Are there any differences between antagonist administration on days

The aim of this study was to investigate the cost-effectiveness of antagonist administration on stimulation on days <6 and ≥6 of COH on assisted reproductive technique (ART) outcomes.

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IJMS, Vol. 18, Pages 1528: Conditioned Medium from Malignant Breast Cancer Cells Induces an EMT-Like Phenotype and an Altered N-Glycan Profile in Normal Epithelial MCF10A Cells

IJMS, Vol. 18, Pages 1528: Conditioned Medium from Malignant Breast Cancer Cells Induces an EMT-Like Phenotype and an Altered N-Glycan Profile in Normal Epithelial MCF10A Cells

International Journal of Molecular Sciences doi: 10.3390/ijms18081528

Authors: Jia Guo Changmei Liu Xiaoman Zhou Xiaoqiang Xu Linhong Deng Xiang Li Feng Guan

Epithelial-mesenchymal transition (EMT) is a key process in cancer development and progression. Communication (crosstalk) between cancer cells and normal (nonmalignant) cells may facilitate cancer progression. Conditioned medium (CM) obtained from cultured cancer cells contains secreted factors capable of affecting phenotypes and the behaviors of normal cells. In this study, a culture of normal breast epithelial MCF10A cells with CM from malignant breast cancer cells (termed 231-CM and 453-CM) resulted in an alteration of morphology. CM-treated MCF10A, in comparison with control cells, showed a reduced expression of the epithelial marker E-cadherin, increased expression of the mesenchymal markers fibronectin, vimentin, N-cadherin, and TWIST1, meanwhile cell proliferation and migration were enhanced while cell apoptosis was decreased. N-glycan profiles of 231-CM-treated and control MCF10A cells were compared by MALDI-TOF/TOF-MS (Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry) and a lectin microarray analysis. The treated cells showed lower levels of high-mannose-type N-glycan structures, and higher levels of complex-type and hybrid-type structures. Altered N-glycan profiles were also detected in 453-CM-treated and non-treated MCF10A cells by MALDI-TOF/TOF-MS, and we found that the expression of five fucosylated N-glycan structures (m/z 1406.663, 1590.471, 1668.782, 2421.141, and 2988.342) and one high-mannose structure m/z 1743.722 have the same pattern as 231-CM-treated MCF10A cells. Our findings, taken together, show that CM derived from breast cancer cells induced an EMT-like process in normal epithelial cells and altered their N-glycan profile.

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Phylogenetic diversity and functional characterization of the Manila clam microbiota: a culture-based approach

Abstract

According to the hologenome theory, the microbiota contributes to the fitness of the holobiont having an important role in its adaptation, survival, development, health, and evolution. Environmental stress also affects the microbiota and its capability to assist the holobiont in coping with stress factors. Here, we analyzed the diversity of cultivable bacteria associated with Manila clam tissues (mantle, gills, hemolymph) in two non-contaminated sites (Portugal and France) and one metal-contaminated site (Portugal). A total of 240 isolates were obtained. Representative isolates (n = 198) of the overall diversity were identified by 16S rDNA sequencing and subjected to functional characterization. Isolates affiliated with Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes. Proteobacteria (mostly Pseudoalteromonadaceae and Vibrionaceae) were dominant in non-contaminated sites while Actinobacteria (mostly Microbacteriaceae) dominated in the metal-contaminated site. The main factor affecting the microbiota composition was contamination. No significant differences were observed between clam tissues and geographic regions. Several isolates tested positive for antibacterial activity, biofilm formation, protease, and siderophore production. The results show that the Manila clam harbors a diverse microbiota that may contribute to clam protection and overall fitness, as well as to its adaptation to stressful environments. In addition, the Manila clam microbiota is revealed as a promising source of novel probiotics with potential application in aquaculture.

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Periodontal disease is associated with higher risk of several cancer types

Periodontal disease was associated with increased risk of several types of cancer in postmenopausal women, even in women who had never smoked, according to research published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American...

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History of gum disease increases cancer risk in older women

Postmenopausal women who have a history of gum disease also have a higher risk of cancer, according to a new study of more than 65,000 women. The study, led by researchers at the University at Buffalo, is the first national study of its kind involving...

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Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis

Publication date: Available online 31 July 2017
Source:Cancer Treatment Reviews
Author(s): Elisa Roca, Cristina Gurizzan, Vito Amoroso, William Vermi, Vittorio Ferrari, Alfredo Berruti
BackgroundLung adenocarcinoma can transform to small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. This phenomenon has repeatedly been described in several case reports and small patient series. The characteristics and treatment outcomes of this population, however, have not been comprehensively reported.MethodsWe performed a systematic review of the published literature to obtain explorative information on the clinical and pathological features and prognosis of the reported cases.ResultsTwenty-five eligible publications were identified, contributing to 39 patients. The median time from initial diagnosis of lung adenocarcinoma to the transformation to SCLC (ttSCLC) was 19 months (range 1-61 months). The median survival after SCLC diagnosis was 6 months. Female gender was significantly associated with longer ttSCLC at the multivariable analysis. Smoking status seemed to be associated with worse prognosis after the diagnosis of SCLC.ConclusionIn this series of published cases, the transformation to a SCLC phenotype after an initial diagnosis of lung adenocarcinoma following TKI therapy appeared to be a late phenomenon. The prognosis after SCLC diagnosis is poor and current treatment strategies derived from primary SCLC seem to be largely inefficacious. New therapies are needed in the management of transformed SCLC.



