans biofilm-associated infections.

http://ift.tt/2yJZopq

Effect of incubation temperature on antibiotic resistance and virulence factors of Acinetobacter baumannii ATCC 17978. [PublishAheadOfPrint]

Acinetobacter baumannii is a notorious opportunistic pathogen mainly prevalent in hospital settings. A. baumannii's ability to adapt and survive in a range of environments has been a key feature for its persistence and success as an opportunistic pathogen. In this study, we investigated the effect of temperature on the clinically relevant phenotypes displayed by A. baumannii at 37°C and at 28°C. Surface associated motility was significantly reduced at 28°C, while biofilm formation on plastic surfaces increased at 28°C. Decreased susceptibility to aztreonam and increased susceptibility to Trimethoprim – sulfamethoxazole was observed at 28°C. No differences in virulence, as assayed by a G. mellonella model, were observed. Proteomic analysis showed differential expression of 629 proteins of which 366 were upregulated and 263 were downregulated at 28°C. Upregulation of the Csu- and iron – uptake proteins at 28°C was a key finding to understanding some of the phenotypes displayed at 28 °C by A. baumannii.

http://ift.tt/2yMOroT

Vitamin D compounds are bactericidal against Streptococcus mutans and target the bacitracin-associated efflux system [PublishAheadOfPrint]

Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of Streptococcus mutans in a high-throughput screen of FDA-approved drugs. Previous studies have demonstrated that certain derivatives of Vitamin D possess lytic activity against other bacteria, though the mechanism has not yet been established. Through the use of a combinatorial approach, the Vitamin D derivative doxercalciferol was shown to act synergistically with bacitracin, a polypeptide-type drug that is known to interfere with cell wall synthesis, suggesting that doxercalciferol may act in a bacitracin-related pathway. Innate resistance to bacitracin is attributed to efflux by a conserved ABC-type transporter, which in S. mutans is encoded by the mbrABCD operon. S. mutans possesses two characterized resistance mechanisms to bacitracin including the ABC transporter, S. mutans bacitracin resistance (Mbr) cassette, consisting of MbrABCD, and the rhamnose-glucose polysaccharide (Rgp) system, RgpABCDEFGHI. Loss of function of the transporter, in mbrA or mbrD mutants, exacerbated the effect of combination of doxercalciferol and bacitracin. Despite conservation of a transporter homologous to mbrABCD, the combination of doxercalciferol and bacitracin appeared to only be synergistic in streptococcal species. We conclude that Vitamin D-derivatives possess lytic activity against S. mutans and act through a mechanism dependent on the bacitracin-resistance mechanism of MbrABCD.

http://ift.tt/2yIZHAB

Molecular Mechanisms of Intrinsic Streptomycin Resistance in Mycobacterium abscessus [PublishAheadOfPrint]

Streptomycin, the first drug used for the treatment of tuberculosis, shows limited activity against the highly resistant pathogen Mycobacterium abscessus. We recently identified two aminoglycoside-acetylating genes [aac(2') and eis2] which however do not affect susceptibility to streptomycin. This suggests the existence of a discrete mechanism of streptomycin resistance. M. abscessus BlastP analysis identified MAB_2385 as a close homologue of the 3' '-O-phosphotransferase [APH(3' ')] from the opportunistic pathogen Mycobacterium fortuitum, as a putative streptomycin resistance determinant. Heterologous expression of MAB_2385 in M. smegmatis increased the streptomycin minimal inhibitory concentration while the gene deletion mutant M. abscessus MAB_2385 showed increased streptomycin susceptibility. The minimal inhibitory concentration of other aminoglycosides was not altered in M. abscessus MAB_2385. This concludes that MAB_2385 is a specific and prime innate streptomycin resistance determinant in M. abscessus. We further explored the feasibility to apply an rpsL-based streptomycin counter selection to generate gene deletion mutants in M. abscessus. Spontaneous streptomycin resistant mutants of M. abscessus MAB_2385 were selected and we demonstrated that the wild-type rpsL is dominant over the mutated rpsL^K43R in merodiploid strains. In a proof of concept study we exploited this phenotype for construction of a targeted deletion mutant thereby establishing an rpsL-based counter selection method in M. abscessus.

