Self-Organized Superlattice and Phase Coexistence inside Thin Film Organometal Halide Perovskite

Abstract

Organometal halide perovskites have attracted widespread attention as the most favorable prospective material for photovoltaic technology because of their high photoinduced charge separation and carrier transport performance. However, the microstructural aspects within the organometal halide perovskite are still unknown, even though it belongs to a crystal system. Here direct observation of the microstructure of the thin film organometal halide perovskite using transmission electron microscopy is reported. Unlike previous reports claiming each phase of the organometal halide perovskite solely exists at a given temperature range, it is identified that the tetragonal and cubic phases coexist at room temperature, and it is confirmed that superlattices composed of a mixture of tetragonal and cubic phases are self-organized without a compositional change. The organometal halide perovskite self-adjusts the configuration of phases and automatically organizes a buffer layer at boundaries by introducing a superlattice. This report shows the fundamental crystallographic information for the organometal halide perovskite and demonstrates new possibilities as promising materials for various applications.

Coexistence of cubic and tetragonal phases at room temperature and the existence of self-assembled superlattices are confirmed in organometal halide perovskite with transmission electron microscopy. The superlattices are composed of a mixture of tetragonal and cubic phases without compositional change. Based on the phase coexistence and the superlattices, the organometal halide perovskite self-adjusts its microstructural configuration.

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Microspherical Particles of Solid Dispersion of Polyvinylpyrrolidone K29-32 for Inhalation Administration

Inhalation administration is a promising alternative to the invasive drug delivery methods. The particle size required for ideal drug aerosol preparation is between 1 and 3 μm. The application of microspherical particles of solid dispersions enhances bioavailability of poorly soluble drugs due to the solubilization. In the present work, the spray drying process of the production of microspherical particles of solid dispersions of polyvinylpyrrolidone K29-32 with model hydrophobic drug, phenacetin, was optimized using the results of DSC, PXRD, and viscometry. The diameter of the obtained particles is within 1–3 μm range. The Gibbs energy of dissolution in water was shown to be negative for the mixture with polymer/phenacetin mass ratio 5 : 1. We have demonstrated that the optimal size distribution for the inhalation administration is obtained for microspherical particles produced using spray caps with 7.0 μm hole size. The dissolution rates of phenacetin from the produced microspherical particles were faster than that of drug powder. As evidenced by powder X-ray diffraction data, phenacetin stayed in amorphous state for 4 months in microspherical particles of solid dispersions. According to the obtained results, strategic application of the spray drying process could be beneficial for the improvement of the pharmaceutical properties of model drug, phenacetin.

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Cancers, Vol. 10, Pages 15: Acknowledgement to Reviewers of Cancers in 2017

Cancers, Vol. 10, Pages 15: Acknowledgement to Reviewers of Cancers in 2017

Cancers doi: 10.3390/cancers10010015

Authors: Cancers Editorial Office

Peer review is an essential part in the publication process, ensuring that Cancers maintains high quality standards for its published papers[...]

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Larval infestation of chronic ischaemic leg ulcer

Description

Several cases of obligatory wound myiasis have been reported in the medical literature.1–3 For a long time, such infestation was perceived as a complication of poor quality wound care in patients with chronic ulcers. There are only three cases of wound myiasis reported in the literature. Demirel et al reported on a 68-year-old male patient with larvae infestations of diabetic wound that were discovered during surgical debridement.3 Another two cases of traumatic larval infestation associated with Bowen carcinoma and with chronic leg ulcer were reported.3 Up to date, there is no report of chronic ulcer with massive larvae infestation as in this patient.

Figure 1 with video capture (video 1) demonstrates a massive larvae infestation of severe chronic ischaemic ulcer in a 60-year-old homeless male patient with HIV, who presented with unilateral leg pain without systemic or...

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Hepatic amyloidosis: a cause of rapidly progressive jaundice

Description

An 83-year-old man presented with an acute history of weight loss and jaundice. He had a history of type 2 diabetes mellitus and hypertension. He consumed 30 units of alcohol per week.

The patient was cachectic and jaundiced with non-tender hepatomegaly and no evidence of chronic liver disease. There was evidence of hypoalbuminaemia (albumin 25 g/L, reference 34–51 g/L), hyperbilirubinaemia (bilirubin 188 μmol/L, reference <22 μmol/L) and a raised alkaline phosphatase (629 IU/L, reference 35–105 IU/L). Full blood count, coagulation tests and the remaining liver function tests were normal. An estimated Glomerular filtration rate (eGFR) was 71 mL/min/1.73 m². Autoantibodies and immunoglobulins were normal. Hepatitis viral serology was negative. Serum light chain measurements revealed kappa chain concentration of 13.3 (reference 3.3–19.4 mg/L) and lambda chain concentration of 28.5 (reference 5.7–26.6 mg/L) with a ratio of 0.47 (reference 0.26–1.75). A CT abdomen revealed hepatomegaly and ascites. He subsequently had a liver biopsy (figures 1–3

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Extraocular muscle cysticercosis: never skip steroids

DescriptionCase description

A 16-year-old girl presented with a 2-month history of recurrent (three episodes) right upper eyelid drooping and oedema (figure 1A). Examination showed fullness in the right upper eyelid along with elevation deficit. Visual acuity was 20/20 in each eye, and anterior and posterior segments were essentially within normal limits in both the eyes. To explain the cause, ultrasonography of the orbit for extraocular muscles revealed a large cyst in the superior rectus muscle along with a central hyperechoic spot corresponding to the scolex (figure 1B). Non-contrast CT of the orbit and brain revealed inflammatory thickening of the superior rectus muscle with the central cystic area harbouring the scolex without any intracranial foci (figure 1C). Based on the history and imaging findings a diagnosis of myocysticercosis was confirmed and the patient was started on tablet prednisolone 1mg/kg body weight from day 1 and tablet albendazole 15 mg/kg from day 3. The patient...

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Coats disease with exudative retinal detachment simulating cysticercus cyst: misleading ultrasonography!

Description

A 5-year-old boy was brought to our clinic when parents noticed white reflex and divergent squint in the left eye. Snellen visual acuity was 20/20 in the right eye and inaccurate projection of rays in the left eye along with a 30 prism dioptre divergent squint in the latter. Anterior segment was within normal limits in both eyes on slit lamp evaluation. As the child was uncooperative for detailed fundus examination, we performed an ocular ultrasonography. Ocular ultrasonography of the left eye showed an intraocular cystic mass with a localised hyperechoic area adjacent to cyst wall which is typical of a cysticercus cyst with scolex (figure 1). On Optomap ultra-wide-field fundus photography (Optos, Scotland, UK) we found that the cystic mass on ultrasonography was actually a localised exudative retinal detachment and the scolex-like area of hyperechogenicity was a large confluent exudate collection in the subretinal...

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Acute-on-chronic mesenteric ischaemia by early and diffuse atherosclerosis in a young adult patient

Description

A 48-year-old Caucasian man with gypsy ethnicity had smoking habits (35 pack-years) and previous alcohol consumption (10 g/day; abstinent for 3 years). There was no relevant personal/family cardiovascular disease, history of illicit drug abuse, non-steroidal anti-inflammatory drug use or other previous/current medications. He had a 3-year history of chronic diarrhoea (3–4 bowel movements/day), abdominal pain and weight loss (25.9% of usual weight; body mass index=13.7 kg/m²). In the last month, an exacerbation of abdominal pain occurred with excruciating postprandial episodes requiring opioid analgesia. Laboratory analysis showed leucocytosis (34.8; N: 4–11x10⁹/L), neutrophilia (90.6%), normocytic/normochromic anaemia (haemoglobin: 8.0; N: 13–17 g/dL), high Erythrocyte sedimentation rate (ESR) (54; N<20 mm/hour), faecal calprotectin (4890; n<50 mg/kg) and C-reactive protein (CRP) (10.7; N<0.5 mg/dL). Oesophagogastroduodenoscopy and ileocolonoscopy with biopsies showed multiple Helicobacter pylori-negative gastroduodenal ulcers (figure 1A,B) and non-specific mild ulceration of the terminal ileum and proximal colon, without granulomas. CT enterography showed distended small bowel loops without...

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Birt-Hogg-Dube syndrome: spontaneous pneumothorax as a first symptom

Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary autosomal dominant condition characterised by benign cutaneous lesions, lung cysts, increased risk of spontaneous pneumothorax and renal cancer. It shows great heterogenous presentation within and between affected families. We report a case of a Danish female patient with recurrent pneumothoraces as the first symptom of BHDS. Over the years, she developed skin changes, and a family history of skin changes, pneumothoraces and renal cancer was discovered. BHDS was suspected, a genetic analysis was performed and a pathogenic variation c.1285delC in FLCN gene was detected in the patient. As we stated the diagnosis BHDS, we discovered several undiagnosed family members all of them now entering a lifelong follow-up programme with abdominal imaging because of the increased risk of developing renal cancer. BHDS should be known to oncologists, dermatologists and pulmonologists as the patients most often present to these medical disciplines.

