Structural properties of bioactive peptides with α-glucosidase inhibitory activity

Abstract

Bioactive peptides are emerging as promising class of drugs that could serve as α-glucosidase inhibitors for the treatment of type 2 diabetes. This article identifies structural and physicochemical requirements for the design of therapeutically-relevant α-glucosidase inhibitory peptides. So far, a total of 43 fully sequenced α-glucosidase inhibitory peptides have been reported and 13 of them had IC₅₀ values several folds lower than acarbose. Analysis of the peptides indicates that the most potent peptides are tri– to hexapeptides with amino acids containing a hydroxyl or basic side chain at the N-terminal. The presence of proline within the chain and alanine or methionine at the C-terminal appears to be relevant for high activity. Hydrophobicity and isoelectric points are less important variables for α-glucosidase inhibition while a net charge of 0 or +1 was predicted for the highly active peptides. In silico simulated gastrointestinal digestion revealed that the high and moderately active peptides, including the most potent peptide (STYV), were gastrointestinally unstable, except SQSPA. Molecular docking of SQSPA, STYV and STY (digestion fragment of STYV) with α-glucosidase suggested that their hydrogen bonding interactions and binding energies were comparable with acarbose. The identified criteria will facilitate the design of new peptide-derived α-glucosidase inhibitors.

This article is protected by copyright. All rights reserved.

Identified structural requirements for α-glucosidase inhibitory peptides are tri – to hexapeptides with serine, threonine, tyrosine, lysine or arginine as the ultimate N-terminal residue and proline preferably at the penultimate C- terminal position while alanine or methionine at ultimate C-terminal position while hydrophobicity and charge are less important variables

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Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints' range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390 K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved.

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A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies

Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed.

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Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1

Mutations in GLE1 underlie Lethal Congenital Contracture syndrome (LCCS) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD). Both LCCS and LAAHD are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively. We identified bi-allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties, and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near the C-terminus of GLE1 that are predicted to disrupt protein–protein interaction or GLE1 protein targeting. We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause LAAHD whereas mutations that abolish the function of the coiled-coil domain cause LCCS. The phenotype of LAAHD is now expanded to include multiple individuals surviving into childhood suggesting that LAAHD is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease (AAHD).

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Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability

We present a 4-year-old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2-related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides-Baraitser syndrome and Coffin-Siris syndrome, providing further arguments to reclassify these disorders as "SWI/SNF-related intellectual disability syndromes."

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Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45

SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole-exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations. NT5C2 mutations seem to have a broad clinical spectrum and should be sought in patients manifesting either as uncomplicated or complicated HSP.

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Congenital heart defects in molecularly proven Kabuki syndrome patients

The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%). Additional CHDs diagnosed in single patients included aortic dilatation with mitral anomaly and hypoplastic left heart syndrome. We also reviewed CHDs in patients with a molecular diagnosis of Kabuki syndrome reported in the literature. In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left-sided obstructive lesions, including multiple left-sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. Clinical management of Kabuki syndrome should include echocardiogram at the time of diagnosis, with particular attention to left-sided obstructive lesions and mitral anomalies, and annual monitoring for aortic arch dilatation.

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Two novel mutations in XYLT2 cause spondyloocular syndrome

We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome.

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Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting

Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co-twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin. We used 3D surface imaging and spatially-dense morphometry to compare facial shape in a sample of 44 unaffected co-twins and age- and sex-matched unaffected controls (n = 241). Unaffected co-twins showed statistically significant differences in the midface, lateral upper face, and forehead regions, compared to controls. Furthermore, co-twins were characterized by a distinct pattern of midfacial retrusion, broader upper faces, and greater protrusion of the mandible and brow ridges. This same general facial pattern was shown in both unaffected monozygotic and dizygotic co-twin subsets. These results provide additional support that altered facial shape is a phenotypic marker for OFC susceptibility.

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FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.

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Variable phenotypic expression in a large Noonan syndrome family segregating a novel SOS1 mutation

Noonan syndrome (NS) is an autosomal dominant multisystem condition with a variable phenotype. The most characteristic features are short stature, congenital heart defects, and recognizable facial features. Mutations in SOS1 are found in 10–20% of patients with NS. Different genotype–phenotype studies mention correlations between SOS1 mutations and some features, such as ectodermal abnormalities and specific facial features. We present a large NS family with a novel pathogenic mutation; SOS1 c.3134C>G, p.Pro1045Arg. Ten family members with NS are included with genetically confirmed mutation and clinical evaluation. The phenotype shows a broad spectrum from only few suggestive features for NS in the older generation to typical features in the youngest generation. We report on a novel pathogenic mutation in the SOS1 gene and a large clinical spectrum in a NS family with ten genetically confirmed affected individuals.

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Peeling skin syndrome associated with novel variant in FLG2 gene

Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings.

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Chimerism for 20q11.2 microdeletion of GDF5 explains discordant phenotypes in monochorionic-diamniotic twins

Microdeletions of 20q11.2 are rare but have been associated with characteristic clinical findings. A 1.6 Mb minimal critical region has been identified that includes three OMIM genes: GDF5, EPB41L1, and SAMHD. Here we describe a male monozygotic, monochorionic-diamniotic twin pair with discordant phenotypes, one with multiple findings that overlap with those reported in 20q11.2 deletions, and the other unaffected. Microarray analysis revealed mosaicism for a 363 Kb deletion encompassing GDF5 in the peripheral blood of both twins, which was confirmed by FISH. Subsequent FISH on buccal cells identified the deletion only in the affected twin. The blood FISH findings were interpreted as representing chimerism resulting from anastomosis and the blood exchange between the twins in utero. The implications of this finding are discussed, as is the contribution of GDF5 to the associated clinical findings of 20q11.2 deletions.

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Effectiveness of Shortwave Diathermy for Subacromial Impingement Syndrome and Value of Night Pain for Patient Selection: A Double-Blinded, Randomized, Placebo-Controlled Trial.

Objective: The aim of this study was to investigate the effectiveness of short wave diathermy (SWD) in patients with subacromial impingement syndrome. Design: In this double-blinded, randomized, placebo-controlled trial, 57 patients (aged 35-65 yrs) were classified into night pain positive (NP[+]) (n = 28) and night pain negative (NP[-]) (n = 29) groups. Both groups were randomly assigned to SWD (NP[+], n = 14; NP[-], n = 14) and sham (NP[+], n = 15; NP[-], n = 14) subgroups. Visual analog scale, Constant-Murley Scale (CS), and Shoulder Disability Questionnaire (SDQ) scores were used for evaluation. Results: There was only a significant difference in pain with activity at 1-mo (mean difference [MD], -1.65; 95% confidence interval, -3.01 to -0.28]) and 2-mo evaluations (MD, -2.1; 95% confidence interval, -3.51 to -0.69) between SWD versus sham groups. In the NP(+) SWD group, the CS pain score was significantly higher than in the NP(+) sham group at all evaluations after treatment. At 1 mo, the NP(-) SWD group showed significantly better pain, strength, total CS, and SDQ scores than the NP(-) sham group. At 2 mos, the pain, range of motion, strength, and total CS and SDQ scores were better in the NP(-) SWD group than in the NP(-) sham group (P

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The ploidy of Vibrio cholerae is variable and is influenced by growth phase and nutrient levels

Abstract

The ploidy of V. cholerae was quantified under different growth conditions. The V. cholerae was found to be (mero) oligoploid or polyploid. The ploidy levels per cell were found to be growth phase regulated. The ploidy is highest during the early stationary phase (56–72 per cell) and lowest in the long term starved state. In addition to growth phase, an external parameter such as nutrient level influences the ploidy, i.e. ploidy reduces rapidly at the onset of the starvation. The reduction is significant with p-value < 0.05 within 2h of starvation. Even after prolonged starvation of 10 days, the ploidy number remained above 2 per cell. Failure to obtain a monoploid V. cholerae indicates that during starvation the genome is not distributed equally to daughter cells. The activity of DNase enzyme increased during starvation which decreased the ploidy. The ploidy was restored to the pre-starvation levels with nutrient supplementation.