http://ift.tt/2yMYRFe

A drug repositioning approach reveals Streptococcus mutans is susceptible to a diverse range of established antimicrobials and non-antibiotics [PublishAheadOfPrint]

Streptococcus mutans is the primary causative agent of dental caries and contributes to the multispecies biofilm known as dental plaque. An adenylate kinase-based assay was optimized for S. mutans to detect cell lysis when exposed to the Selleck library of 853 FDA-approved drugs, in, to our knowledge, the first high-throughput drug screen in S. mutans. We found 126 drugs with activity against S. mutans planktonic cultures and they were classified into six categories: antibacterials (61), antineoplastics (23), ion channel effectors (9), other antimicrobials (7), antifungals (6), and other (20). These drugs were also tested for activity against S. mutans biofilm cultures, and 24 compounds were found to inhibit biofilm formation, 6 killed pre-existing biofilms, 84 exhibited biofilm inhibition and killing activity, and 12 had no activity against biofilms. The activity of 9 selected compounds that exhibited antimicrobial activity were further characterized for their activity against S. mutans planktonic and biofilm cultures. Together, our results suggest that S. mutans exhibits a susceptibility profile to a diverse array of established and novel antibacterials.

http://ift.tt/2yIZDAR

Mechanism of action of miltefosine on Leishmania donovani involves the impairment of acidocalcisomes function and the activation of the sphingosine-dependent plasma membrane Ca2+ channel [PublishAheadOfPrint]

Leishmania donovani is the causing agent of visceral leishmaniasis, a common infection that affects millions of people from the most underdeveloped countries. Miltefosine is the only oral drug to treat infections caused by L. donovani. Nevertheless, its mechanism of action is not well understood. While miltefosine inhibits the synthesis of phosphatidylcholine, and also affects the parasite mitochondrion inhibiting the cytochrome C oxidase, it is to be expected that this potent drug also produces its effect through other targets. In this context, it has been reported that the disruption of the intracellular Ca²⁺ homeostasis represents an important object for the action of drugs in trypanosomatids. Recently, we have described a plasma membrane Ca²⁺ channel in L. mexicana, which is similar to the L-type voltage-gated Ca²⁺ channel (VGCC) present in humans. Remarkably, the parasite Ca²⁺ channel is activated by sphingosine while the L-Type VGCC is not affected by this sphingolipid. In the present work we demonstrated that, similar to sphingosine, miltefosine is able to activate the plasma membrane Ca²⁺ channel from L. donovani. Interestingly, nifedipine, the classical antagonist of the human channel was not able to fully block the parasite plasma membrane Ca²⁺ channel, indicating that the mechanism of interaction is not identical to sphingosine. In this work we also show that miltefosine is able to strongly affect the acidocalcisomes from L. donovani, inducing the rapid alcalinization of these important organelles. In conclusion, we demonstrate two new mechanisms of action of miltefosine in L. donovani, both related to disruption of parasite Ca²⁺ homeostasis.

http://ift.tt/2yNBmvJ

Pharmacokinetics of a long-acting nanoformulated dolutegravir prodrug in rhesus macaques [PublishAheadOfPrint]

A nanoformulated myristoylated dolutegravir prodrug (NMDTG) was prepared using Good Laboratory Practice protocols. Intramuscular injection of NMDTG (118 ± 8 mg/ml, 25.5 mg DTG equivalents/kg) to three rhesus macaques led to plasma DTG levels of 86 ± 12 and 28 ± 1 ng/ml on days 35 and 91, respectively. The NMDTG platform extended the drug half-life without demonstrable adverse events. Further modification may extend the long-acting nanoformulation platform for human use.