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Iatrogenic foreign body in an adult with presbyacusis

Description

Foreign bodies in the external auditory meatus are a common presentation to Otolaryngology both to clinic and as an emergency.1 Most objects referred to Otolaryngology are round and hard such as beads and are more difficult to remove.1While many patients are aware of what might be in their ear, some do not. The causative event can be missed, and the symptoms can be non-specific.2 They may present with a foreign body sensation, a feeling of fullness in the ear, otalgia and recurrent otitis externa. Many of these symptoms can be applied to a presentation of impacted cerumen.

These images refer to a 67-year-old man who presented to Otolaryngology having been referred by his General Practitioner. On presentation to the clinic, he had persistent otalgia in the left ear and reduced hearing for the past 3 months. He also described a feeling of fullness...

http://ift.tt/2mmsWV7

Downregulation of Drp1, a fission regulator, is associated with human lung and colon cancers

Abstract

Dynamin-related protein 1 (Drp1), a dynamin-related GTPase, is a key regulator of mitochondrial fission. Although recent studies have shown that Drp1 plays important roles in various important cellular processes, such as maintaining proper mitochondrial function, apoptosis and necrosis, the potential involvement of Drp1 in cancer development has not been fully addressed. To explore the role of Drp1 in cancer, we examined Drp1 levels in various human cancer tissues. Tissue array analysis showed that the level of Drp1 was decreased significantly in malignant colon and lung cancer tissues, whereas no change in Drp1 was observed in breast and prostate tumors. Pairwise comparisons of cancer tissue and adjacent normal tissue from colon and lung cancer patients further confirmed decreases in Drp1 expression of 75% in colon cancer patients and 78% in lung cancer patients. Moreover, Drp1 levels were decreased further with advanced grade in both colon and lung cancers, suggesting that loss of Drp1 is associated with the progression of human lung and colon cancer. Consistent with this observation, knockdown of Drp1 increased cellular migration activity in human lung cancer cells and tumor formation in a xenograft tumor model. Taken together, these results suggest that the loss of Drp1 expression could contribute to the development of human lung and colon cancers.

http://ift.tt/2DfKkBV

Clostridium butyricum regulates visceral hypersensitivity of irritable bowel syndrome by inhibiting colonic mucous low grade inflammation through its action on NLRP6

Abstract

Visceral hypersensitivity induced by stress is quite common in irritable bowel syndrome (IBS) patients. Probiotics play an important role in reducing visceral hypersensitivity in IBS patients. However, the mechanism has not been clearly elucidated. In this study, we investigated the role of nod-like receptor pyrin domain-containing protein 6 (NLRP6) in Clostridium butyricum-regulated IBS induced by stress. Our results showed that NLRP6 was down-regulated in IBS group colon tissues. In addition, IL-18, IL-1β, myeloperoxidase (MPO), d-lactic acid (D-LA), and CD172a were up-regulated in the IBS group of colonic mucous. IL-18 and IL-1β were also increased after the NLRP6 gene was silenced. Pathological score suggested low inflammation of colonic mucous rather than terminal ileum. Water-avoidance stress (WAS) showed visceral hypersensitivity to colonic distension. However, treatment with Clostridium butyricum reversed these results, exerting a beneficial effect. In conclusion, Clostridium butyricum may exert a beneficial action on visceral hypersensitivity of IBS by inhibiting low grade inflammation of colonic mucous through its action on NLRP6.

http://ift.tt/2CLIW9j

Tumor suppressor miR-128-3p inhibits metastasis and epithelial–mesenchymal transition by targeting ZEB1 in esophageal squamous-cell cancer

Abstract

MicroRNAs (miRNAs) are some short RNAs that regulate multiple biological functions at post-transcriptional levels, such as tumorigenic processes, inflammatory lesions and cell apoptosis. Zinc finger E-box binding homeobox factor 1 (ZEB1) is a crucial mediator of epithelial–mesenchymal transition (EMT). It induces malignant progression of various cancers including human esophageal squamous-cell carcinoma (ESCC). In this study, we found that miR-128-3p was downregulated in ESCC tissues and cells by using PCR. Moreover, down-regulated expression of miR-128-3p was testified to be associated with poor prognosis of ESCC patients and might be regarded as an independent prognostic factor. Then, we examined the role of miR-128-3p in ESCC cells, and found that miR-128-3p could suppress the cell migration and invasion in vitro. Furthermore, ZEB1 was confirmed to be a direct target of miR-128-3p by luciferase reporter assay. Rescue experiments proved that EMT was regulated by miR-128-3p via suppression of ZEB1. Taken all together, we conclude that miR-128-3p suppresses EMT and metastasis via ZEB1, and miR-128-3p may be a critical mediator in ESCC.

http://ift.tt/2DcFo0F

Suitability of the CellientTM cell block method for diagnosing soft tissue and bone tumors

Background

The diagnosis of tumors of soft tissue and bone (STB) heavily relies on histological biopsies, whereas cytology is not widely used. Cellient^TM cell blocks often contain small tissue fragments. In addition to Hematoxylin and Eosin (H&E) interpretation of histological features, immunohistochemistry (IHC) can be applied after optimization of protocols. The objective of this retrospective study was to see whether this cytological technique allowed us to make a precise diagnosis of STB tumors.

Methods

Our study cohort consisted of 20 consecutive STB tumors, 9 fine-needle aspiration (FNAC) samples, and 11 endoscopic ultrasonography (EUS) FNACs and included 8 primary tumors and 12 recurrences or metastases of known STB tumors.

Results

In all 20 cases, H&E stained sections revealed that diagnostically relevant histological and cytological features could be examined properly. In the group of 8 primary tumors, IHC performed on Cellient^TM material provided clinically important information in all cases. For instance, gastrointestinal stromal tumor (GIST) was positive for CD117 and DOG-1 and a PEComa showed positive IHC for actin, desmin, and HMB-45. In the group of 12 secondary tumors, SATB2 was visualized in metastatic osteosarcoma, whereas expression of S-100 was present in 2 secondary chondrosarcomas. Metastatic chordoma could be confirmed by brachyury expression. Two metastatic alveolar rhabdomyosarcomas were myf4 positive, a metastasis of a gynecologic leiomyosarcoma was positive for actin and estrogen receptor (ER) and a recurrent dermatofibrosarcoma protuberans expressed CD34.

Conclusion

In the proper clinical context, including clinical presentation with imaging studies, the Cellient^TM cell block technique has great potential for the diagnosis of STB tumors.

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Transplanted human thymus slices induce and support T-cell development in mice after cryopreservation

Abstract

Here we show that slices of human thymus tissue that have been frozen and thawed can induce and support T-cell development when transplanted into nude mice. Babies born without a thymus require urgent treatment to reconstitute T-cell immunity. Thymus tissue is removed from infants during cardiac surgery, to allow access to the heart. This discarded thymus tissue can be transplanted into athymic infants to reconstitute T-cell immunity. Slices of thymus tissue are transplanted into the thigh, after a two-three week culture period to deplete thymocytes. This procedure is life-saving, but recipients have low T-cell counts, and may develop autoimmunity. It is not possible to attempt to MHC-match transplants between-donor and recipient because of the urgency of performing the procedure. As delays in thymus transplantation could be life-threatening, the procedure would be improved if it were possible to freeze thymus slices for transplantation. Cryopreservation would also open up the possibility of partial MHC-matching. We adapted a slow cooling protocol based on cryopreservation of ovarian tissue fragments to freeze slices of human thymus of 1mm thickness and showed that on thawing such slices can induce and support T-cell development in vivo in an animal model.

This article is protected by copyright. All rights reserved

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The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

Abstract

The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB-resistant (VR) lung cancer cells (NCI-H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP-binding Cassette Sub-family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB-resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.

We established vinorelbine-resistant lung cancer cells and examined its transcriptional changes, protein expressions, and activations. On the basis of these results, we focused on the focal adhesion (FA) pathway and tested the effects of gene silencing and inhibitors. In conclusion, FA pathway, particularly integrin and SFK, are promising targets for vinorelbine-resistant lung cancer.

http://ift.tt/2AL9uFS

Mood disorders in familial epilepsy: A test of shared etiology

Summary

Objective

Mood disorders are the most common comorbid conditions in epilepsy, but the cause remains unclear. One possible explanation is a shared genetic susceptibility to epilepsy and mood disorders. We tested this hypothesis by evaluating lifetime prevalence of mood disorders in relatives with and without epilepsy in families containing multiple individuals with epilepsy, and comparing the findings with rates from a general population sample.

Methods

The Composite International Diagnostic Interview was administered to 192 individuals from 60 families, including 110 participants with epilepsy of unknown cause (50 focal epilepsy [FE], 42 generalized epilepsy [GE], 6 FE and GE, 12 unclassifiable) and 82 relatives without epilepsy (RWOE). Odds ratios (ORs) for lifetime prevalence of mood disorders in participants with versus without epilepsy were computed through logistic regression, using generalized estimation equations to account for familial clustering. Standardized prevalence ratios (SPRs) were used to compare prevalence in family members with general population rates.