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Climate change and vector-borne diseases of public health significance

Abstract

There has been much debate as to whether or not climate change will have, or has had, any significant effect on risk from vector-borne diseases. The debate on the former has focused on the degree to which occurrence and levels of risk of vector-borne diseases are determined by climate-dependent or –independent factors; while the debate on the latter has focused on whether changes in disease incidence are due to climate at all, and/or are attributable to recent climate change. Here I review possible effects of climate change on vector-borne diseases, methods used to predict these effects, and the evidence to date of changes in vector-borne disease risks that can be attributed to recent climate change. Predictions have both over- and under-estimated the effects of climate change. Mostly under-estimations of effects are due to a focus only on direct effects of climate on disease ecology while more distal effects on society's capacity to control and prevent vector-borne disease are ignored. There is increasing evidence for possible impacts of recent climate change on some vector-borne diseases but for the most part, observed data series are too short (or non-existent), and impacts of climate-independent factors too great, to confidently attribute changing risk to climate change.

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Advances in cyanobacterial polyhydroxyalkanoates production

Abstract

Polyhydroxyalkanoates (PHAs) have received much attention at the current scenario due to their attractive material properties, viz. biodegradability, biocompatibility, thermoplasticity, hydrophobicity, piezoelectricity, and stereospecificity. All these properties make them highly competitive for various industrial applications similar to non-degradable conventional plastics. In PHA biosynthesis, PHA synthase acts as a natural catalyst for PHA polymerization process using the (R)-hydroxyacyl-CoA as substrate. Cyanobacteria can accumulate PHAs under photoautotrophic and/or mixotrophic growth conditions with organic substrates such as acetate, glucose, propionate, valerate, etc. The natural incidence of PHAs accumulation by the cyanobacteria is known since 1966. Nevertheless, PHAs accumulation in cyanobacteria based on the cell biomass and volumetric productivity is critically lower than the heterotrophic bacteria. Consequently, cyanobacteria are nowadays not considered for commercial production of PHAs. Thus, strain improvements by genetic modification, new cultivation and harvesting techniques, advanced photobioreactor developments, efficient and sustainable downstream processes, alternate economical carbon sources and usage of various metabolic inhibitors are suggested for enhancing cyanobacterial PHAs accumulation. In addition, identification of transcriptional regulators like RNA polymerase sigma factor (SigE) and a response regulator (Rre37) together with the recent major scientific breakthrough on the existence of complete Krebs cycle in cyanobacteria would be helpful in taking PHAs production from cyanobacteria to a new-fangled height in near future.

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The potential forensic significance of convict archives from Van Diemen’s Land, 1820–1877

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International tuberculosis research collaborations within Asia

Asia bears more than half the global tuberculosis (TB) burden. Economic development in the region has increased available funding for biomedical research and opportunity for collaboration. We explored the exte...

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Factors influencing the practice of exclusive breastfeeding among nursing mothers in a peri-urban district of Ghana

Exclusive breastfeeding (EBF) is one of the optimal infant and young child feeding practices. Globally,

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AmpC and extended spectrum beta-lactamases production among urinary isolates from a tertiary care hospital in Lalitpur, Nepal

Production of AmpC and extended spectrum beta-lactamases among urinary isolates has created a serious problem to the successful management of the urinary tract infection. The main purpose of this study was to ...

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Prevalence and significance of Mycoplasma genitalium in women living with HIV in Denmark

Mycoplasma genitalium (M. genitalium) is a sexually transmitted pathogen associated with urethritis, cervicitis, and pelvic inflammatory disease. Previous studies have shown a strong a...

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Successful treatment of acute renal failure secondary to complicated infective endocarditis by peritoneal dialysis: a case report

Infective endocarditis is one of the most common infections among intravenous drug addicts. Its complications can affect many systems, and these can include acute renal failure. There is a scarcity of cases in...

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EGFR T790M mutation testing of non-small cell lung cancer tissue and blood samples artificially spiked with circulating cell-free tumor DNA: results of a round robin trial

Abstract

The European Commision (EC) recently approved osimertinib for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutations. Besides tissue-based testing, blood samples containing cell-free circulating tumor DNA (ctDNA) can be used to interrogate T790M status. Herein, we describe the conditions and results of a round robin trial (RRT) for T790M mutation testing in NSCLC tissue specimens and peripheral blood samples spiked with cell line DNA mimicking tumor-derived ctDNA. The underlying objectives of this two-staged external quality assessment (EQA) approach were (a) to evaluate the accuracy of T790M mutations testing across multiple centers and (b) to investigate if a liquid biopsy-based testing for T790M mutations in spiked blood samples is feasible in routine diagnostic. Based on a successfully completed internal phase I RRT, an open RRT for EGFR T790M mutation testing in tumor tissue and blood samples was initiated. In total, 48 pathology centers participated in the EQA. Of these, 47 (97.9%) centers submitted their analyses within the pre-defined time frame and 44 (tissue), respectively, 40 (plasma) successfully passed the test. The overall success rates in the RRT phase II were 91.7% (tissue) and 83.3% (blood), respectively. Thirty-eight out of 48 participants (79.2%) successfully passed both parts of the RRT. The RRT for blood-based EGFR testing initiated in Germany is, to the best of our knowledge, the first of his kind in Europe. In summary, our results demonstrate that blood-based genotyping for EGFR resistance mutations can be successfully integrated in routine molecular diagnostics complementing the array of molecular methods already available at pathology centers in Germany.

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Erratum to: “Immunohistochemistry staining for mismatch repair proteins: the endoscopic biopsy material provides useful and coherent results” [Hum Pathol 2015;46:1705-1711]

The publisher regrets that the affiliation for the author Ya'ara Leibovici-Weissman in the above-mentioned article was incorrectly listed as Internal Medicine Department D, Beilinson Hospital, Petah Tiqva, PO 49100, Israel. It should have instead been listed as Internal Medicine D, Beilinson Hospital, Petah Tiqva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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Relative pressure estimation from velocity measurements in blood flows: state-of-the-art and new approaches

Summary

The relative pressure difference across stenotic blood vessels serves as an important clinical index for the diagnosis of many cardiovascular diseases. While the clinical gold standard for relative pressure difference measurements is invasive catheterization, Phase-Contrast Magnetic Resonance Imaging has emerged as a promising tool for enabling a non-invasive quantification, by linking highly spatially resolved velocity measurements with relative pressures via the incompressible Navier-Stokes equations. In this work we provide a review and analysis of current methods for relative pressure estimation and propose three additional techniques. Methods are compared using synthetic data from numerical examples and sensitivity to subsampling and noise was explored. Through our analysis, we verify that the newly proposed approaches are more robust with respect to spatial subsampling and less sensitive to noise, and therefore provide improved means for estimating relative pressure differences non-invasively. This article is protected by copyright. All rights reserved.

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Low serum vitamin D levels in type 2 diabetes patients are associated with decreased mycobacterial activity

Concurrent diabetes mellitus and tuberculosis represent a significant health problem worldwide. Patients with diabetes mellitus have a high risk of tuberculosis, which may be mediated by an abnormal innate imm...

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Early Caffeine Prophylaxis and Risk of Failure of Initial Continuous Positive Airway Pressure in Very Low Birth Weight Infants

To test the hypothesis that early caffeine treatment on the day of birth, compared with later treatment in very low birth weight (VLBW, <1500 g) infants receiving continuous positive airway pressure (CPAP) therapy, is associated with a decreased risk of CPAP failure in the first week of life.

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Toward an Ethical Application of Intersectionality in Art Therapy

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Post-ASFA Permanency Planning for Children in Foster Care: Clinical and Ethical Considerations for Art Therapists

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Sociopolitical Oppression, Trauma, and Healing: Moving Toward a Social Justice Art Therapy Framework

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http://ift.tt/2vRcjHK

Beyond Erasure: The Ethics of Art Therapy Research With Trans and Gender-Independent People

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http://ift.tt/2j9tkXR

Facilitative Leadership: A Framework for the Creative Arts Therapies

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The Ethics of Art Therapy: Promoting Creativity as a Force for Positive Change

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Per oral endoscopic myotomy in achalasia and large epiphrenic diverticulum - a case study

Abstract

Symptomatic epiphrenic diverticula are mostly treated surgically with laparoscopic diverticulectomy, myotomy and anterior fundoplication. However, in case the patient does not agree with surgical therapy or is contraindicated there are limited ways of alternative treatment. We present a case report of a 72-year-old female patient with severe dysphagia, regurgitation, paroxysmal cough, weight loss and malnutrition who was diagnosed with achalasia and large epiphrenic diverticulum. She did not give consent with surgical treatment that was proposed. Alternatively the per oral endoscopic myotomy (POEM) was carried out. In one year follow up we observed complete symptom resolution, significant weight gain, improvement of nutritional status and no complications. We suggest that POEM could serve as an effective and safe alternative treatment for patients with achalasia and esophageal epiphrenic diverticula.