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Peptidoglycan cross-linking activity of L,D-transpeptidases from Clostridium difficile and inactivation of theses enzymes by {beta}-lactams [PublishAheadOfPrint]

In most bacteria, the essential targets of β-lactam antibiotics are the D,D-transpeptidases that catalyze the last step of peptidoglycan polymerization by forming 4->3 cross-links. The peptidoglycan of Clostridium difficile is unusual since it mainly contains 3->3 cross-links generated by L,D-transpeptidases. To gain insight into the characteristics of C. difficile peptidoglycan cross-linking enzymes, we have purified the three putative C. difficile L,D-transpeptidases paralogues, Ldt_Cd1, Ldt_Cd2, and Ldt_Cd3, which have been previously identified by sequence analysis. The catalytic activity of the three proteins was assayed with a disaccharide-tetrapeptide purified form the C. difficile cell wall. Ldt_Cd2 and Ldt_Cd3 catalyzed the formation of 3->3 cross-links (L,D-transpeptidase activity), the hydrolysis of the C-terminal D-Ala residue of the disaccharide-tetrapeptide substrate (L,D-carboxypeptidase activity), and the exchange of the C-terminal D-Ala by D-Met. Ldt_Cd1 only displayed L,D-carboxypeptidase activity. Mass spectrometry analyses indicated that Ldt_Cd1 and Ldt_Cd2 were acylated by β-lactams belonging to the carbapenem (imipenem, meropenem, and ertapenem), cephalosporin (ceftriaxone), and penicillin (ampicillin) classes. Acylation of Ldt_Cd3 by these β-lactams was not detected. The acylation efficacy of Ldt_Cd1 and Ldt_Cd2 was higher for the carbapenems (480 to 6,600 M^-1 s^-1) than for ampicillin and ceftriaxone (3.9 to 82 M^-1 s^-1). In contrast, the efficacy of hydrolysis of β-lactams by Ldt_Cd1 and Ldt_Cd2 was higher for ampicillin and ceftriaxone than for imipenem. These observations indicate that Ldt_Cd1 and Ldt_Cd2 are only inactivated by β-lactams of the carbapenem class due to a combination of rapid acylation coupled to the stability of the resulting covalent adducts.

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Methionine Ameliorates Polymyxin-induced Nephrotoxicity by Attenuating Cellular Oxidative Stress [PublishAheadOfPrint]

Polymyxins are a last-line defence against multidrug-resistant Gram-negative pathogens. Recent pharmacological data show that intravenous polymyxins can cause nephrotoxicity in up to 60% of patients, and plasma concentrations of polymyxins are suboptimal in a large proportion of patients with the currently recommended dosage regimens. Simply increasing the daily dose of polymyxins is not possible due to nephrotoxicity. This study aimed to examine the protective effect of methionine against polymyxin-induced nephrotoxicity. Methionine (400 mg/kg), polymyxin B (35 mg/kg), a combination of methionine (100 or 400 mg/kg) and polymyxin B, and saline were administered in mice twice daily over 3.5 days. Kidneys were collected immediately at the end of the experiment for histological examination. Effect of methionine on the pharmacokinetics of polymyxin B was investigated in rats. Attenuation of polymyxin B (0.75 mM) induced mitochondrial superoxide production by methionine (10.0 mM) was examined in rat kidney cells (NRK-52E). Histological results revealed that polymyxin-induced nephrotoxicity in mice was ameliorated by methionine in a dose-dependent manner. Methionine doses were well tolerated in mice and rats, and the pharmacokinetics of polymyxin B in rats was not affected by methionine. In the polymyxin B + methionine group, the total body clearance of polymyxin B was very similar to that of polymyxin B alone (3.71±0.57 vs 3.12±1.66 mL/min/kg, P >0.05). Substantial attenuation of polymyxin-induced mitochondrial superoxide production in NRK-52E cells was observed following pre-treatment with methionine. Our results demonstrate that co-administration of methionine significantly ameliorated polymyxin-induced nephrotoxicity and decreased mitochondrial superoxide production in renal tubular cells.