Results

Compared with RWOE, ORs for mood disorders were significantly increased in participants with FE (OR = 2.4, 95% confidence interval [CI] = 1.1-5.2) but not in those with GE (OR = 1.0, 95% CI = 0.4-2.2). In addition, prevalence of mood disorders was increased in individuals with epilepsy who had ≥1 relative with FE. Compared with general population rates, mood disorders were significantly increased in individuals with FE but not in those with GE. Rates were also increased in RWOE, but not significantly so (SPR = 1.4, P = .14).

Significance

These findings are consistent with the hypothesis of shared genetic susceptibility to epilepsy and mood disorders, but suggest (1) the effect may be restricted to FE, and (2) the shared genetic effect on risk of mood disorders and epilepsy may be restricted to individuals with epilepsy, that is, to those in whom the genetic risk for epilepsy is "penetrant."

http://ift.tt/2mfmk9Z

Effect of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan on pharmacokinetics and pharmacodynamics of a single-dose of furosemide

Summary

Aims

Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be co-administrated with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two- period, single-sequence study in healthy subjects (N=28).

Methods

All subjects received 40 mg oral single dose furosemide during period 1 followed by washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) bid was administered for 5 days and a single dose of 40 mg furosemide was co-administered on Day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated.

Results

Co-administration with sacubitril/valsartan decreased plasma C_max (estimated geometric mean ratio [90% CI]: 0.50 [0.44, 0.56]), plasma AUC_inf (0.72 [0.67, 0.77]), and 24h urinary excretion of furosemide (0.74 [0.69, 0.79]). When co-administered with sacubitril/valsartan, 0-4h, 4-8h and 0-24h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15% respectively. Post-hoc analysis of the pivotal Phase III PARADIGM-HF study indicated that the median furosemide dose was similar at baseline and end of the study in the sacubitril/valsartan group.

Conclusions

Sacubitril/valsartan reduced plasma C_max and AUC and 24h urinary excretion of furosemide while not significantly impacting its pharmacodynamic effects in healthy subjects.

http://ift.tt/2D0hZCd

Gene Identification of Pheromone Gland Genes Involved in Type II Sex Pheromone Biosynthesis and Transportation in Female Tea Pest Ectropis grisescens

Moths can biosynthesize sex pheromones in the female sex pheromone glands (PGs) and can distinguish species-specific sex pheromones using their antennae. However, the biosynthesis and transportation mechanism for Type II sex pheromone components has rarely been documented in moths. In this study, we constructed a massive PG transcriptome database (14.72 giga bases) from a moth species, Ectropis grisescens, which uses Type II sex pheromones and is a major tea pest in China. We further identified the putative sex pheromone biosynthesis and transportation related genes: 111 cytochrome P450 monooxygenases (P450s, CYPs), 25 odorant binding proteins (OBPs), and 20 chemosensory proteins (CSPs). Tissue expression and phylogenetic tree analyses showed that one CYP (EgriCYP341-fragment3), one OBP (EgriOBP4), and one CSP (EgriCSP10) gene displayed an enriched expression in the PGs, and that EgriOBP2, 3, and 25 are clustered in the moth PBP clade. We considered these our candidate genes. Our results yielded large-scale PG sequence information for further functional studies.

http://ift.tt/2qMocNb

Hiss and snort call types of wild-living giraffes Giraffa camelopardalis: acoustic structure and context

Vocalization as part of vigilance behaviour is widespread across animal taxa, including ruminants. Calls of wild-living giraffes have never been recorded and spectrographically investigated. This study reports...

http://ift.tt/2mmzAKM

Genome-wide diversity and runs of homozygosity in the “Braque Français, type Pyrénées” dog breed

Braque Français, type Pyrénées is a French hunting-dog breed whose origin is traced back to old pointing gun-dogs used to assist hunters in finding and retrieving game. This breed is popular in France, but sel...

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Myelomeningocele with Unilateral Right Renal Agenesis: A Case Report

AJP Rep 2018; 08: e1-e3
DOI: 10.1055/s-0037-1615818

Congenital anomalies of the spine may occur with malformations of the central nervous, cardiovascular, gastrointestinal, respiratory, and genitourinary systems. This is a case of myelomeningocele with unilateral right renal agenesis in a newborn. The patient suffered complications of cerebrospinal fluid leak and meningitis, but was successfully treated and discharged on day 86. In this case, unilateral right renal agenesis represented a significant surgical risk because failure of the remaining kidney could result in renal failure. Because congenital anomalies of the spine may be associated with malformations of the genitourinary system, and additional surgeries were necessary in our case following birth, it is very important that the presence of genitourinary malformations be evaluated.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

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Autophagy sustains pancreatic cancer growth through both cell autonomous and non-autonomous mechanisms [Research Briefs]

Autophagy has been shown to be elevated in pancreatic adenocarcinoma (PDAC) and its role in promoting established tumor growth has made it a promising therapeutic target. However, due to limitations of prior mouse models as well as the lack of potent and selective autophagy inhibitors, the ability to fully assess the mechanistic basis of how autophagy supports pancreatic cancer has been limited. To test the feasibility of treating PDAC using autophagy inhibition and further our understanding of the mechanisms of pro-tumor effects of autophagy, we developed a novel mouse model that allowed the acute and reversible inhibition of autophagy. We observed that autophagy inhibition causes significant tumor regression in an autochthonous mouse model of PDAC. A detailed analysis of these effects indicated that the tumor regression was likely multifactorial, involving both tumor cell intrinsic as well as host effects. Thus, our study supports autophagy inhibition in PDAC may have future utility in the treatment of pancreatic cancer and illustrates the importance of assessing complex biological processes in relevant autochthonous models.

http://ift.tt/2ErN9zo

NF-κB/miR-223-3p/ARID1A axis is involved in Helicobacter pylori CagA-induced gastric carcinogenesis and progression

NF-κB/miR-223-3p/ARID1A axis is involved in Helicobacter pylori CagA-induced gastric carcinogenesis and progression

NF-κB/miR-223-3p/ARID1A axis is involved in <i>Helicobacter pylori</i> CagA-induced gastric carcinogenesis and progression, Published online: 09 January 2018; doi:10.1038/s41419-017-0020-9

NF-κB/miR-223-3p/ARID1A axis is involved in Helicobacter pylori CagA-induced gastric carcinogenesis and progression

http://ift.tt/2Fk25AJ

The expression of inhibitor of bruton’s tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis

The expression of inhibitor of bruton's tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis

The expression of inhibitor of bruton's tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis, Published online: 09 January 2018; doi:10.1038/s41419-017-0026-3

The expression of inhibitor of bruton's tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis

http://ift.tt/2EsSeHo

miRNA-3473b contributes to neuroinflammation following cerebral ischemia

miRNA-3473b contributes to neuroinflammation following cerebral ischemia

miRNA-3473b contributes to neuroinflammation following cerebral ischemia, Published online: 09 January 2018; doi:10.1038/s41419-017-0014-7

miRNA-3473b contributes to neuroinflammation following cerebral ischemia

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Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness

Abstract

Background

The circadian clock is the basis for biological time keeping in eukaryotic organisms. The clock mechanism relies on biochemical signaling pathways to detect environmental stimuli and to regulate the expression of clock-controlled genes throughout the body. MAPK signaling pathways function in both circadian input and output pathways in mammals depending on the tissue; however, little is known about the role of p38 MAPK, an established tumor suppressor, in the mammalian circadian system. Increased expression and activity of p38 MAPK is correlated with poor prognosis in cancer, including glioblastoma multiforme; however, the toxicity of p38 MAPK inhibitors limits their clinical use. Here, we test if timed application of the specific p38 MAPK inhibitor VX-745 reduces glioma cell invasive properties in vitro.

Methods

The levels and rhythmic accumulation of active phosphorylated p38 MAPK in different cell lines were determined by western blots. Rhythmic luciferase activity from clock gene luciferase reporter cells lines was used to test the effect of p38 MAPK inhibition on clock properties as determined using the damped sine fit and Levenberg–Marquardt algorithm. Nonlinear regression and Akaike's information criteria were used to establish rhythmicity. Boyden chamber assays were used to measure glioma cell invasiveness following time-of-day-specific treatment with VX-745. Significant differences were established using t-tests.

Results

We demonstrate the activity of p38 MAPK cycles under control of the clock in mouse fibroblast and SCN cell lines. The levels of phosphorylated p38 MAPK were significantly reduced in clock-deficient cells, indicating that the circadian clock plays an important role in activation of this pathway. Inhibition of p38 MAPK activity with VX-745 led to cell-type-specific period changes in the molecular clock. In addition, phosphorylated p38 MAPK levels were rhythmic in HA glial cells, and high and arrhythmic in invasive IM3 glioma cells. We show that inhibition of p38 MAPK activity in IM3 cells at the time of day when the levels are normally low in HA cells under control of the circadian clock, significantly reduced IM3 invasiveness.

Conclusions

Glioma treatment with p38 MAPK inhibitors may be more effective and less toxic if administered at the appropriate time of the day.

http://ift.tt/2EtdJIh

The preventive effect of sensorimotor- and vibration exercises on the onset of Oxaliplatin- or vinca-alkaloid induced peripheral neuropathies - STOP

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected.

CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait.

These symptoms not only affect activities of daily living, subsequently reducing patients' quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking.

Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN.

Methods

We are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint.

Discussion

We hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients' quality of life.