This article is protected by copyright. All rights reserved.

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Endoscopic submucosal dissection in the West: current status and future directions

Abstract

Endoscopic submucosal dissection (ESD) was first conceptually described almost 30 years ago in Japan and is now widely practiced throughout East Asia. ESD expands the boundaries of endoscopic resection (ER) by allowing en bloc resection of large early neoplastic lesions within the gastrointestinal tract (GIT). This offers advantages over other ER techniques by facilitating definitive histological staging and curative treatment of early cancer in selected cases. Indeed the experience of ESD in Eastern countries is significant, and excellent outcomes from high volume centres are reported. The potential benefits of ESD are recognised by Western endoscopists, but its adoption has been limited. A number of factors contribute to this, including epidemiological differences in GIT neoplasia between Western and Eastern populations and limitations in training opportunities. In this review, we discuss the role of ESD, its current status and the future in Western endoscopic practice.

This article is protected by copyright. All rights reserved.

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CD155T/TIGIT Signaling Regulates CD8+ T Cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

The T cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer (GC). We show that the percentage of CD8 T cells that are TIGIT+ was increased in GC patients compared to healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production and metabolism, all of which were rescued by glucose. In addition, GC tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-GC cell co-culture system, GC cells deprived CD8 T cells of glucose and impaired CD8 T cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In GC tumor cells, CD155 silencing increased T cell metabolism and IFNγ production, whereas CD155 overexpression inhibited T cell metabolism and IFNγ production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T cell reaction and improved survival in tumor bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T cell activation and improved survival in tumor bearing mice. Our results suggest that GC cells inhibit CD8 T cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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FSTL1 promotes metastasis and chemoresistance in esophageal squamous cell carcinoma through NF{kappa}B-BMP signaling crosstalk

Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis and molecular markers to improve early detection and predict outcomes are greatly needed. Here we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q where it is located occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Elevating FSTL1 levels by various means was sufficient to drive ESCC cell proliferation, clonogenicity, migration, invasion, self-renewal and cisplatin resistance in vitro and tumorigenicity and distant metastasis in vivo. Conversely, FSTL1 attenution by shRNA or neutralizing antibody elicited the opposite effects in ESCC cells. mRNA profiling analyses suggested that FSTL1 drives ESCC oncogenesis and metastasis through various pathways with deregulation of NF-κB and BMP signaling figuring prominently. Crosstalk between the NF-κB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NF-κB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinate NF-κB and BMP pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and a candidate therapeutic target in this disease setting.

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Discovery of human-similar gene fusions in canine cancers

Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathological features as well as oncogenic events including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human-dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine.

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Genetic dissociation of glycolysis and the TCA cycle affects neither normal nor neoplastic proliferation

Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas (HB) was only modestly slowed in the face of 80-90% reductions in AcCoA and significant alterations in the levels of key TCA cycle intermediates and amino acids. Overall, oxphos activity in KO livers and HB was comparable to that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances.

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Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma

The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell intrinsic and extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host.

http://ift.tt/2xQZv0K

Transplantation of iPS-derived tumor cells with a homozygous MHC haplotype induces GRP94 antibody production in MHC-matched macaques

Immune surveillance is a critical component of the anti-tumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo. We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro. These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance.

http://ift.tt/2wNxEzf

miR-193b-regulated signaling networks serve as tumor suppressors in liposarcoma and promote adipogenesis in adipose-derived stem cells

Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared to normal fat. Re-introduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated ROS signaling by targeting the antioxidant methionine sulfoxide reductase A (MSRA) to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma, but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration.

http://ift.tt/2xQLvUp

Improving undergraduate pathology teaching: medical students' perspective

We read with great interest the article by Chu et al. [1] regarding pathology in undergraduate clinical clerkships. As medical students in our fifth year, we have had limited opportunities to experience the day-to-day activities of pathologists. Therefore, we have less clinical exposure to pathology compared to other specialities that are assigned dedicated block placements.

http://ift.tt/2xakZbK

Improving undergraduate pathology teaching: medical students’ perspective—reply

We agree with Aggarwal and colleagues about the need to help students appreciate the importance of pathology in patient care across specialties. The online provision of interactive medical cases in the style of New England Journal of Medicine or patient vignettes with questions, explanations, and high-resolution photomicrographs in the style of the US Medical Licensing Exam (USMLE) would certainly provide a more complete and lasting understanding of the material than would the traditional passive lecture format [1].

http://ift.tt/2eKCNQ5

Blood monocytes sample MelanA/MART1 antigen for long-lasting cross-presentation to CD8+ T cells after differentiation into dendritic cells

Abstract

Human blood monocytes are very potent to take up antigens. Like macrophages in tissue, they efficiently degrade exogenous protein and are less efficient than dendritic cells at cross-presenting antigens to CD8⁺ T cells. Although it is generally accepted that dendritic cells take up tissue antigens and then migrate to lymph nodes to prime T cells, the mechanisms of presentation of antigens taken up by monocytes are poorly documented so far. In the present work, we show that monocytes loaded in vitro with MelanA long peptides retain the capacity to stimulate antigen-specific CD8⁺ T cell clones after 5 days of differentiation into monocytes-derived dendritic cells (MoDC). Tagged-long peptides can be visualized in electron-dense endocytic compartments distinct from lysosomes, suggesting that antigens can be protected from degradation for extended periods of time. To address the pathophysiological relevance of these findings, we screened blood monocytes from eighteen metastatic melanoma patients and found that CD14⁺ monocytes from 2 patients effectively activate a MelanA-specific CD8 T cell clone after in vitro differentiation into MoDC. This in vivo sampling of tumor antigen by circulating monocytes might alter the tumor-specific immune response and should be taken into account for cancer immunotherapy. This article is protected by copyright. All rights reserved.

http://ift.tt/2eQwTRi

Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival and the influence of prognostic factors in 129,692 patients

Abstract

This large population-based study compared breast-conserving surgery with radiation therapy (BCT) with mastectomy on (long-term) breast cancer-specific (BCSS) and overall survival (OS), and investigated the influence of several prognostic factors.

Patients with primary T1-2N0-2M0 breast cancer, diagnosed between 1999-2012, were selected from the Netherlands Cancer Registry. We investigated the 1999-2005 (long-term outcome) and the 2006-2012 cohort (contemporary adjuvant systemic therapy). Cause of death was derived from the Statistics Netherlands (CBS). Multivariable analyses, per time cohort, were performed in T1-2N0-2, and separately in T1-2N0-1 and T1-2N2 stages. The T1-2N0-1 stages were further stratified for age, hormonal receptor and HER2 status, adjuvant systemic therapy and comorbidity.

In total, 129,692 patients were included. In the 1999-2005 cohort, better BCSS and OS for BCT than mastectomy was seen in all subgroups, except in patients <40 years with T1-2N0-1 stage. In the 2006-2012 cohort, superior BCSS and OS were found for T1-2N0-1, but not for T1-2N2. Subgroup analyses for T1-2N0-1 showed superior BCSS and OS for BCT in patients >50 years, not treated with chemotherapy and with comorbidity. Both treatments led to similar BCSS in patients <50 years, without comorbidity and those treated with chemotherapy.