http://ift.tt/2yJgRhA

KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer

Purpose: KRAS mutation is a common canonical mutation in CRC, found at differing frequencies in all Consensus Molecular Subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. Experimental Design: Transcriptional analysis of immune genes/signatures was performed with RNA-seq using The Cancer Genome Atlas (TCGA) and the KFSYSCC data set. Multivariate analysis included KRAS status, CMS, tumour location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-Class II, and CXCL10 was analysed by digital immunohistochemistry. Results: The Th1-centric co-ordinated immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS mutant CRC in both data sets.  Cytotoxic T cells, neutrophils and the interferon gamma pathway were suppressed in KRAS mutant samples.  The expression of STAT1 and CXCL10, were reduced at the mRNA and protein levels. In multivariate analysis KRAS mutation, CMS2 and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS mutant CRC: CMS2 KRAS mutant samples have the lowest CIRC expression, reduced expression of the interferon gamma pathway, STAT1 and CXCL10 and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to CMS2 KRAS wild type samples in the TCGA.  These trends held in the KFSYSCC data set. Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in CRC, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of CRC.

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Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis, however a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths. Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical, and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing. Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR-deficiency and RB1 loss were correlated and co-occurrence was significantly associated with prolonged survival. Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR-deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients.

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Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition.

Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models, and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. Experimental design: We utilised a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalised and primary early passage mesothelioma lines, alongside comprehensive molecular characterisation using Illumina whole exome sequencing, copy number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models. Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harboured genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in a MPM mouse xenograft model and by BAP1 knock-down and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18.  These associations were confirmed in a cohort of MPM patient samples. Conclusion: A subgroup of mesotheliomas cell lines harbour sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup, and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies.

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A Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals

Purpose: The response rate of head and neck squamous cell carcinoma (HNSCC) patients to cetuximab therapy is only 15-20%, despite frequent EGFR overexpression. Since immunosuppression is common in HNSCC, we hypothesized that adding a pro-inflammatory TLR8 agonist to cetuximab therapy might result in enhanced T lymphocyte stimulation and anti-EGFR specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3-4 weekly doses of motolimod (2.5 mg/m²) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells. Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed MDSC suppression of T cell proliferation in vitro. These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in TIL. Motolimod plus cetuximab also decreased induction of Treg, and reduced markers of suppression, including CTLA-4, CD73 and membrane bound TGF-β. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T cell infiltration into tumors. These T cells manifested increased TCR clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT. Conclusions:Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC.

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Multilayered omics-based analysis of a head and neck cancer model of cisplatin resistance reveals intratumoral heterogeneity and treatment-induced clonal selection

Purpose: Platinum-based drugs, in particular cisplatin (CDDP), are used for treatment of squamous cell carcinoma of the head and neck (SCCHN). Despite initial responses, CDDP treatment often results in chemoresistance, leading to therapeutic failure. The role of primary resistance at subclonal level and treatment-induced clonal selection in the development of CDDP resistance remains unknown. Experimental Design: By applying targeted next-generation sequencing, fluorescence in-situ hybridization, microarray-based transcriptome and mass spectrometry-based phosphoproteome analysis to the CDDP-sensitive SCCHN cell line FaDu, a CDDP-resistant subline and single-cell derived subclones, the molecular basis of CDDP resistance was elucidated. The causal relationship between molecular features and resistant phenotypes was determined by siRNA-based gene silencing. The clinical relevance of molecular findings was validated in SCCHN patients with recurrence after CDDP-based chemoradiation and the TCGA SCCHN dataset. Results: Evidence of primary resistance at clonal level and clonal selection by long-term CDDP treatment was established in the FaDu model. Resistance was associated with aneuploidy of chromosome 17, increased TP53 copy numbers and overexpression of the gain-of-function (GOF) mutant variant p53 R248L. siRNA-mediated knock-down established a causal relationship between mutant p53 R248L and CDDP resistance. Resistant clones were also characterized by increased activity of the PI3K-AKT-mTOR pathway. The poor prognostic value of GOF TP53 variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort. Conclusions: Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF TP53 variants and the PI3K/mTOR pathway as molecular targets for treatment optimization.

http://ift.tt/2yJJZqs

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular co-stimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown HER2-CARs containing the 4-1BB co-stimulatory domain confer improved tumor targeting with reduced T cell exhaustion phenotype and enhanced proliferative capacity compared to HER2-CARs containing the CD28 co-stimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo anti-tumor activity in an orthotopic xenograft models. Importantly, we demonstrated robust anti-tumor efficacy following regional intraventricular delivery of HER2-CAR T cells for treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases.