Trial registration

Deutsche Register Klinischer Studien (DRKS00006088, registered 07.05.2014).

http://ift.tt/2FnpCAD

Are prognostic indices for brain metastases of melanoma still valid in the stereotactic era?

Abstract

Background

Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melanoma cells are regarded as very radioresistant. Therapeutic possibilities have fundamentally changed since the availability of stereotactic radiotherapy (SRT), where it is possible to apply high ablative doses in a very precise manner. In this work we analyze prognostic factors of overall survival (OS) after SRT in patients with MBM and evaluate the applicability of popular prognostic indices that mainly stem from the WBRT-era.

Materials and methods

This work is a retrospective analysis of OS of 80 malignant melanoma (MM) patients who received SRT for intracranial melanoma metastases between 2004 and 2014 who had not received prior treatment for MBM in terms of surgery or WBRT. Potential prognostic factors were analyzed using univariable and multivariable analysis. Existing prognostic scores [Graded Prognostic Assessment (GPA), Diagnosis-Specific-GPA (DS-GPA), Golden Grading System (GGS) and RADES] were calculated and tested using log-rank analysis.

Results

Eighty patients, respectively 177 brain metastases, were irradiated. The median survival time from radiation was 7.06 months. Overall, GGS, GPA and DS-GPA were significant predictors of survival. The MM-specific index DS-GPA showed the best p-value but did not show adequate division when looking at the two intermediate risk subgroups. RADES did not show any statistically significant prognostic value. In univariable as well as in multivariable analyses a higher Karnofsky-Index, a single BM, and non nodular melanoma (NM) histology were positive predictors of survival.

Conclusion

The existing prognostic scores do not seem to ideally fit for this special group of patients. Our results indicate that the histologic subtype of MM could add to the prognostic value of specialized future indices.

http://ift.tt/2qOEFjM

Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia

Summary

Aim

The objective of this study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia (CIN) treated with filgrastim and pegfilgrastim.

Methods

Data were extracted from 10 phase 1-3 studies conducted in 110 healthy adults and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug-receptor-binding model that assumed quasi-equilibrium and stimulation of production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by KPD-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production.

Results

The systemic half-lives of filgrastim (2.6 hours) and pegfilgrastim (10.1 hours) were as expected. The effective half-life of chemotherapy was 9.6 hours, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme inter-individual variability (% coefficient of variation > 200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. Stimulatory effects of pegfilgrastim were significantly higher than filgrastim. Model qualification confirmed the predictive capability of this model.

Conclusion

This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

http://ift.tt/2CWywYh

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma, Published online: 09 January 2018; doi:10.1038/bjc.2017.469

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma

http://ift.tt/2FicbCh

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses’ Health Study

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study, Published online: 09 January 2018; doi:10.1038/bjc.2017.437

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study

http://ift.tt/2FlDb3U

MED12, TERT promoter and RBM15 mutations in primary and recurrent phyllodes tumours

MED12, TERT promoter and RBM15 mutations in primary and recurrent phyllodes tumours

<i>MED12</i>, <i>TERT</i> promoter and <i>RBM15</i> mutations in primary and recurrent phyllodes tumours, Published online: 09 January 2018; doi:10.1038/bjc.2017.450

MED12, TERT promoter and RBM15 mutations in primary and recurrent phyllodes tumours

http://ift.tt/2FnV7Le

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study, Published online: 09 January 2018; doi:10.1038/bjc.2017.449

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study

http://ift.tt/2FkabJH

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma, Published online: 09 January 2018; doi:10.1038/bjc.2017.418

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

http://ift.tt/2FkmsO5

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer, Published online: 09 January 2018; doi:10.1038/bjc.2017.417

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

http://ift.tt/2FnV8ig

Meta-analysis shows similar re-bleeding rates among Western and Eastern populations after index video capsule endoscopy

Video capsule endoscopy (VCE) is the first-line diagnostic procedure for investigating obscure gastrointestinal bleeding (OGIB). Different re-bleeding rates following index VCE have been reported among Western and Eastern studies.

http://ift.tt/2mjHyEF

Donor PNPLA3 rs738409 genotype is a steatosis. A post-transplant biopsy-based study

& Aims The rs738409 c.444C > G (p.I148 M) polymorphism in PNPLA3 is a major factor predisposing to non-alcoholic fatty liver disease. The aim of the study was to clarify the impact of liver and extrahepatic expression of the PNPLA3 p.148 M variant on liver graft steatosis after liver transplantation.

http://ift.tt/2qMM3Mt

UPLC-QTOF MS-Based Serum Metabolomic Profiling Analysis Reveals the Molecular Perturbations Underlying Uremic Pruritus

As one of the most troublesome complications in patients with chronic renal disease, the etiology of uremic pruritus remains unknown, and the current therapeutic approaches are limited and unsatisfactory. To identify potential biomarkers for improving diagnosis and treatment and obtain a better understanding of the pathogenesis of uremic pruritus, we compared serum metabolome profiles of severe uremic pruritus (HUP) patients with mild uremic pruritus (LUP) patients using ultraperformance liquid chromatography-quadruple time-of-flight mass spectrometry (UPLC-QTOF MS). Partial least squares discriminant analysis (PLS-DA) showed that the metabolic profiles of HUP patients are distinguishable from those of LUP patients. Combining multivariate with univariate analysis, 22 significantly different metabolites between HUP and LUP patients were identified. Nine of the 22 metabolites in combination were characterized by a maximum area-under-receiver operating characteristic curve (AUC = 0.899) with a sensitivity of 85.1% and a specificity of 83.0% distinguishing HUP and LUP. Our results indicate that serum metabolome profiling might serve as a promising approach for the diagnosis of uremic pruritus and that the identified biomarkers may improve the understanding of pathophysiology of this disorder. Because the 9 metabolites were phospholipids, uremic toxins, and steroids, further studies may reveal their possible role in the pathogenesis of uremic pruritus.

http://ift.tt/2qKwXXX

Patient Access, Unmet Medical Need, Expected Benefits, and Concerns Related to the Utilisation of Biosimilars in Eastern European Countries: A Survey of Experts

This policy research aims to map patient access barriers to biologic treatments, to explore how increased uptake of biosimilars may lower these hurdles and to identify factors limiting the increased utilisation of biosimilars. A policy survey was developed to review these questions in 10 Central and Eastern European (CEE) and Commonwealth of Independent States (CIS) countries. Two experts (one public and one private sector representative) from each country completed the survey. Questions were related to patient access, purchasing, clinical practice, and real-world data collection on both original biologics and biosimilars. Restrictions on the number of patients that can be treated and related waiting lists were reported as key patient access barriers. According to respondents, for both clinicians and payers the primary benefit of switching patients to biosimilars would be to treat more patients. However, concerns with therapeutic equivalence and fear of immunogenicity may reduce utilisation of biosimilars. Similar limitations in patient access to both original biologics and biosimilars raise concerns about the appropriateness and success of current biosimilar policies in CEE and CIS countries. The conceptual framework for additional real-world data collection exists in all countries which may provide a basis for future risk-management activities including vigorous pharmacovigilance data collection.

http://ift.tt/2mkiX2h

Difference in Subjective Accessibility of On Demand Recall of Visual, Taste, and Olfactory Memories

We present here significant difference in the evocation capability between sensory memories (visual, taste, and olfactory) throughout certain categories of the population. As object for this memory recall we selected French fries that are simple and generally known. From daily life we may intuitively feel that there is much better recall of the visual and auditory memory compared to the taste and olfactory ones. Our results in young (age 12–21 years) mostly females and some males show low capacity for smell and taste memory recall compared to far greater visual memory recall. This situation raises question whether we could train smell and taste memory recall so that it could become similar to visual or auditory ones. In our article we design technique of the volunteers training that could potentially lead to an increase in the capacity of their taste and olfactory memory recollection.

http://ift.tt/2qKwVPP

Gene Therapy and Genome Editing

The β-thalassemias are inherited blood disorders that result from insufficient production of the β-chain of hemoglobin. More than 200 different mutations have been identified. β-Thalassemia major requires life-long transfusions. The only cure for severe β-thalassemia is to provide patients with hematopoietic stem cells. Globin gene therapy promises a curative autologous stem cell transplantation without the immunologic complications of allogeneic transplantation. The future directions of gene therapy include enhancement of lentiviral vector-based approaches, fine tuning of the conditioning regimen, and the design of safer vectors. Progress in genetic engineering bodes well for finding a cure for severe globin disorders.

http://ift.tt/2EpD8mb

Author’s Response

We thank the reader for pointing out this important issue in our previous meta-analysis. [1] We wish to clarify that we have included both Michna et al [2] and Iyer et al [3] albeit being the same study because one of the secondary outcomes in the meta-analysis is "change in pain scores" and the data for this outcome was provided only by the latter article. We have not included the data from latter study for assessment of any other outcomes. Similarly, Thomas et al [4] and Chamberlain et al [5] although are the same studies, the data on another secondary outcome, "Time to achieve rescue free bowel movement" was not stated clearly in the former article for placebo group unlike the latter and so it was included for this outcome analysis and the reported pooled estimate for this outcome was not significantly different from placebo for subcutaneous methyl naltrexone.