Although confounding by severity and residual confounding cannot be excluded, this study showed better long-term BCSS for BCT than mastectomy. Even with more contemporary diagnostics and therapies we identified several subgroups that may benefit from BCT. Our results support the hypothesis that BCT might be preferred in most breast cancer patients when both treatments are suitable. This article is protected by copyright. All rights reserved.

http://ift.tt/2xSgIYn

Transcriptional repression of Aurora-A gene by wild-type p53 through directly binding to its promoter with histone deacetylase 1 and mSin3a

Abstract

In this study, we firstly showed that p53 transcriptionally represses Aurora-A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay indicated that p53 physically bound to the Aurora-A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora-A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides -360 to -354 (CCTGCCC), upstream of the Aurora-A transcriptional start site, was responsible for the p53-mediated repression. Mutation within this site disrupted its interaction with p53, mSin3a and HDAC1, as well as attenuated the repressive effect of p53 on Aurora-A promoter activity. Treatment with trichostatin A (TSA), a HDAC1 inhibitor, disrupted the interaction of p53-HDAC1-mSin3a complex with the nucleotides -365∼-345 region, and enhanced the Aurora-A promoter activity and gene expression. Additionally, knockdown of p53 or mSin3a also drastically blocked the formation of p53-HDAC1-mSin3a repressive complex onto this promoter region and elevated the Aurora-A promoter activity and gene expression. Moreover, the p53-HDAC1-mSin3a repressive complex also involved in the inhibition of Aurora-A gene expression upon cisplatin treatment. Finally, the clinical investigation showed that Aurora-A and p53 exhibited an inverse correlation in both the expression level and prognostic status and the low p53/high Aurora-A showed the poorest prognosis of NSCLC patients. Our findings showed novel regulatory mechanisms of p53 in regulating Aurora-A gene expression in NSCLC cells.

Many types of cancer feature a boost in production of the kinase Aurora-A, and several studies have implicated the protein in transformation and tumorigenesis. Some evidence suggests that p53 affects Aurora-A expression, and in this study, the authors set out to describe that relationship. They found that p53 binds directly to the Aurora-A promoter, repressing transcription. Next, they showed that treatment with trichostatin A thwarts this repression, allowing Aurora-A transcription to proceed. Clinical investigation revealed that lung cancer patients with low p53 and high Aurora-A expression had the worst prognosis. This article is protected by copyright. All rights reserved.

http://ift.tt/2eQwTkg

Recognition by Natural Killer cells of N6-isopentenyladenosine-treated human glioma cell lines

Abstract

Cancer cell stress induced by cytotoxic agents promote antitumor immune response. Here we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of NKG2D ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1µM) control the selective upregulation of ULBP2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for natural killer (NK) cell mediated recognition through a NKG2D restricted mechanism. p53 siRNA mediated knock-down and pharmacological inhibition (pifithrin-α), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest.

Collectively, our results indicate that behind the well established cytotoxic and anti-angiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in anti-glioma research. This article is protected by copyright. All rights reserved.

http://ift.tt/2xSgAYT

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Chamith Y Fonseka | Deepak A Rao | Soumya Raychaudhuri

http://ift.tt/2f7Gvnx

Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy

Willem van de Veen | Oliver F Wirz | Anna Globinska | Mübeccel Akdis

http://ift.tt/2f7Cj7l

Potential for peritoneal cancer cell seeding in endoscopic full-thickness resection for early gastric cancer

During endoscopic full-thickness resection (EFTR) for cancers, whether exposure of the lumen to the abdominal cavity during the procedure is acceptable is controversial because of the potential risk of tumor cell seeding. To assess the possibility of transplantation due to contact with tumor cells during the procedure, we prospectively investigated the ability of cancer cells to be detached by touching the tumor surface.

http://ift.tt/2gQB1By

Morphometric analysis of the uncinate processes of the cervical vertebrae

Background: Uncinate processes (UPs) are distinct features unique to cervical vertebrae. They are consistently found on posterolateral aspect of the superior end plate of 3rd to 7th cervical vertebrae. In this study, we investigated the morphology of the UPs with a particular emphasis on the regional anatomy and clinical significance.

Materials and methods: The study included 63 vertebrae. The width, height and length of UPs were measured with a digital calliper. We also assessed inclination angle of UP relative to sagittal plane, angle between medial surface of UP and superior surface of vertebra, angle between long axis of the UP and frontal plane, angle between long axis of UP and sagittal plane.

Results: Average width of the UPs ranged from 4.25 mm at C3 to 6.33 mm at T1; average height ranged from 4.88 mm at T1 to 7.54 mm at C4; and average length ranged from 6.88 mm at T1 to 11.46 mm at C4. We measured the inclination angle of UP relative to sagittal plane, and found it to be relatively constant with T1 having the largest value. The average angle was 41.39°, and the range was 17° to 85°. The angle between the long axis of the UP and the sagittal plane was increasing signifi­cantly from C5 to T1. The average angle was 20.74° and the range was 6° to 65°.

Conclusions: Anatomy of UPs is significant for surgeon who operates on the cervical spine. Hopefully, the information presented herein would decrease complications during surgical approaches to the cervical spine

http://ift.tt/2gO6xjw

Reflective journals: unmasking student perceptions of anatomical education

Background: In medical education, reflection has been considered to be a core skill in professional competence. The anatomy laboratory is an ideal setting for faculty/ student interaction and provides invaluable opportunities for active learning and reflection on anatomical knowledge.

Materials and methods: This study was designed to record student attitudes regarding human cadaveric dissection, explore their experiences of anatomy through an analysis of their journal-reflective writings and determine whether this type of creative writing had a beneficial effect on those students who chose to complete them. A total of 75 journals from Medical and Allied Health Science students were collected and analysed.

Results: Results were categorised according to the following themes: (i) Dissecting room stressors (27.6%); (ii) Educational value of dissection (26.3%); (iii) Appreciation, Gratitude, Respect and Curiosity for the cadaver (18.9%); (iv) Positive and negative sentiments expressed in the dissecting room (25.8%); (v) Benefit of alternate teaching modalities (4.6%); (vi) Spirituality/Religious Beliefs (3.7%); (vii) Shared humanity and emotional bonds (3.69%); (viii) Acknowledgement of human anatomical variations (3.2%); (ix) Beauty and complexity of the human body (1.8%) and (x) Psychological detachment (0.9%). Students appreciated the opportunity to share their emotions and reflect on the humanistic dimension of anatomy as a subject. Student reflections illustrated clearly their thoughts and some of the difficult issues with which they wrestled.

Conclusions: The anatomy laboratory is seen as the budding clinician's first encounter with a patient, albeit a cadaver. This was the first time that reflective journals were given to students in the discipline. Reflective journals allow students to express themselves in an open-ended and creative fashion. It also assists students to integrate anatomy and clinical medicine and assists in applying their basic anatomical knowledge in an authentic, yet safe environment

http://ift.tt/2eQ2ouD

Prevalence and distribution of the fabella: a radiographic study in Turkish subjects

Background: The purpose of this study is to examine the plain knee radiographs in Turkish subjects in order to determine the prevalence of the fabella and analyse the differences between age, gender, laterality and its symmetry pattern.

Materials and methods: Bilateral antero-posterior and lateral knee radiographs of 500 patients (250 male and 250 female subjects, 1000 knee radiographs) were randomly selected from the clinical database and retrospectively evaluated. Data on patient age, gender, and knee laterality (right–left) were evaluated from hospital records. The differences between the sesamoid bones at a particular location and the side, sex and age groups were analysed.

Results: The overall prevalence of the fabella (unilateral or bilateral) was 22.8% (114 subjects). The fabella was present unilaterally in 38 (7.6%) subjects, while it was present bilaterally in 76 (15.2%) subjects. The prevalence of the fabella was similar between the body sides. The prevalence of the fabella was also similar between genders (unilateral or bilateral cases) and age groups.

Conclusions: We examined the prevalence, symmetry pattern, age and gender differences in Turkish population. It is the first study performed on Turkish population with the largest sample in current literature. Prevalence of fabella is found to be 22.8% which is quite similar with other Caucasian ethnic populations.

http://ift.tt/2eQ1XjZ

Tongue and lingual salivary glands of the canary: scanning electron microscopy and histochemical study

In this study, morphological characteristics of the canary tongue were examined macroscopically and histologically besides using scanning electron microscopy. Furthermore, histochemical features of the lingual salivary glands of the canary were also examined. The results suggest that the tongue of the canary has an equilateral quadrangle shape is sloped towards the apex on its dorsal surface; where its sides are bounded by tall epithelial extensions. Additionally, histological examination showed that salivary glands were only present on the body of the tongue and there were no taste buds. However, the tongue has mechanical sen­sory cell groups in its subepithelial connective tissue. Histochemical examination, demonstrated that the salivary gland epithelial cells contained carbohydrates which were composed of acidic sialo-mucins.

http://ift.tt/2gO5FLM

Variation in morphology and branching pattern of superior mesenteric artery

The anatomical variations of superior mesenteric artery branches are common. In this study we reported an extraordinary morphology and branching of superior mesenteric artery, during our routine dissection of a 38-year-old Sudanese male cadaver, where the superior mesenteric artery forms an arch over the confluence of inferior vena cava and left renal vein.