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Lenalidomide enhances the function of CS1 chimeric antigen receptor redirected T cells against multiple myeloma

Purpose:Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel CARs for the treatment of MM and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. Experimental Design: We redirected central memory T cells to express second-generation CAR specific for CS1 and adoptively transferred them into MM tumor-bearing mice to test their anti-MM activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide in vitro. The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat MM bearing mice as combinatorial therapy.Results: CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T cell expansion in vitro enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the anti-tumor activity and persistence of adoptively transferred CS1 CAR T cells in vivo. Conclusions:The study demonstrates that lenalidomide improves the anti-MM properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma.

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Meiosis-like Functions in Oncogenesis: A New View of Cancer

Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 1–5. ©2017 AACR.

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miR-6883 family miRNAs target CDK4/6 to induce G1 phase cell cycle arrest in colon cancer cells

CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and TCGA dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer (CRC). The 3′UTR of CDK4/6 mRNAs are targeted by a family of miRNAs which includes miR-6883-5p, miR-149*, miR-6785-5p and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human CRC cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in CRC patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G0/G1 phase cell cycle arrest and apoptosis in CRC cells. CDK4/6 targeting by miR-6883-5p and miR-149* could only partially explain the observed anti-proliferative effects. Notably, both miRNAs synergized with the frontline CRC chemotherapy drug irinotecan. Further, they re-sensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve CRC management.

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Optimization of Phenolic Compounds Extraction from Flax Shives and Their Effect on Human Fibroblasts

The goal of this study was to evaluate the most effective technique for extraction of phenolics present in flax shives and to assess their effect on human fibroblasts. Flax shives are by-products of fibre separation, but they were found to be a rich source of phenolic compounds and thus might have application potential. It was found that the optimal procedure for extraction of phenolics was hydrolysis enhanced by the ultrasound with NaOH for 24 h at 65°C and subsequent extraction with ethyl acetate. The influence of the flax shives extract on fibroblast growth and viability was assessed using the MTT and SRB tests. Moreover, the influence of flax shives extract on the extracellular matrix remodelling process was verified. The 20% increase of the viability was observed upon flax shives extract treatment and the decrease of mRNA collagen genes, an increase of matrix metalloproteinase gene expression, and reduction in levels of interleukin 6, interleukin 10, and suppressor of cytokinin signaling 1 mRNA were observed. Alterations in MCP-1 mRNA levels were dependent on flax shives extract concentration. Thus, we suggested the possible application of flax shives extract in the wound healing process.

http://ift.tt/2h1F4b9

Human Infection with Fusobacterium necrophorum without Jugular Venous Thrombosis: A Varied Presentation of Lemierre’s Syndrome

Lemierre's syndrome is also known as postangina septicemia, which is commonly caused by Fusobacterium necrophorum also known as Necrobacillus and also by other microorganisms like Staphylococcus, Streptococcus, Peptostreptococcus, and Bacteroides. Though the disease starts as an upper respiratory tract infection, it may spread and cause thrombophlebitis of the internal jugular vein. It may present itself through cranial nerve palsy or sepsis involving distant organs like the lungs or bones. It is also known as forgotten disease because of its rarity. Fusobacterium necrophorum usually causes infection in animals and rarely affects humans. We hereby present a case of Necrobacillus infection which did not cause any thrombophlebitis but resulted in severe pneumonia and acute kidney injury, leading to respiratory failure and requiring mechanical ventilation.

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Parainfluenza 3 Respiratory Infection Associated with Pericardial Effusion in a Very Low Birthweight Infant

Parainfluenza 3 virus is a frequent cause of respiratory infections in the pediatric population although it is uncommonly diagnosed in neonates, being usually reported as neonatal intensive care unit microepidemics. We report a case of parainfluenza 3 respiratory infection associated with pericardial effusion in a very low birthweight infant.