http://ift.tt/2CVQ9HX

Communication Disparity between Bereaved and Others: What Hurts Them and What is Unhelpful? – A Nationwide Study of the Cancer Bereaved

The importance of communication between the cancer bereaved and others has been emphasized, but little is known about the more problematic aspects of this communication such as "unhelpful communication".

http://ift.tt/2AJkB1P

Frontmatter

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: i-iii

http://ift.tt/2AKY1pJ

Structure and function of the human parvulins Pin1 and Par14/17

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: 101-125

http://ift.tt/2CXP9D7

Structural mechanisms of HECT-type ubiquitin ligases

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: 127-145

http://ift.tt/2AK1UeD

Mechanisms, pathophysiological roles and methods for analyzing mitophagy – recent insights

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: 147-178

http://ift.tt/2CXP9mB

PARP-1 and PARP-2 activity in cancer-induced cachexia: potential therapeutic implications

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: 179-186

http://ift.tt/2AKY2dh

The dinoponeratoxin peptides from the giant ant Dinoponera quadriceps display in vitro antitrypanosomal activity

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: 187-196

http://ift.tt/2CVLeGM

The inhibition of the mitochondrial F1FO-ATPase activity when activated by Ca2+ opens new regulatory roles for NAD+

Journal Name: Biological Chemistry
Volume: 399
Issue: 2
Pages: 197-202

http://ift.tt/2ALj5MS

BRCA1 and BRCA2 mutation spectrum – an update on mutation distribution in a large cancer genetics clinic in Norway

Abstract

Background

Founder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway.

Methods

A total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.

Results

There were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.

Conclusions

The spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway's largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.

http://ift.tt/2CK6yuY

Missed Opportunities in Colorectal Cancer Prevention in Patients with Inadequate Bowel Preparations

http://ift.tt/2FjPu0m

Confusion for Fifteen Years; A Case of Abernethy Malformation

http://ift.tt/2EsEWdY

Postoperative rehabilitation after deep brain stimulation surgery for movement disorders

Deep brain stimulation (DBS) is highly effective for the treatment of movement disorders such as Parkinson's disease (PD) (Timmermann et al., 2015a), tremor (Oliveria et al., 2017) and dystonia (Volkmann et al., 2014), but also further neurologic and psychiatric disorders (Welter et al., 2017). During DBS, continuous electrical stimulation is applied in appropriate subcortical areas to achieve clinical improvement of disabling symptoms. The unique feature of this therapeutic approach is the ability to preferentially modulate, through the choice of stimulation site, specific cerebral networks.

http://ift.tt/2qOUcQw

Dynamic contrast-enhanced EUS for quantification of tumor perfusion in colonic cancer: a prospective cohort study

Dynamic contrast enhanced endoscopic ultrasound (CE-EUS) for quantification of perfusion in colonic tumors has not previously been reported in the literature. The aim of the study was to investigate correlations between perfusion parameters and vessel density assessed by immunohistochemical staining with antibodies toward CD31 and CD105.

http://ift.tt/2qJ9Ywl

EUS elastography (strain ratio) and fractal-based quantitative analysis for the diagnosis of solid pancreatic lesions

EUS elastography is useful in characterizing solid pancreatic lesions (SPLs), and fractal analysis-based technology has been used to evaluate geometric complexity in oncology. The aim of this study was to evaluate EUS elastography (strain ratio) and fractal analysis for the characterization of SPLs.

http://ift.tt/2mlrjXq

A Qualitative Assessment of Academic Radiation Oncology Department Chairs’ Insights on Diversity, Equity, and Inclusion: Progress, Challenges, and Future Aspirations

This qualitative study sought to understand how to promote diversity, equity, and inclusion in radiation oncology. The authors conducted telephone interviews with department chairs, with attention to the experiences of the few women and underrepresented minorities in these positions. Chairs' insights had policy-relevant implications. Bias training should attempt to tap into the sensitive contextual areas of tokenism, blindness, and intersectionality. Efforts to recruit and support diverse talent should be deliberate and proactive. Bridge programs could engage diverse learners across the education spectrum.

http://ift.tt/2CYwlnl

Radiation Therapy to Sites of Metastatic Disease as Part of Consolidation in High-risk Neuroblastoma: Can Long-term Control be Achieved?

Although radiation therapy to persistent sites of metastatic disease is recommended as part of consolidative therapy for high-risk neuroblastoma, there is little data evaluating the value of this approach in achieving long-term control. Our results show that irradiation of metastatic sites of disease is effective in achieving local control, and that response to induction chemotherapy is a significant prognostic factor for control at irradiated sites.

http://ift.tt/2CW4Omr

The Role of Radiation Therapy in Patients with Relapsed/Refractory Hodgkin Lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group

Relapsed and refractory Hodgkin lymphoma (HL) challenges clinicians to devise treatment strategies that are effective and safe. This problem is particularly prominent in an era when de-escalation trials are designed to minimize therapeutic toxicities in both early and advanced stage disease. Radiation therapy is the single most effective treatment modality for HL, and its integration into salvage regimens, or its independent use in select patients, must be understood in order to maximize our success in treating these patients.

http://ift.tt/2ALhWoi

The radiation resistance of human multipotent mesenchymal stromal cells is independent of their tissue of origin

Mesenchymal stromal cells (MSCs) from different tissues may aid the regeneration of radiation-induced organ lesions; however, the influence of ionizing radiation on tissue-specific human MSCs is unknown. Here we show that the radiation resistance of MSCs is independent of their tissue of origin, and irradiated MSCs from adipose tissue, bone marrow and umbilical cord preserved their defining characteristics. Efficient repair of radiation-induced DNA damage may contribute to this radiation resistance.

http://ift.tt/2CZUKZG

Endoscopic Surgery for Delayed Sinonasal Complications of Radiotherapy for Nasopharyngeal Carcinoma: a Subjective Outcome

Delayed sino-nasal complications of radiotherapy include choanal stenosis, osteoradionecrosis, chronic sinusitis and intranasal synechiae. Their incidence and burden on their quality of life are underestimated. Results of our prospective study show good subjective outcome of surgical treatment of these delayed sino-nasal complications. It should encourage clinicians to be cognizant of symptoms suspicious for this pathology and to be diligent in referring the patients for further evaluation and treatment.

http://ift.tt/2ALcy4A

The efficacy and safety of conventional and hypofractionated high-dose radiotherapy for prostate cancer in an elderly population: a subgroup analysis of the CHHiP trial

The efficacy and toxicity of radiotherapy for localised prostate cancer in CHHiP trial participants aged 75 and over was compared with patients younger than 75. There was no evidence of a difference in biochemical or clinical recurrence free survival or clinically significant toxicity between the older and younger patient groups. Hypofractionated radiotherapy is an effective and well tolerated treatment for localised prostate cancer in an elderly population with good performance status.

http://ift.tt/2AKS8J8

Patient Experiences and Clinician Views on the Role of Radiotherapy for Ductal Carcinoma In-Situ

In a population-based survey of patients with DCIS, we observed that a quarter of patients omit radiotherapy after breast conserving surgery, with a two-fold difference in the rate of radiotherapy omission between the 2 SEER regions studied. In a corresponding survey of clinicians, we observed systematic differences in opinions between the two SEER regions regarding the role of radiation.

http://ift.tt/2CYo8PM

Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study

The aim of this clinical trial was to assess the efficacy and safety of curcuminoid complex extract from turmeric rhizome with turmeric volatile oil (CuraMed®) and its combination with boswellic acid extract f...

http://ift.tt/2CWGQHR

Five Hypermethylated MicroRNA Genes as Potential Markers of Ovarian Cancer

MicroRNA and methylation are important epigenetic mechanisms in the pathogenesis of cancer. The role of a group of microRNA hypermethylated genes in the pathogenesis of ovarian cancer was studied and their diagnostic and prognostic potential was evaluated. Studies on a representative sample of 54 ovarian cancer specimens with the use of methyl-specific PCR resulted in detection of five microRNA genes (MIR-9-1, MIR-9-3, MIR-107, MIR-1258, and MIR-130b) methylated in the majority of tumor specimens in comparison with paired specimens of histologically intact tissue (37-57% vs. 4-9%, p<0.01). Methylation of three genes (MIR-9-1, MIR-9-3, and MIR-130b) was significantly (p≤0.05) associated with the parameters of ovarian cancer progress (clinical stage, differentiation degree, tumor size, and presence of metastases). These findings attest to oncosuppressive role of the studied microRNA genes (MIR-9-1, MIR-9-3, MIR-107, MIR-1258, and MIR-130b) in the pathogenesis and progress of ovarian cancer and indicated their prognostic potential.

http://ift.tt/2CW20FV

The Barrel Vascular Reconstruction Device

Abstract

Background and Purpose

The Barrel device is an electrolytically detachable laser cut, closed-cell microstent that is used for neck reconstruction in wide-necked bifurcation and branching aneurysms to support coiling. The key feature is a barrel section that herniates over the aneurysmal ostium. The objective was to evaluate the safety, feasibility and the immediate and mid-term occlusion results of this new device.