Other variations observed were: 1) The superior mesenteric artery shares the same origin of coeliac trunk; 2) The unusual origin of right hepatic artery.

We think that the knowledge of these variations plays an important role in conducting and planning of radiological and surgical procedures especially in hepatobiliary and pancreatic surgery. Morphology and branching patterns of this artery is anecdotic, which makes this case the most unique.

http://ift.tt/2eQkZHb

Site-dependent acellularisation effects explain altered tissue mechanics: ultrastructural insights

Acellular scaffolds are used for the surgical repair of soft tissue injury forming a biological basis for cell remodelling. Previously tissue-dependent effects sodium-dodecyl-sulphate (SDS) have been determined on the extracellular matrix (ECM) of different tissue types. This short report aims at extending these findings onto a tissue-layer level with focus on the ECM. Porcine ureters, oesophagi and skin underwent acellularisation using SDS, whereas control samples remained in a native condition. The samples were investigated histologically and ultrastructurally electron microscopy. Dense collagen bundles were seen in all native samples throughout the layers, and moderate to strong decreases in collagen density in the acellular state, accompanied by clumping. Collagen bundles were altered differently. Transition from straightened into coiled alignment was observed in the ureters' intima and all oesophageal layers, the opposite was observed in the ureters' media and adventitia. Skin samples appeared discontinuously following acellularisation, with collagens curling in the subcutis and dermis and disruptions in the subepidermis. Collagen fibre integrity appeared unchanged. SDS-related alterations include tissue- and site-dependent alterations of the collagen bundles. These insights into the ECM provide further explanation of acellularisation-induced change in mechanical properties, resulting in increased stiffness in ureters, and stiffness in skin.

http://ift.tt/2gOLk8W

The challenge of extra-intra craniometry: a computer-assisted three-dimensional approach on the equine skull

Background: The topographical correlations between certain extracranial and intracranial osseous points of interest (POIs), and their age-related changes, are indispensable to know for a diagnostical or surgical access to intracranial structures; however, they are difficult to assess with conventional devices.

Materials and methods: In this pilot study, the 3-dimensional coordinates of extra-/intracranial POIs were determined, thus avoiding perspective distortions that used to be intrinsic problems in 2-dimensional morphometry. The data sets were then analysed by creating virtual triangles. The sizes, shapes, and positions of these triangles described the extent and the directions of the age-related shifts of the POIs. A selection of extracranial and intracranial POIs were marked on half skulls of four warmblood horses in two age groups (young: 6 weeks, n = 2; old: 14 and 17 years, n = 2). The x-, y-, and z-coordinates of these POIs were determined with a measurement arm (FaroArm Fusion, FARO Europe®). Direct distances between the POIs as well as their indirect distances on the x-, y-, and z-axis, and angles were calculated.

Results: The analysed virtual triangles revealed that some parts of the skull grew in size, but did not change in shape/relative proportions (proportional type of growth, as displayed by POI A and POI B at the Arcus zygomaticus). The same POIs (A and B) remained in a very stable relationship to their closest intracranial POI at the Basis cranii on the longitudinal axis, however, shifted markedly in the dorso-lateral direction. In contrast, a disproportional growth of other parts of the cranium was, for example, related to POI C at the Crista nuchae, which shifted strongly in the caudal direction with age. A topographically stable reference point (so-called anchor point) at the Basis cranii was difficult to determine.

Conclusions: Two candidates (one at the Synchondrosis intersphenoidalis, another one at the Synchondrosis sphenooccipitalis) were relatively stable in their positions. However, the epicentre of (neuro-)cranial growth could only be pinpointed to an area between them.

http://ift.tt/2ePYRg6

An investigation on cardioprotective potential of Marrubium vulgare aqueous fraction against ischaemia-reperfusion injury in isolated rat heart

Background: The aim of this study was to evaluate the cardioprotective effects of aqueous fraction of Marrubium vulgare hydroalcoholic extract on cardiac parameters in ischaemic-reperfused isolated rat hearts.

Materials and methods: The aerial parts of the plant were extracted with methanol 70% by maceration. The water-soluble portion of the total hydroalcoholic extract was prepared with liquid-liquid extraction (LLE). Afterwards, the antioxidant activity, total phenolic and flavonoids content of the aqueous fraction were determined. In order to evaluate the effects of the aqueous fraction on cardiac parameters and ischaemia-reperfusion (I/R) injury, the Langendroff method was used on male Wistar rats. Harvested hearts were cannulated immediately to the Langendroff apparatus and subjected into 30 min regional ischaemia and 2 h reperfusion, either by a modified Krebs-Henseleit buffer (KHB) solution or enriched KHB solution with plant extract (10, 20, 40 μg/mL).

Results: The aqueous fraction was found to be a scavenger of DPPH radical with RC50 value of 47 μg/mL. The total phenolic and flavonoids content of the fraction was 6.05 g gallic acid equivalent and 36.13 mg quercetin equivalent per 100 g of dry plant material. In addition, 40 μg/mL of Marrubium vulgare aqueous fraction significantly decreased infarct size in comparison to control group. All doses considerably reduced the total ventricular ectopic beats during 30 min of ischaemia. The extract at dose of 40 μg/mL noticeably decreased the arrhythmias during the first 30 min of reperfusion.

Conclusions: The results of the study indicated aqueous fraction of Marrubium vulgare possesses a protective effect against I/R injuries in isolated rat hearts

http://ift.tt/2gOMNw3

Location of the narrowest area of the pharynx regarding body mass index and obstructive sleep apnoea severity

Background: Among authors studying morphological determinants of the obstructive sleep apnoea (OSA) controversies exist on the location of the narrowest area within the pharynx, critical for development of obstruction. Those disagreements primarily revolve around differences between obese and nonobese OSA patients. Determination whether the location and size of the narrowest area within the pharynx differentiates the obese and nonobese OSA patients.

Materials and methods: A population of 55 subjects was investigated after being diagnosed with OSA in the Polysomnography Laboratory of the Department and Clinic of Otolaryngology in the Medical University of Warsaw, Poland. Additionally a head computed tomography (CT) was performed in all the subjects. The CT images were used to do several crucial measurements which described the geometry of the facial skeleton as well as soft tissues of the head. The obtained results were correlated with apnoea-hypopnoea index (AHI) and body mass index (BMI) values. The data were statistically analysed.

Results: The distance between the hard palate and posterior pharyngeal wall parallel to the horizontal plane as well as the shortest distance between the soft palate and posterior pharyngeal wall significantly differentiated patients in the subgroups by AHI but not by BMI.

Conclusions: Pharyngeal obstruction at the level of the hard and soft palate differentiates patients with severe OSA from patients with mild and moderate OSA regardless of BMI.

http://ift.tt/2ePYQc2

The expression of inhibitor of nuclear factor kappa-B kinase epsilon (IKKe) in human aortic aneurysm

Background: Aortic aneurysm (AA) is one of the most common causes of sudden death among elderly people. Although AA can be detected by non-invasive imaging techniques, there are no pharmacological treatments currently available to prevent progression at any stage of the disease. In this study we will explore the expression of inhibitor of nuclear factor kappa-B kinase epsilon (IKKe) in AA and its potential underlying molecular mechanism in AA.

Materials and methods: Human aortic tissue was taken from 14 patients who underwent surgical repair of AA for the AA group and another 11 patients with normal aorta who underwent aortic valve replacement surgery for the control group. After excision, we used haematoxylin-eosin staining, Masson staining, immunohistochemistry analysis and Western blot analysis to observe the expres­sion, location and morphological changes of the IKKe, P50 and the extracellular matrix within the AA.