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Efficacy and Safety of Digital Single-Operator Cholangioscopy for Difficult Biliary Stones

It is not clear whether digital single-operator cholangioscopy (D-SOC) with electrohydraulic and laser lithotripsy is effective in removal of difficult biliary stones. We investigated the safety and efficacy of D-SOC with electrohydraulic and laser lithotripsy in an international, multi-center study of patients with difficult biliary stones.

http://ift.tt/2yEQxHN

Copper-beaten skull appearance in the setting of Marfan syndrome

http://ift.tt/2y10j7L

Microglial dysfunction as a key pathologic change in adrenomyeloneuropathy

Abstract

Objective: Mutations in ABCD1 cause the neurodegenerative disease adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease but its role in the spinal cord is unclear.

Methods: We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. As mutations in ABCD1 lead to incorporation of very long chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.

Results: Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis-related markers such as MFGE8 and TREM2 precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1-deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis and leads to neuronal injury. Furthermore, exposure to a MFGE8 blocking antibody reduces phagocytic activity.

Interpretation: Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. This article is protected by copyright. All rights reserved.

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Thrombosis in adult patients with acute leukemia

Purpose of review: Recent studies indicate that the risk of thrombosis in hematologic patients may be similar or even higher than that found in patients with solid tumors. However, available information about pathogenesis and incidence of thrombosis in acute leukemia is limited. This review focuses on mechanisms underlying thrombosis in acute leukemia and discusses recent literature data. Recent findings: In the last few years, proofs have been provided that leukemic cells release free prothrombotic products, such as micro-vesicles, tissue factors, circulating free DNA and RNA. Furthermore, leukemic blasts can activate the procoagulant population of platelets, which initiate and amplify coagulation, causing thrombosis. In addition to factors produced by acute leukemia itself, others concur to trigger thrombosis. Some drugs, infections and insertion of central venous catheter have been described to increase risk of thrombosis in patients with acute leukemia. Summary: Thrombosis represents a serious complication in patients affected by myeloid and lymphoid acute leukemia. A proper knowledge of its pathophysiology and of the predisposing risk factors may allow to implement strategies of prevention. Improving prevention of thrombosis appears a major goal in patients whose frequent conditions of thrombocytopenia impede an adequate delivery of anticoagulant therapy.

http://ift.tt/2yMeNat

New anti-HER2 agents: from second-generation tyrosine kinases inhibitors to bifunctional antibodies

Purpose of review: HER2-positive breast cancers have benefited since the end of the twentieth century, not only from the improvement of biological knowledge, but also from major technological advances. The latter allowed the synthesis of the first generation of enzymatic inhibitors of the HER receptor family such as lapatinib, but above all, monoclonal antibodies such as trastuzumab or pertuzumab having profoundly modified the management of these cancers. However, despite outstanding progresses, there are still patients who are not cured with these first-generation treatments, and they will need new approaches to improve disease control and impact patients' survival. Recent findings: Understanding the mechanisms of escape to these treatments, more than real resistance, has profoundly changed our pharmacological approaches. They have enabled the development of molecules blocking the signaling pathway downstream of receptors such as mTOR, PI3K inhibitors or molecules interacting with the cellular traffic of the receptor in combination with the first-generation treatments. In addition, new second-generation tyrosine kinase inhibitors have demonstrated increased in-vitro efficacy, but still need to show clinical relevance because of new toxicity profiles. The antibody engineering had also permitted a paradigm evolution of the role of the antibody treatments, particularly with the synthesis of bispecific and trifunctional antibodies, promoting the link between the tumor and the immune system, with the goal to amplify the immune anticancer response. Summary: Among the new anti-HER2 agents, second-generation tyrosine kinase inhibitors and bifunctional antibodies are promising approaches that will help to improve disease control and curability of HER2-positive breast cancers.