Material and Methods

The databases of two tertiary care centers were screened for all Barrel-based stent-assisted intracranial coil embolization of wide-necked aneurysms between June 2015 and September 2016. Case files and imaging data were retrospectively analyzed for angiographic and clinical outcome parameters, including immediate and mid-term modified Raymond-Roy aneurysm occlusion classification (RROC) rates and procedural complications.

Results

A total of 21 patients comprising 21 intracranial aneurysms (20 unruptured, 1 ruptured) were treated with the Barrel device and additional coiling of the aneurysm sac. All aneurysms were wide-necked, saccular bifurcation aneurysms defined by a dome/neck ratio ≤2. Immediate complete occlusion (RROC1) was observed in 19/21 (90%). An intra-interventional in-stent thrombus formation in two cases (10%) was medically resolved without neurological sequelae. A single case of symptomatic in-stent stenosis (5%) was cleared by balloon angioplasty. Follow-up (FU) was available in 20/21 cases (95%) after a median of 282 days (range: 17–591 days). At follow-up 19/20 aneurysms (95%) were completely occluded (RROC1).

Conclusion

The Barrel device showed a satisfactory safety profile and a promising rate of immediate and mid-term complete aneurysm occlusion for stent-assisted coil embolization of wide-necked intracranial bifurcation aneurysms, warranting further investigation of the device.

http://ift.tt/2mc8Mfy

Morphometry of the Hand Knob Region and Motor Function Change in Eloquent Area Glioma Patients

Abstract

Purpose

The hand knob area is the cortical representation of motor hand function. The current study aimed to investigate the effects of eloquent area gliomas on the morphometry of the hand motor cortex and preoperative hand motor function.

Methods

A retrospective study of 320 glioma patients was conducted. Seventy-eight patients with gliomas involving motor functional area were finally enrolled. Using axial T2-weight magnetic resonance images, the width and height of the hand knob were measured in both hemispheres, and differences were compared between the affected and unaffected hemispheres. Receiver operating characteristic (ROC) curve and logistic regression analysis were used to estimate the degree of correlation between distance measurements and motor impairment.

Results

The width and height of the hand knob in the affected and unaffected hemispheres were significantly different (p < 0.0001). The width, height and distance from the tumor to hand knob were reduced in the functionally impaired group compared to the unimpaired group (p = 0.0003, p < 0.0001, p = 0.0005, respectively). The three parameters were significantly correlated and remained significant in ROC and logistic regression analysis. The optimal cut-off value of width, height and distance for identifying preoperative hand muscle strength were 5.73 mm, 5.80 mm and 5.92 mm, respectively.

Conclusion

The morphometry of the hand knob is often changed by the infiltration or extrusion of the tumors that were located in or near the hand knob. The width, height of hand knob and the distance from tumor to hand knob could serve as anatomic biomarkers related to preoperative neurological motor deficits.

http://ift.tt/2CYSjWe

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma

http://ift.tt/2CKj3qn

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

http://ift.tt/2Ddxx34

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses’ Health Study

http://ift.tt/2CJdhoJ

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

http://ift.tt/2Dd4oVD

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study

http://ift.tt/2Fhcehv

MED12, TERT promoter and RBM15 mutations in primary and recurrent phyllodes tumours

http://ift.tt/2ErMeii

Improved evaluation of antivascular cancer therapy using constrained tracer-kinetic modeling for multi-agent dynamic contrast-enhanced MRI

Dynamic contrast-enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to anti-vascular therapies. Multi-agent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we employed multi-agent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multi-agent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 h and 24 h after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was employed to estimate flow F, blood volume fraction vb, mean capillary transit time tc, bolus arrival time td, extracellular extravascular fraction ve, vascular heterogeneity index α-1 (all identical between agents) and extraction fraction E (reflective of permeability) and transfer constant Ktrans (both agent-specific) in perfused pixels. F, vb, and α-1 decreased at both time points after DMXAA, while tc increased. E (G2 and G5) showed an initial increase after which both parameters restored. Ktrans (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, tc, and Ktrans Gd-DOTA showed significant changes. Histological perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multi-agent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy, by separating simultaneous changes in tumor hemodynamics and vascular permeability.

http://ift.tt/2DeUJhn

Investigating low-velocity fluid flow in tumors using convection-MRI

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel magnetic resonance imaging (MRI) technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extra-vascular flow. Here we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers.

http://ift.tt/2CK5I16

In silico evaluation of pharmacokinetic optimization for antimitogram-based clinical trials

Antimitograms are prototype in vitro tests for evaluating chemotherapeutic efficacy using patient-derived primary cancer cells. These tests might help optimize treatment from a pharmacodynamic (PD) standpoint by guiding treatment selection. However, they are technically challenging and require refinements and trials to demonstrate benefit in order to be widely used. In this study, we performed simulations aimed at exploring how to validate antimitograms and how to complement them by pharmacokinetic (PK) optimization. A generic model of advanced cancer including PK-PD monitoring was used to link dosing schedules with progression-free survival (PFS), as built from previously validated modules. This model was used to explore different possible situations in terms of PK variability, PD variability, and antimitogram performance. The model recapitulated tumor dynamics and standalone therapeutic drug monitoring efficacy consistent with published clinical results. Simulations showed that combining PK and PD optimization should increase PFS in a synergistic fashion. Simulated data were then used to compute required clinical trial sizes, which were 30 to 90% smaller when PK optimization was added to PD optimization. This improvement was observed even when PK optimization alone exhibited only modest benefit. Overall, our work illustrates the synergy derived from combining antimitograms with therapeutic drug monitoring, permitting a disproportionate reduction of the trial size required to prove a benefit on PFS. Accordingly, we suggest that strategies with benefits too small for standalone clinical trials could be validated in combination in a similar manner.

http://ift.tt/2CKeBYH

Daily repetitive sensory stimulation of the paretic hand for the treatment of sensorimotor deficits in patients with subacute stroke: RESET, a randomized, sham-controlled trial

Repetitive sensory stimulation (RSS) adapts the timing of stimulation protocols used in cellular studies to induce synaptic plasticity. In healthy subjects, RSS leads to widespread sensorimotor cortical reorga...

http://ift.tt/2CXfTne

Plasma long non-coding RNA BACE1 as a novel biomarker for diagnosis of Alzheimer disease

Long non-coding RNA (LncRNA) have been reported to be involved in the pathogenesis of neurodegenerative diseases, but whether it can serve as a biomarker for Alzheimer disease (AD) is not yet known.

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Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS and C9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes

Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragi...

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Phloem Sap Sampling from Brassica napus for 3D-PAGE of Protein and Ribonucleoprotein Complexes

Here we present a protocol to analyze the protein composition of large native protein:protein and protein:nucleic acid complexes from oilseed rape (B. napus) phloem exudate using a 3D polyacrylamide gel electrophoresis (PAGE) approach combining blue native (BN) with two denaturing PAGEs followed by mass spectrometric identification.

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Cytotechnologists as coinvestigators in anatomical pathology research

BACKGROUND

The amount of time available to pathologists with which to perform research is becoming limited due to an increasing manpower shortage in pathology, decreased reimbursement, and increased workload. This is occurring at the same time as demands escalate for pathologists to develop new companion tests, correlate the molecular findings with traditional methods, and assist in the development of individualized medicine. This study examined whether cytotechnologists may be integrated into a research team that uses their expertise in understanding pathology and clinical disease to provide interpretations of experiments that traditionally were performed by pathologists.

METHODS

Cytotechnologists worked with pathologists to choose blocks for tissue microarrays (TMAs) and to interpret immunohistochemically stained TMA slides. The pathologist met with the cytotechnologist to review the study design. The cytotechnologists reviewed the slides and blocks and chose the most appropriate blocks for the TMA. Either 10% or all of the slides/blocks selected for TMA construction were reviewed by the supervising pathologist. The final selections were given to the TMA technologist to make the TMA. A minimum of 10% of the immunohistochemically stained TMA slides were reviewed by the supervising pathologist.

RESULTS

A total of 32 TMAs were created with 6 cytotechnologists collaborating with 6 pathologists. Immunohistochemical stains of 190 TMAs were interpreted by 4 cytotechnologists collaborating with 3 pathologists. All the TMAs and TMA interpretation data were used successfully for the research for which they were designed.

CONCLUSIONS

The collaboration of cytotechnologists and pathologists in research can improve the quality of effort and increase satisfaction and productivity. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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Advanced practitioner in anatomic pathology: The time has come

Appropriately trained cytotechnologists have been shown to have the skills necessary to safely assist the pathologist in nontraditional tasks. These advanced-level individuals may be necessary to stem the leakage of traditional pathology services to other specialties or even prevent them from not being done at all. The time has arrived to move this concept forward.See also pages 000-000.

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Orthopedia homeobox is preferentially expressed in typical carcinoids of the lung

BACKGROUND

Twenty-seven percent of neuroendocrine tumors (NETs) are associated with distant metastases, and in some patients, the primary site is unknown. Orthopedia homeobox protein (OTP) has been described as a useful marker for lung carcinoids (LCs) and for separating low-grade typical carcinoids (TCs) from intermediate-grade atypical carcinoids (ACs) in resection specimens. This study evaluated OTP, thyroid transcription factor 1 (TTF-1), and Ki-67 expression in fine-needle aspiration (FNA) samples of various NETs.