Results: In the AA group, haematoxylin-eosin staining revealed a loss of medial integrity and inflammatory cell infiltration. Masson staining confirmed the degradation of the extracellular matrix in the AA group. Immunohistochemistry analysis showed increased infiltration of inflammatory cells and up-regulation of proinflammatory cytokines in the AA group when compared to the control group. Based on immunohistochemistry and Western blot analysis, there was clearly over-expression of IKKe, P50 and MMP2 in AA group, mainly in the intrinsic aortic cells of the media.

Conclusions: The over-expression of IKKe may play an important role in the ori­gination and progression of AA and might be a vital target for their treatment.

http://ift.tt/2gOxVO4

Triple arterial blood supply to the liver and double cystic arteries

A rare combination of variations in the arterial supply of the liver and gallbladder was encountered in a male cadaver. The simultaneous occurrence of an accessory left hepatic artery and an accessory right hepatic artery from which double cystic arteries arose (one of which was low-lying). This combination has not yet been reported. The accessory left hepatic artery originated from the left gastric artery. The accessory right hepatic artery originated from the superior mesenteric artery. Such arterial variations are caused by differences in embryological development. This, however, may lead to complications related to diagnostic and therapeutic procedures in the upper abdomen.

http://ift.tt/2ePU66a

Intracranial region of the vertebral artery: morphometric study in the context of clinical usefulness

Background: The aim of this study was to analyse the morphometry of the intracranial segment of the vertebral artery in the context of clinical usefulness. The results were compared with published data available in full-text archived medical journals.

Materials and methods: More than 100 digital subtraction angiography (DSA) and 3-dimensional (3D) angio-computed tomography (CT) examinations were used to measure the following parameters: the whole and partial length of V4 in characteristic anatomical points, the diameter in three places (on the level of foramen magnum, in point of exit to the posterior inferior cerebellar artery, and in the vertebro-basilar junction), the angle of connection to the vertebral arteries, and all anatomical variations including fenestration, duplication, dolichoectasia or absent artery.

Results: The left V4 section was predominant over the right artery, which is manifested by length, width, cases of ectasia and fewer cases of hypoplasia. The incidences of V4 ectasia were identified more often than those documented in the accessible literature, and they were found in the natural location of formation of saccular aneurysms.

Conclusions: The presented knowledge of anatomical variation and abnormali­ties of vertebral circulation can improve the accuracy and "safety" of the surgical procedures in this region, help to determine the range of surgical approach and avoid associated complications. The radiological examinations using 3D CT, DSA reveal unlimited observation of anatomical structures in contrast to studies based on cadavers, and can complement the morphometry in anatomical preparations.

http://ift.tt/2gRc60n

Diversity among posterior thalamoperforating branches originated from P1 segment: systematic review

Background: The P1 segment of the posterior cerebral artery (PCA) begins at the termination of the basilar artery and ends at the origin of posterior commu­nicating artery, within the interpeduncular cistern. Perforating branches arising from this segment are called posterior thalamoperforating arteries (TPAs) and the main and biggest artery among those is called TPA. Perforating branches are a crucial component of cerebrovascular system supplying the posterior part of the thalamus, subthalamus, hypothalamus, substantia nigra, perforated substance, posterior part of internal capsule and the nucleus of III and IV cranial nerve. It is very important for neurosurgeon to know the anatomy of perforating branches because of their susceptibility to injury. The aim of this study is to determine the morphometry of posterior TPAs and allow a better understanding of their bran­ching patterns and relation to basilar artery.

Materials and methods: An extensive search was undertaken in order to identify published literature related to the posterior cerebral circulation system and the anatomy of posterior TPAs using key words. Medline, Embase, Ovid and Google Scholar databases were searched for publications dated from 1970 until July 2016. We collected and analysed all the data describing the mean number of branches per P1 segment, range of branches, number of analysed PCA, largest diameter of TPA, mean diameter of TPA and average distance from the basilar artery bifurcation.

Results: Thirteen cadaver studies were analysed and the data was extracted. We focused on the mean number of branches arising from P1 segment, perforators range, mean diameter of perforating branches, largest diameter of perforating branches.

Conclusions: Mean number of branches per hemisphere was 2.91 (min. 1.51, max. 4.1). In more than half of analysed studies, authors did not find any pre­sence of posterior TPAs. Mean diameter of those perforators was 0.51 mm (min. 0.125 mm, max. 0.8 mm). Average distance from basilar artery bifurcation was 2.29 mm (min. 1.93 mm, max. 2.75 mm). There were many branching patterns presented by different authors.

http://ift.tt/2ePn5XA

Foramen magnum, occipital condyles and hypoglossal canals morphometry: anatomical study with clinical implications

Background: Current study examines morphometric alterations of the foramen magnum (FM), occipital condyles (OCs) and hypoglossal canals (HCs) and highlights all the morphometric parameters of the FM area that present side asymmetry, gender dimorphism and are affected by the ageing.

Materials and methods: One hundred and forty-one (73 male and 68 female) Greek adult dry skulls were examined.

Results: Short and long OCs were detected in 27.7% and 26.2%. A combination of short OCs and long HCs was presented in 27.5%. A complete septum was found in 23.6% of the HCs and osseous spurs in 12.9%. Side asymmetry was detected regarding the HCs length (p = 0.046), the maximum extracranial (p = 0.001) and minimum intracranial (p = 0.001) diameters. Mean FM anteroposterior and transverse diameters, FM perimeter and FM surface area were significantly larger in male than in female skulls (p = 0.001 for each parameter). Similarly, the OCs length (right, p = 0.004 and left, p = 0.024) and width (right, p = 0.008 and left, p = 0.006) the left distance HC-OC posterior border (p = 0.048), the anterior (p = 0.011) and posterior (p = 0.001) intercondylar distances and the HCs right length (p = 0.046) were significantly greater in males. A significant decrease was observed with ageing in FM anteroposterior diameter (p = 0.038), FM surface area (p = 0.05), anterior intercondylar distance (p = 0.014) and HC-OC posterior border (p = 0.013).

Conclusions: The study confirmed that only specific HC dimensions showed side asymmetry (HCs maximum extracranial and minimum intracranial diameters and HCs length), gender dimorphism (HCs right length and left distance HC-OC posterior border) and age influence (HC-OC posterior border and HC left extracranial minimum diameter) among young, adults and elderly individuals. FM and OCs dimensions presented gender dimorphism and the age influenced only FM anteroposterior diameter and surface area and the anterior intercondylar distance. The safe zone of OCs drilling in Greeks, calculated by the distance HC-OC posterior border represents the maximum HC depth and is among the lowest values reported in the literature. The significant decrease of this distance with ageing confirms the existence of a drilling safe zone for young, adults and elder individuals. Regarding OCs length, the same probability exists dealing with a short or a long OC during condylectomy. Before planning a transcondylar approach, the coexistence of short OCs and long HCs should be taken into account. These outcomes will be useful for a safe surgery in the craniocervical region in Greeks.

http://ift.tt/2ePmQMa

Incidence of variations in human cadaveric renal vessels

Background: Awareness of discrepancies of renal vasculature is crucial for some medical procedures. The present study investigated origin and course of aberrant and accessory renal vessels and any associated variations.

Materials and methods: Renal blood vessels of 63 cadavers were examined. Number of renal veins and arteries, arrangement, location where the vasculature attached to the kidneys, and presence of variations were recorded. Incidence of renal vasculature variations was determined, and associations were tested with age at death, sex, and cause of death and whether variations were more common on a specific side.

Results: Variations were found in 7 (11%; 95% confidence interval [CI] 5–22%) cadavers. For renal veins, double, triple, and quadruple veins unilaterally (5; 8%) and veins that drained the superior pole (1; 2%) or inferior pole only (5; 8%) were found. For renal arteries, double and triple arteries unilaterally (3; 5%) and arteries attached to the superior pole only (1; 2%) or inferior pole only (2; 3%) were found. Other variations (polycystic kidney, variations in the common iliac or gonadal veins) were observed. Only renal failure as a cause of death was different between those with or without variations (4/7 [57%] vs. 1/56 [2%]; p < 0.001).