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Advances in immunotherapy in multiple myeloma

Purpose of review: Here, we explore the significant progress made in the treatment of multiple myeloma, focusing on immunotherapy and the promise it has offered to patients suffering from advanced disease. Recent findings: Multiple myeloma, a B-cell malignancy, is characterized by unregulated plasma cell growth in the bone marrow as well as strong immunosuppression in the tumor microenvironment. mAbs targeting tumor antigens overcome this, increasing T-cell activation, multiple myeloma cell death, and depth of response. Similarly, adoptive T-cell therapy aims to engineer or isolate tumor-specific T cells for a targeted approach. Finally, peptide and dendritic cell/tumor fusion vaccines reeducate the immune system, expanding the immune response and generating long-term memory to prevent relapse of disease. Many of these approaches have been combined with existing therapies to enhance antitumor immunity. Summary: Immunotherapeutic approaches have remarkably changed the treatment paradigm for multiple myeloma, and encouraging patient responses have warranted further investigation into mAbs, adoptive T-cell therapy, vaccines, and combination therapy.

http://ift.tt/2yN50RR

Notch inhibitors and their role in the treatment of triple negative breast cancer: promises and failures

Purpose of review: Notch signaling is a highly evolutionarily conserved cell-to-cell communication system that is involved in a number of pivotal cellular processes, such as development, stem cell maintenance, cell fate specification, differentiation, proliferation, and death. Much progress has been made in understanding Notch signaling. This review will focus on the role of canonical Notch signaling pathway in breast cancer cause and progressing. Recent findings: In this review, we will discuss the results of the studies using drugs, which target the Notch pathway. Summary: Notch sustains a proliferative signaling and protects from apoptosis, favors the angiogenic switch, the chemoresistance and radioresistance, controls the cancer stemness, and induces a prometastatic phenotype. Therefore, Notch-signaling represented an interesting target in the strategy against cancer growth.

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Editorial introductions

No abstract available

http://ift.tt/2yN4Zxh

Extending indication of cyclin-dependent kinase 4/6 inhibitors in the adjuvant and neoadjuvant setting

Purpose of review: A burst of recent activity has surrounded the study of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors for the treatment of metastatic breast cancer. The success of these drugs in the metastatic setting has pushed the evaluation of these agents in early-stage disease. The use of CDK 4/6 inhibitors as neoadjuvant and adjuvant therapy is a hot topic and several studies are underway. Recent findings: Ongoing studies are exploring the addition of CDK 4/6 inhibitors to endocrine therapy in early breast cancer. Summary: Identification of the optimal treatment combinations is the goal of current research. Finding biomarkers for patients' selection will be the goal of future research.

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Role of stem cell transplant in lymphoma in the era of new drugs

Purpose of review: Better understanding of the lymphoma pathogenesis and molecular biology has introduced a new era in the lymphoma therapy with the advent of targeted drugs. In this new era, the role of hematopoietic stem cell transplantation (HSCT) is evolving, and the purpose of this review is to demonstrate how the introduction of novel agents has affected the current treatment strategy of different subtypes of lymphoma. Recent findings: Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed Hodgkin Lymphoma and high-grade non-Hodgkin lymphoma (NHL). In the group of the indolent lymphomas, ASCT maintains its role in the relapsed setting. Novel targeted agents like idelalisib and ibrutinib have shown to induce prolonged remissions with a very good safety profile. However, the follow-up is still relatively short and none of these drugs have demonstrated a curative potential, as opposed to HSCT. Summary: For many authors, the advent of new targeted drugs is challenging the role of HSCT in different subsets of lymphoma. The actual challenge is how to make the best use of these drugs, in certain circumstances in combination with HSCT, to further improve the outcome of patients with lymphoma.