METHODS

A search for NETs diagnosed via FNA with subsequent resection was performed. Cell block sections were stained for OTP, TTF-1, and mindbomb E3 ubiquitin protein ligase 1 (Mib-1). Nuclear expression for OTP and TTF-1 was considered positive. Nuclear Ki-67 staining was reported as a percentage. Results were correlated with the grade and primary site for resection specimens.

RESULTS

Sixty-three FNA samples of NETs were identified: 14 liver samples, 14 pancreatic samples, 13 lymph node samples, 12 lung samples, 3 retroperitoneum samples, 2 small intestine samples, and 5 other samples. OTP was positive in 12 of 63 NETs (19%) from the following sites: lung (n = 8), liver (lung primary; n = 2), skin (n = 1), and lymph node (lung primary; n = 1). In well-differentiated NETs, only LCs were OTP-positive, whereas TTF-1 was positive in LCs and nonlung NETs (67% vs 7%). Within the LC category, OTP was positive in 100% of the TCs versus 17% of the ACs.

CONCLUSIONS

OTP is specific for LCs because well-differentiated nonlung NETs are negative for OTP. OTP preferentially stains TCs over ACs. In well-differentiated NETs, OTP staining is highly specific for LCs, and in combination with a low Ki-67 index, it suggests a pulmonary TC. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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Observational study in healthy volunteers to define interobserver reliability of ultrasound haemodynamic monitoring techniques performed by trainee doctors

Objectives Bedside ultrasound is increasingly being used to guide fluid management in shocked patients. Little data exist on the inter-rater reliability of techniques used, especially when performed by nonexpert trainee doctors. The primary aim of this study is to measure the inter-rater reliability of five ultrasound techniques commonly used to guide fluid management: inferior vena cava collapsibility index (IVCCI), transthoracic echocardiography (TTE)-derived stroke volumes, ultrasound cardiac output monitor (USCOM) derived stroke volume and carotid artery blood flow and corrected flow time measurements. Methods Two Royal College of Emergency Medicine level one ultrasound-certified emergency medicine trainees performed paired ultrasound measurements on 31 healthy nonpatient volunteers. Inter-rater reliability was assessed through three indices: interclass correlation coefficient (ICC), limits of agreements (LOAs) derived from Band–Altman plots and the proportion of paired scans with absolute differences of less that 15% (defined as agreement). Results TTE-derived measurements performed the best overall, with an LOA of 22%, an ICC of 0.55 and an agreement of 80%. USCOM also performed well, with an LOA of 33%, an ICC of 0.68 and an agreement of 58%. IVCCI and carotid artery-derived measurements performed poorly across all indices. Conclusion TTE-derived measurements showed the highest level of inter-rater reliability and can thus be expected to provide reliable measures over time with different sonographer clinicians. USCOM interobserver reliability was also adequate for clinical use. However, on the basis of inter-reliability measures, IVCCI and carotid artery measurements were found to be inadequate for clinical use. Correspondence to Benjamin M. Bussmann, MBBCh, Emergency Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK Tel: +44 203 594 0045; e-mail: bussmann.benjamin@gmail.com Received June 11, 2017 Accepted November 29, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Increased pathologic upstaging with rising time to treatment initiation for head and neck cancer: A mechanism for increased mortality

BACKGROUND

Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC).

METHODS

Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively.

RESULTS

Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P < .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality (P < .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P = .023).

CONCLUSIONS

Tumor progression, measured by clinical-to-pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018. © 2018 American Cancer Society.

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Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation

BACKGROUND

The objective of this study was to evaluate whether modifiable cardiovascular risk conditions and lifestyle factors were temporally associated with an increased risk for ischemic heart disease and overall mortality in a cohort of hematopoietic cell transplantation (HCT) survivors.

METHODS

HCT recipients who had survived for ≥1 year, were ≥20 years old, and had undergone transplantation between 1970 and 2010 at a transplant referral center were surveyed in 2010-2011 about cardiovascular health and lifestyle factors (n = 3833). Respondents (n = 2360 [61.6%]) were followed to 2016 for incident ischemic heart disease and overall mortality.

RESULTS

Among the 2360 transplant survivors (median age at the baseline survey, 55.9 years; median time since transplantation, 10.8 years), 162 (6.9%) reported ischemic heart disease at the baseline survey. Among those without ischemic heart disease at the baseline survey (n = 2198), the 5-year cumulative incidence of subsequent ischemic heart disease was 4.3%. Obesity, dyslipidemia, diabetes, and physical inactivity at baseline were associated with an increased risk for subsequent ischemic heart disease (hazard ratio [HRs] ≥ 1.8). Greater physical activity and fruit/vegetable intake at baseline were associated with subsequent lower overall mortality (HRs ≤ 0.7). When jointly considered, each additional cardiovascular risk condition and each adverse lifestyle factor were independently associated with subsequent ischemic heart disease (HR for risk conditions, 1.4; 95% confidence interval [CI], 1.0-1.9; HR for lifestyle factors, 1.9; 95% CI, 1.2-2.9), and adverse lifestyle factors remained associated with overall mortality (HR, 1.8; 95% CI, 1.5-2.3).

CONCLUSIONS

These results support strong efforts to promote healthy lifestyle behaviors and to treat cardiovascular risk factors aggressively in HCT survivors. This may reduce future ischemic heart disease and overall mortality in this high-risk population. Cancer 2018. © 2018 American Cancer Society.

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Who is at risk after risk reduction?

After gynecologic risk-reducing surgery, BRCA1/2 mutation carriers remain at risk of developing primary peritoneal cancer. The study by Harmsen et al in this issue of Cancer provides information regarding who might be at greater risk after risk-reduction surgery. See also pages 00-00.

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Peritoneal carcinomatosis after risk-reducing surgery in BRCA1/2 mutation carriers

BACKGROUND

Risk-reducing salpingo-oophorectomy (RRSO) is recommended for BRCA1/2 mutation carriers because of their increased risk of ovarian carcinoma. Despite RRSO, metachronous peritoneal carcinomatosis occasionally is diagnosed.

METHODS

The literature was searched for BRCA1/2 mutation carriers with peritoneal carcinomatosis after risk-reducing surgery. The authors were asked for additional data. Clinical and histopathological data were descriptively analyzed. Cases were compared with a single-institution control cohort.

RESULTS

Of 36 cases, 86.1% concerned BRCA1 mutation carriers. The median age of the patients was 52 years (range, 30-71 years) at the time of risk-reducing surgery and 60 years (range, 37-75 years) at the time of diagnosis of peritoneal carcinomatosis. The median interval between the 2 events was 54.5 months (range, 11-292 months). Peritoneal carcinomatosis was mostly high-grade serous carcinoma. Histopathological details of the RRSO specimens were retrieved in 8 cases; 5 (62.5%) were found to have serous tubal intraepithelial carcinoma and 1 had epithelial atypia. Cases were older (P = .025) at the time of risk-reducing surgery and harbored more serous tubal intraepithelial carcinomas (P<.001) compared with women from the control cohort.

CONCLUSIONS

Metachronous peritoneal carcinomatosis after risk-reducing surgery occurs predominantly in BRCA1 mutation carriers, usually within 5 years. Data have suggested that surgery at a younger age lowers the rates of peritoneal carcinomatosis. These data can be used in the gynecologic counseling of BRCA1/2 mutation carriers. RRSO should include complete salpingectomy. Detailed histopathological examination of specimens removed during RRSO is essential. Cancer 2018. © 2018 American Cancer Society.

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Chinese and South Asian ethnicity, immigration status, and clinical cancer outcomes in the Ontario Cancer System

BACKGROUND

In the United States, certain minority groups have been shown to have inferior cancer outcomes compared with the white majority population. However, to the authors' knowledge, the majority of research has not separated ethnicity from immigration status. The objective of the current study was to determine the impact of ethnicity, independent of immigration status, on cancer outcomes in Chinese and South Asian populations in Ontario, Canada.

METHODS

The authors conducted a population-based retrospective cohort study using administrative databases in Ontario, Canada. Incident cancer cases were captured in Canadian-born Chinese and South Asian individuals, Chinese and South Asian immigrants, and the general Ontario reference population (non-Chinese/non-South Asian and non-immigrant) between 2000 and 2012. Subjects were followed until death (all-cause and cancer-specific), and Cox proportional hazard models were used to estimate the impact of Chinese and South Asian ethnicity on cancer outcomes after adjusting for explanatory variables.

RESULTS

A total of 423,678 cancer cases were identified; at total of 6631 cases were identified in Canadian-born Chinese individuals and 2752 cases in Canadian-born South Asian individuals. After adjustment, the rate of all-cause mortality was lower for Canadian-born Chinese (hazard ratio [HR], 0.829; 95% confidence interval [95% CI], 0.795-0.865), Canadian-born South Asian (HR, 0.856; 95% CI, 0.797-0.919), and Chinese immigrant (recent immigrant: HR, 0.661 [95% CI, 0.610-0.716] and non-recent immigrant: HR, 0.853 [95% CI, 0.803-0.906]) populations compared with the general Ontario population. A similar effect was found for cancer-specific mortality.