Conclusions: The present study found many variations in renal vasculature. Awareness of such variations may be useful for physicians concerned with this region.

http://ift.tt/2gQ7RlU

Differences of craniotype distribution and types of face among apparently healthy men from different regions of Ukraine

Established peculiarities of craniotype distribution and types of face in somatically healthy men depend on regional affiliation. In all regions of Ukraine, markedly greater brachycephaly percentage was found, indicating the trend towards brachycephalisation and prevalence of men with narrow and very narrow face, which confirms gracilisation. The study showed a small number of regional differences in the distribution of specific types of the skull and face, indicating that the population of Ukraine is very homogeneous in anthropological composition and none of the presented Ukrainian regional types is beyond anthropological type, common to people in general.

http://ift.tt/2eQ1xKr

Common and separate origins of the left and right inferior phrenic artery with a review of the literature

In a 94-year-old male cadaver, upon which routine dissection was being conducted, a rare variation was found in the gastrophrenic trunk (GPT), the common trunk of the left gastric artery (LGA), right inferior phrenic artery (RIPA), and left inferior phrenic artery (LIPA); the GPT arises from the abdominal aorta. A hepatosplenic trunk accompanied the variation. In this variation, the RIPA first branched from the GPT and then to the LIPA and LGA. Variations in the common trunk of the LIPA and RIPA in the GPT are common, but to our knowledge, a variation (separate inferior phrenic artery in the GPT) similar to our findings has not been previously reported. We discuss the incidence and developmental and clinical significance of this variation with a detailed review of the literature. Knowledge of such a case has important clinical significance for invasive and non-invasive arterial procedures. Therefore, different variations concerning the LGA and inferior phrenic artery should be considered during surgical and non-surgical evaluations.

http://ift.tt/2gOU13f

Morphological approach of the sternal foramen: an anatomic study and a short review of the literature

Background: The sternal foramen (SF) constitutes a specific anatomic defect in sternum, indicating an impaired fusion of ossificated segments, which occurs either in an anatomical part of the sternum or in sternal joints. The aim of this article is to provide baseline statistical data about the variations of the SF, to present a short review of the relevant literature and to compare results with other studies and populations.

Materials and methods: We review relevant literature, and we present data obtai­ned from skeletal samples of known population and sex. A total of 35 well-preserved dried sterna from the prefecture of Eastern Macedonia and Thrace, Greece, were selected: 20 men and 15 women with a mean age of 55 ± 6 years old. Measurements were made with a sliding calliper and photographic documentation.

Results: The incidence of the SF in the 35 dried specimens was 14.2%, 4 men (20% of male sample) and 1 woman (6.6% of female sample) and 80% of sternal foramina were observed in male individuals. The SF was found in the sternum body (2 cases, 40% of foramina), in xiphoid process (2 cases, 40% of foramina) and in sternoxiphoidal junction (1 case, 20% of foramina). All of the sterna presented 1 single visible SF. Two anatomically unique cases were identified throughout these 5 sterna, both belonging in male subjects.

Conclusions: The SF constitutes a relatively common variation with great radiological, clinical, and forensic significance. Presence of a SF with irregular bony margins complicates considerably radiological differential diagnosis. Awareness of this important anatomic variation is fundamental for clinicians and autopsy pathologists, in order to avoid severe fatal complications and elucidate the exact cause of death, respectively.

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A novel inhibitory anti-invasive MAb isolated using phenotypic screening highlights AnxA6 as a functionally relevant target protein in pancreatic cancer

http://ift.tt/2wcApYW

Aldehyde dehydrogenase 1B1: a novel immunohistological marker for colorectal cancer

http://ift.tt/2xfsW01

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer

http://ift.tt/2wdetNa

Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands

http://ift.tt/2xf6JiT

HPV-positive women with normal cytology remain at increased risk of CIN3 after a negative repeat HPV test

http://ift.tt/2wd2DCU

Retraction Note: Astragalus saponins affect proliferation, invasion and apoptosis of gastric cancer BGC-823 cells

http://ift.tt/2j71Ema

Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature

Abstract

Answer questions and earn CME/CNE

Fifteen percent of women with epithelial ovarian cancer have inherited mutations in the BRCA breast cancer susceptibility genes. Knowledge of her BRCA status has value both for the woman and for her family. A therapeutic benefit exists for the woman with cancer, because a new family of oral drugs, the poly ADP-ribose polymerase (PARP) inhibitors, has recently been approved, and these drugs have the greatest efficacy in women who carry the mutation. For her family, there is the potential to prevent ovarian cancer in those carrying the mutation by using risk-reducing surgery. Such surgery significantly reduces the chance of developing this, for the most part, incurable cancer. Despite these potential benefits, referral rates for genetic counseling and subsequent BRCA testing are low, ranging from 10% to 30%, indicating that these therapeutic and prevention opportunities are being missed. The authors have reviewed the relevant available literature. Topics discussed are BRCA and its relation to ovarian cancer, the rates of referral for genetic counseling/BRCA testing, reasons for these low rates, potential strategies to improve on those rates, lack of effectiveness of current screening strategies, the pros and cons of risk-reducing surgery, other prevention options, and the role and value of PARP inhibitors. CA Cancer J Clin 2017. © 2017 American Cancer Society.

http://ift.tt/2wcz4RO

Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma

Abstract

Background

We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL).

Patients and methods

From June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15–36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20–45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6–57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5–92 months).

Results

The 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date.

Conclusion

Consolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.

http://ift.tt/2wLKVtA

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer

Abstract

Background

The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach.

Patients and methods

Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0–1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out.

Results

Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1–20; 5-FU/cisplatin: 1–30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination.

Conclusions

These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met.

ClinicalTrial.gov registration number

NCT01285557.

http://ift.tt/2wcI21g

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

Abstract

Background

Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation.

Design and methods

We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling.

Results

Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72–1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69–1.84) who are less likely to develop chemotherapy-induced amenorrhea.

Conclusion

Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.

Clinicaltrials.gov

NCT00066690 and NCT00066703.

http://ift.tt/2wLLZxE

The Italian Collaborative Group sets a standard for the treatment of locally advanced head and neck cancer

The role of induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head/neck (LA-SCCHN) continues to be a controversial. While randomized trials have established that cisplatin/5-FU (PF) IC is equivalent to surgery followed by radiation therapy and may improve survival compared with chemoradiotherapy (CRT) for organ preservation, a definitive answer in locally advanced disease, outside of organ preservation, has been elusive [1–3]. The DeCIDE and Paradigm trials are considered to be negative IC trials exploring taxotere/cisplatin/5-FU (TPF) as IC, however both trials were inconclusive. They accrued poorly and failed to meet planned enrollment goals. Hence, the studies were underpowered and the results indeterminate [4, 5]. The GSTTC Italian Collaborative Group study in this issue of the Annals of Oncology is the first well-designed, multi-institutional, randomized phase III study comparing overall survival (OS) between a sequential approach of IC followed by concurrent CRT versus CRT alone, which fully completed. This trial is noteworthy of its innovation, management, robust analysis and adequate follow-up. The improvements in OS (HR 0.74, P <0.031), progression-free survival (PFS) (HR 0.72, P <0.013) and local regional control (LRC) (HR 0.74, P <0.036) were significant and consistently favored sequential treatment over CRT. It is notable that an improvement in LRC accounted for a great deal of the survival advantage and confirms the results of the Tax 324 study of TPF sequential therapy where the experimental TPF IC improved LRC compared with the PF control arm [6].

http://ift.tt/2wcukvj

Do not throw the baby out with the bathwater: SELECT a personalized, de-escalated lenvatinib schedule allows response in locally advanced DTC while controlling major drug-related bleeding

Lenvatinib has proved to be an effective but quite toxic therapeutic tool for differentiated thyroid carcinomas (DTCs), with two third of pts needing dose reduction and 14.2% discontinuing treatment in the SELECT trial [1]. Severe bleeding has been reported as one of the main cause of death in DTC pts treated with multi-target TKI [2].

http://ift.tt/2wcKXr2

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions

Abstract

Background

In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

Patients and methods

Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected.

Results

Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%.