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An Unusual Cause of Myelopathy: Ochronotic Spondyloarthropathy With Positive HLA B27

Abstract: Ochronosis is a late developing complication of alkaptonuria, a black brownish pigment in the fibrous and cartilaginous tissues. Although most previous studies reported alkaptonuria and back pain due to ochronosis, thoracic myelopathy is an extremely rare complication. In this report, a paraparetic patient who has ochronotic spondiloarthropathy with the presence of HLA B27 antigen is described. He had low back and leg pain and morning stiffness for 5 yrs. Last year, these were followed by tingling, numbness, and weakness the in lower extremities and he was operated on with preliminary diagnosis of prolapsed disc herniation and cord compression. Surgery is suggested for disc herniations related to ochronotic spondyloarthropathy if it is necessary or neurologic symptoms are present. However, his pain and weakness have partially recovered after the operation. After medical and physical treatment, he showed clinically significant improvements. This case report demonstrates that the management of ochronosis needs a multidisciplinary approach with physiologic, neurologic, and psychologic effects and proper treatment may significantly improve functional outcomes in these patients.

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Precise Target Site of Ultrasound-Guided C5 Cervical Root Block

No abstract available

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Efficacy of Platelet-Rich Plasma in Pain and Self-Report Function in Knee Osteoarthritis: A Best-Evidence Synthesis

Objective: The aim of this study was to assess the efficacy of platelet-rich plasma (PRP) in pain and self-report function of patients with knee osteoarthritis on the basis of comparisons with hyaluronic acid or placebo. Design: Best-evidence synthesis of randomized controlled trials (RCTs) was conducted. Literature retrieval was limited to RCTs assessing the efficacy of PRP in knee osteoarthritis. Methodology evaluation and data extraction were based on Cochrane Collaboration guidelines. Meta-analyses were performed using mean difference or standardized mean difference as effect size. Results: Ten RCTs were included and analyzed. Meta-analysis showed significant superiority of PRP in outcome scores when compared with hyaluronic acid (standardized mean difference = −0.85, P = 0.004, I2 = 93%), but no statistical difference was found in well-designed double-blind trials (standardized mean difference = −0.09, P = 0.38, I2 = 0%). Pooled standardized mean difference of trials comparing PRP with placebo directly was −2.13 (95% confidence interval = −3.29 to −0.98), and that of indirect comparison was −0.22 (95% confidence interval = −0.45 to −0.01). Conclusions: In relieving pain and improving self-report function, PRP showed no superiority over hyaluronic acid in well-designed double-blind trials, and beneficial effects of PRP in most trials probably resulted from insufficient blinding methods. However, PRP is still considered more effective than placebo on the basis of present evidence.

http://ift.tt/2gE8ijE

Effects of the Integration of Dynamic Weight Shifting Training Into Treadmill Training on Walking Function of Children with Cerebral Palsy: A Randomized Controlled Study

Objective: The aim of the study was to determine whether applying an assistance force to the pelvis and legs during treadmill training can improve walking function in children with cerebral palsy. Design: Twenty-three children with cerebral palsy were randomly assigned to the robotic or treadmill only group. For participants who were assigned to the robotic group, a controlled force was applied to the pelvis and legs during treadmill walking. For participants who were assigned to the treadmill only group, manual assistance was provided as needed. Each participant trained 3 times/wk for 6 wks. Outcome measures included walking speed, 6-min walking distance, and clinical assessment of motor function, which were evaluated before, after training, and 8 wks after the end of training, and were compared between two groups. Results: Significant increases in walking speed and 6-min walking distance were observed after robotic training (P = 0.03), but no significant change was observed after treadmill training only. A greater increase in 6-min walking distance was observed after robotic training than that after treadmill only training (P = 0.01). Conclusions: Applying a controlled force to the pelvis and legs, for facilitating weight-shift and leg swing, respectively, during treadmill training may improve walking speed and endurance in children with cerebral palsy. To Claim CME Credits: Complete the self-assessment activity and evaluation online at http://ift.tt/1l80W45 CME Objectives: Upon completion of this article, the reader should be able to: (1) discuss the importance of physical activity at the participation level (sports programs) for children with cerebral palsy; (2) contrast the changes in walking ability and endurance for children in GMFCS level I, II and III following sports programs; and (3) identify the impact of higher frequency of sports program attendance over time on walking ability. Level: Advanced Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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