CONCLUSIONS

Chinese and South Asian ethnic groups appear to have lower cancer mortalities compared with the general Ontario population. After removing the well-documented protective effect of immigration, Chinese and South Asian ethnicities were found to be associated with a cancer survival advantage in Ontario, Canada. Cancer 2018. © 2018 American Cancer Society.

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The clinical implications of immunogenomics in colorectal cancer: A path for precision medicine

Colorectal cancer (CRC) remains the third most common malignancy and the second-leading cause of cancer-related deaths in the United States. Large multi-omic databases, such as The Cancer Genome Atlas and the International Colorectal Cancer Subtyping Consortium, have identified distinct molecular subtypes related to anatomy. The identification of genomic alterations in CRC is now critical because of the recent success and US Food and Drug Administration approval of pembrolizumab and nivolumab for microsatellite-instable tumors. In parallel, landmark studies have established the prognostic significance of the CRC tumor-infiltrating lymphocyte and the clinical impact of the tumor immune microenvironment. As a result, there is a growing appreciation for immunogenomics, the interconnected relation between tumor genomics and the immune microenvironment. The clinical implications of CRC immunogenomics continue to expand, and it will likely serve as a guide for next-generation immunotherapy strategies for improving outcomes for this disease. Cancer 2018. © 2018 American Cancer Society.

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Long-term outcome of dasatinib first-line treatment in gastrointestinal stromal tumor: A multicenter, 2-stage phase 2 trial (Swiss Group for Clinical Cancer Research 56/07)

BACKGROUND

Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and ¹⁸F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction.

METHODS

This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response.

RESULTS

Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached.

CONCLUSIONS

Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2EqHTMk

A Novel Feeder-free System for Mass Production of Murine Natural Killer Cells In Vitro

Here, we present a protocol to mass-produce gene-silencing murine NK cells by using a feeder-free differentiation system for mechanistic study in vitro and in vivo.

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The Treatment of Antibody-Mediated Rejection in Kidney Transplantation: An Updated Systematic Review and Meta-Analysis

ABSTRACTBackgroundCurrent treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B-cells, plasma-cells and the complement system have featured in recent studies of AMR.MethodsWe conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE and CENTRAL from inception to February 2017.ResultsOf 14,380 citations we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found 9 additional studies evaluating: plasmapheresis + intravenous immunoglobulin (IVIG) (2), rituximab (2), bortezomib (2), C1-inhibitor (2), and eculizumab (1). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76; 95% CI 0.35–1.63; P=0.475). Studies showed important heterogeneity in treatments, definition of AMR, quality and follow-up. Plasmapheresis and IVIG were used as standard-of-care in recent studies, and to this combination, rituximab appeared to add little or no benefit. Insufficient data are available to assess the efficacy of bortezomib and complement inhibitors.ConclusionNewer studies evaluating Rituximab showed little or no difference to early graft survival, and the efficacy of bortezomib and complement inhibitors for the treatment of AMR remains unclear. Despite the evidence uncertainty, plasmapheresis and IVIG have become standard-of-care for the treatment of acute AMR. Background Current treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B-cells, plasma-cells and the complement system have featured in recent studies of AMR. Methods We conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE and CENTRAL from inception to February 2017. Results Of 14,380 citations we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found 9 additional studies evaluating: plasmapheresis + intravenous immunoglobulin (IVIG) (2), rituximab (2), bortezomib (2), C1-inhibitor (2), and eculizumab (1). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76; 95% CI 0.35–1.63; P=0.475). Studies showed important heterogeneity in treatments, definition of AMR, quality and follow-up. Plasmapheresis and IVIG were used as standard-of-care in recent studies, and to this combination, rituximab appeared to add little or no benefit. Insufficient data are available to assess the efficacy of bortezomib and complement inhibitors. Conclusion Newer studies evaluating Rituximab showed little or no difference to early graft survival, and the efficacy of bortezomib and complement inhibitors for the treatment of AMR remains unclear. Despite the evidence uncertainty, plasmapheresis and IVIG have become standard-of-care for the treatment of acute AMR. Received 10 July 2017. Revision received 29 October 2017. Accepted 1 November 2017. CORRESPONDANCE: Professor Steve Chadban, Department of Renal Medicine, Royal Prince Alfred Hospital, Missenden Rd, Camperdown NSW 2050, Australia. E: Steve.Chadban@health.nsw.gov.au AUTHORSHIP - Susan Wan – Research design, study protocol preparation, performed search and study selection, data synthesis and manuscript preparation - Tracey Ying – Research design, study protocol preparation, performed search and study selection, data synthesis and manuscript preparation - Kate Wyburn – Research design, data review and manuscript preparation - Darren Roberts – Research design and manuscript preparation - Melanie Wyld – Research design and manuscript preparation - Steve Chadban – Research design, data review and manuscript preparation All authors approved the final manuscript DISCLOSURE The authors declare no conflicts of interest FUNDING SW is funded by the Royal Australasian College of Physicians (RACP) Jacquot Research Entry Scholarship for her postdoctoral studies TY is funded by the Australian Postgraduate Award for her postdoctoral studies Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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High intrapatient variability of tacrolimus exposure in the early period after liver transplantation is associated with poorer outcomes

AbstractBackgroundTacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high inter- and intrapatient variability leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC intrapatient variability (IPV) on graft and patient outcomes after liver transplantation.MethodsWe retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV

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Reduction–oxidation (redox) system in radiation-induced normal tissue injury: molecular mechanisms and implications in radiation therapeutics

Abstract

Every year, millions of cancer patients undergo radiation therapy for treating and destroying abnormal cell growths within normal cell environmental conditions. Thus, ionizing radiation can have positive therapeutic effects on cancer cells as well as post-detrimental effects on surrounding normal tissues. Previous studies in the past years have proposed that the reduction and oxidation metabolism in cells changes in response to ionizing radiation and has a key role in radiation toxicity to normal tissue. Free radicals generated from ionizing radiation result in upregulation of cyclooxygenases (COXs), nitric oxide synthase (NOSs), lipoxygenases (LOXs) as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and their effected changes in mitochondrial functions are markedly noticeable. Each of these enzymes is diversely expressed in multiple cells, tissues and organs in a specific manner. Overproduction of reactive oxygen radicals (ROS), reactive hydroxyl radical (ROH) and reactive nitrogen radicals (RNS) in multiple cellular environments in the affected nucleus, cell membranes, cytosol and mitochondria, and other organelles, can specifically affect the sensitive and modifying enzymes of the redox system and repair proteins that play a pivotal role in both early and late effects of radiation. In recent years, ionizing radiation has been known to affect the redox functions and metabolism of NADPH oxidases (NOXs) as well as having destabilizing and detrimental effects on directly and indirectly affected cells, tissues and organs. More noteworthy, chronic free radical production may continue for years, increasing the risk of carcinogenesis and other oxidative stress-driven degenerative diseases as well as pathologies, in addition to late effect complications of organ fibrosis. Hence, knowledge about the mechanisms of chronic oxidative damage and injury in affected cells, tissues and organs following exposure to ionizing radiation may help in the development of treatment and management strategies of complications associated with radiotherapy (RT) or radiation accident victims. Thus, this medically relevant phenomenon may lead to the discovery of potential antioxidants and inhibitors with promising results in targeting and modulating the ROS/NO-sensitive enzymes in irradiated tissues and organ injury systems.

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Supported self-management for cancer survivors to address long-term biopsychosocial consequences of cancer and treatment to optimize living well

Purpose of review As individuals are living longer with cancer as a chronic disease, they face new health challenges that require the application of self-management behaviors and skills that may not be in their usual repertoire of self-regulatory health behaviors. Increasing attention is focused on supported self-management (SSM) programs to enable survivors in managing the long-term biopsychosocial consequences and health challenges of survivorship. This review explores current directions and evidence for SSM programs that enable survivors to manage these consequences and optimize health. Recent findings Cancer survivors face complex health challenges that affect daily functioning and well being. Multiple systematic reviews show that SSM programs have positive effects on health outcomes in typical chronic diseases. However, the efficacy of these approaches in cancer survivors are in their infancy; and the 'one-size' fits all approach for chronic disease self-management may not be adequate for cancer as a complex chronic illness. This review suggests that SSM has promising potential for improving health and well being of cancer survivors, but there is a need for standardizing SSM for future research. Summary Although there is increasing enthusiasm for SSM programs tailored to cancer survivors, there is a need for further research of their efficacy on long-term health outcomes. Correspondence to Doris D. Howell, RN, PhD, Princess Margaret Cancer Centre, University Health Network, 610 University Ave., Room 15-617, Toronto, ON, Canada M5G 2M9. E-mail: Doris.howell@uhn.ca Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A Simple Cell-based Immunofluorescence Assay to Detect Autoantibody Against the N-Methyl-D-Aspartate (NMDA) Receptor in Blood

We ectopically expressed NR1 subunit of NMDA receptor tagged with green fluorescent protein in human embryonic cells (HEK293) as antigen to detect autoantibodies against NMDA receptor in the blood of patients suspected with autoimmune encephalitis. This simple method may be suitable for screening purposes in clinical settings.

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