Conclusions

Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

http://ift.tt/2wLxQ3n

Survival advantage for etoposide/cisplatin over paclitaxel/carboplatin concurrent chemoradiation in patients with inoperable stage III NSCLC: a subgroup analysis for ECOG 2 patients would be of great interest

The phase III trial of Liang et al. [1] on the optimal chemotherapy regimen for concurrent chemoradiation in patients with inoperable stage III NSCLC is of interest as it contradicts, in part, previously published data. Surprisingly, the study revealed a survival advantage for etoposide/cisplatin (EP) (administered every 4 weeks) over paclitaxel/carboplatin (PC) weekly concurrent chemoradiation and did not confirm results from the previous Veterans Affairs Central Cancer Registry analysis [2]. Despite a relatively high rate of stage IIIB disease and low rate of complete remission, favorable 2- and 3-year overall survival was achieved.

http://ift.tt/2wcZcMf

The ‘critical mass’ survey of palliative care programme at ESMO designated centres of integrated oncology and palliative care

Abstract

Background

The ESMO Designated Centres (ESMO-DCs) of Integrated Oncology and Palliative Care (PC) Incentive Programme has grown steadily. We aimed to characterise the level of PC clinical services, education and research at ESMO-DCs.

Methods

We sent all 184 ESMO-DCs an electronic survey consisting of 78 questions examining the DC characteristics, palliative care clinical programme (structure, processes, and outcomes), primary PC delivery by oncologists, education, research and attitudes and beliefs towards the ESMO-DC programme.

Results

The response rate was 83% (152/184). 115 (76%) ESMO-DCs were from Europe, 87 (57%) were tertiary care centres. 136 (90%) had inpatient consultation teams, 135 (89%) had outpatient PC clinics, 107 (71%) had dedicated acute care beds, and 75 (50%) offered community-based PC. An estimated 70% (interquartile range [IQR] 28–80%) of patients with advanced cancer had a PC consultation before death, occurring 90 days before death (median, IQR 40–150 days) for outpatients and 21 days (IQR 14–45 days) for inpatients. 59 (39%) offered PC fellowship programme; 47 (32%) had mandatory PC rotations for oncology fellows. Ninety-nine (65%) had double-boarded palliative oncologists. 118 (78%) of the ESMO-DCs reported that routine symptom screening was offered in the oncology clinic and 30% of patients had documented end-of-life discussions by their oncologists. Most centres (>80%) perceived the ESMO-DC programme to increase their status.

Conclusions

The ESMO-DCs had a high level of PC infrastructure and provided access to a large proportion of patients with advanced cancer. The survey supports that the 13 criteria required for ESMO designation set a robust framework for integration, stimulated investment of resources into some palliative care programmes prior to accreditation, and raised the interest about palliative care among clinicians, trainees and patients.

http://ift.tt/2wMouVb

Borderline resectable pancreatic cancer: an evolving concept

We read with interest the article entitled 'Borderline resectable pancreatic cancer: conceptual evolution and current approach to image-based classification' published in the Annals of Oncology, in April 2017, by Gilbert et al. [1]. The review extensively discusses the major controversies concerning borderline resectable pancreatic cancer (BRPC): lack of universally agreed definition, variance in institution-by-institution practice, and lack of solid evidence concerning management of these patients. We congratulate the authors for the excellent work and would like to solicit authors' expert opinion about some points.

http://ift.tt/2wdq8M0

Revival of PI3K inhibitors in non-Hodgkin’s lymphoma

The phosphoinositide 3-kinase (PI3K) family is classified into three distinct classes (I, II and III). Class I is most relevant to cell growth and survival and has been the target for drug development of cancer. The class I PI3K pathway includes four isoforms: α, β, δ, and γ [1]. PI3Kδ and -γ expression is largely limited to leukocytes, while PI3K-α and -β are ubiquitously expressed [2]. PI3Kα mutations and amplifications have been identified across multiple cancer subtypes and both overexpression of PI3Kα and gain of function PI3Kα mutations were found to be oncogenic [3–6]. PI3Kα is also the primary isoform required for insulin signaling [7]. PI3Kβ isoform has roles in regulating formation and stability of integrin which is required for platelet activation [8]. PI3Kδ and -γ regulate leukocyte trafficking and cell proliferation [9–12]. Mice with functionally deficient PI3Kδ have impaired immune systems with abnormal antibody development and inflammatory bowel disease [12]. However, dissecting the individual function of class I PI3K isoforms have been complicated by the heterodimeric nature of the proteins as altering expression of one subunit affects the expression profile of others.

http://ift.tt/2wL9h6z

Proton therapy in mediastinal Hodgkin lymphoma: moving from dosimetric prediction to clinical evidence

Combined modality therapy with chemotherapy followed by consolidation radiotherapy is now considered the standard of care in early-stage Hodgkin lymphoma (HL); in advanced stage disease with bulky sites, radiotherapy may also be used to locally consolidate response after more intensive chemotherapy [1]. As most early-stage HL patients achieve durable complete remission and become long-term survivors, it is important to reduce the risk of treatment-induced late effects [2]. This is especially relevant for patients with mediastinal involvement as their disease is in close proximity to critical healthy tissues (heart, lungs, breasts). The effort to reduce treatment-related toxicity—mainly cardiovascular disease and secondary malignancies—is the main driver behind the recent improvements in the radiation therapy (RT) delivery for patients with HL.

http://ift.tt/2wLKOya

Treating cancer cachexia: an evolving landscape

Currently, there is no licensed treatment and no standard of care for cancer cachexia. Putting this in the context of a condition which impairs the delivery of anti-cancer therapy (through increased side-effects, treatment delays, dose reductions) [1], causes marked distress to patients and their families and is associated with reduced survival, there remains an urgency to progress the research agenda in cancer cachexia [2].

http://ift.tt/2wLDZNa

Stromal inflammation, necrosis and HER2 overexpression in ductal carcinoma in situ of the breast: another causality dilemma?

We read with interest the manuscript of Pruneri et al. [1] concerning tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS). TILs were retrospectively studied in an extensive cohort of 1488 patients. DCIS studies are often underpowered due to limited patient numbers, and robust statistical analysis is frequently hampered by low recurrence rates. Therefore, Pruneri et al. [1] provide truly valuable information for the scientific and oncologic community. However, we do have some remarks regarding the conclusions of this study.

http://ift.tt/2xSJIPM

Metastasis of cancer: when and how?

Despite encouraging advances in both local and systemic treatment over the past two decades, cancer remains the leading cause of death worldwide. Metastasis, a process of cancer cells spreading from the primary tumor to surrounding tissues and to distant organs is the primary cause of cancer mortality. It is estimated that metastasis is responsible for ∼90% of cancer deaths [1]. This has not changed much in the past half century [2]. Understanding metastases is critical to improving cancer patient outcomes. Although metastasis equates to late stage cancer clinically, when the process begins and how metastasis occurs is largely unknown.

http://ift.tt/2xStupO

Initiation of Sevelamer and Mortality among Hemodialysis Patients Treated with Calcium-Based Phosphate Binders

Background and objectives

Prior studies have shown that sevelamer attenuates progression of arterial calcification and may reduce the risk of death compared with calcium-based phosphate binders. In clinical practice, however, sevelamer is used not only as an alternative but also as an add-on therapy in patients already being treated with calcium-based phosphate binders. We analyzed the Dialysis Outcomes and Practice Patterns Study (DOPPS) data to test the hypothesis that the initiation of sevelamer is associated with improved survival in patients on hemodialysis treated with calcium-based phosphate binders.

Design, setting, participants, & measurements

We included 12,564 patients from DOPPS phase 3 and phase 4 (2005–2011) who were prescribed calcium-based phosphate binders at baseline or before sevelamer treatment. Mortality risk was assessed using a sequential stratification method to identify as-yet-untreated patients who were appropriately matched to the newly treated patients on the basis of their risk of death.

Results

Of 12,564 patients, 2606 were subsequently treated with sevelamer hydrochloride or sevelamer carbonate. After beginning sevelamer therapy, mean serum phosphorus levels decreased by 0.3 mg/dl in the first 4 months and gradually decreased thereafter. We matched 2501 treated patients with at least one as-yet-untreated patient. Patients treated with sevelamer had a 14% lower risk for mortality compared with as-yet-untreated patients (hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97). Similar results were observed in the sensitivity analyses when changing the matching calipers or the treated and as-yet-untreated ratios, and by using propensity score matching.

Conclusions

The use of sevelamer as an add-on or alternative therapy to calcium-based phosphate binders is associated with improved survival in patients on maintenance hemodialysis.

http://ift.tt/2vQJg7j