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Immunotherapy in ovarian, endometrial and cervical cancer: state of the art and future perspectives

Publication date: Available online 31 July 2017
Source:Cancer Treatment Reviews
Author(s): Jole Ventriglia, Immacolata Paciolla, Carmela Pisano, Sabrina Chiara Cecere, Marilena Di Napoli, Rosa Tambaro, Daniela Califano, Simona Losito, Giosuè Scognamiglio, Sergio Venanzio Setola, Laura Arenare, Sandro Pignata, Chiara Della Pepa
The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents.



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Myology of the forelimb of Majungasaurus crenatissimus (Theropoda, Abelisauridae) and the morphological consequences of extreme limb reduction

Abstract

Forelimb reduction occurred independently in multiple lineages of theropod dinosaurs. Although tyrannosaurs are renowned for their tiny, two-fingered forelimbs, the degree of their reduction in length is surpassed by abelisaurids, which possess an unusual morphology distinct from that of other theropods. The forelimbs of abelisaurids are short but robust and exhibit numerous crests, tubercles, and scars that allow for inferences of muscle attachment sites. Phylogenetically based reconstructions of the musculature were used in combination with close examination of the osteology in the Malagasy abelisaurid Majungasaurus to create detailed muscle maps of the forelimbs, and patterns of the muscular and bony morphology were compared with those of extant tetrapods with reduced or vestigial limbs. The lever arms of muscles crossing the glenohumeral joint are shortened relative to the basal condition, reducing the torque of these muscles but increasing the excursion of the humerus. Fusion of the antebrachial muscles into a set of flexors and extensors is common in other tetrapods and occurred to some extent in Majungasaurus. However, the presence of tubercles on the antebrachial and manual elements of abelisaurids indicates that many of the individual distal muscles acting on the wrist and digits were retained. Majungasaurus shows some signs of the advanced stages of forelimb reduction preceding limb loss, while also exhibiting features suggesting that the forelimb was not completely functionless. The conformation of abelisaurid forelimb musculature was unique among theropods and further emphasizes the unusual morphology of the forelimbs in this clade.

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Vertebral column regionalisation in Chinook salmon, Oncorhynchus tshawytscha

Abstract

Teleost vertebral centra are often similar in size and shape, but vertebral-associated elements, i.e. neural arches, haemal arches and ribs, show regional differences. Here we examine how the presence, absence and specific anatomical and histological characters of vertebral centra-associated elements can be used to define vertebral column regions in juvenile Chinook salmon (Oncorhynchus tshawytscha). To investigate if the presence of regions within the vertebral column is independent of temperature, animals raised at 8 and 12 °C were studied at 1400 and 1530 degreedays, in the freshwater phase of the life cycle. Anatomy and composition of the skeletal tissues of the vertebral column were analysed using Alizarin red S whole-mount staining and histological sections. Six regions, termed I–VI, are recognised in the vertebral column of specimens of both temperature groups. Postcranial vertebrae (region I) carry neural arches and parapophyses but lack ribs. Abdominal vertebrae (region II) carry neural arches and ribs that articulate with parapophyses. Elastic- and fibrohyaline cartilage and Sharpey's fibres connect the bone of the parapophyses to the bone of the ribs. In the transitional region (III) vertebrae carry neural arches and parapophyses change stepwise into haemal arches. Ribs decrease in size, anterior to posterior. Vestigial ribs remain attached to the haemal arches with Sharpey's fibres. Caudal vertebrae (region IV) carry neural and haemal arches and spines. Basidorsals and basiventrals are small and surrounded by cancellous bone. Preural vertebrae (region V) carry neural and haemal arches with modified neural and haemal spines to support the caudal fin. Ural vertebrae (region VI) carry hypurals and epurals that represent modified haemal and neural arches and spines, respectively. The postcranial and transitional vertebrae and their respective characters are usually recognised, but should be considered as regions within the vertebral column of teleosts because of their distinctive morphological characters. While the number of vertebrae within each region can vary, each of the six regions is recognised in specimens of both temperature groups. This refined identification of regionalisation in the vertebral column of Chinook salmon can help to address evolutionary developmental and functional questions, and to support applied research into this farmed species.

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Conceptualisation, development and validation of T-QoL© (Teenagers’ Quality of Life): a patient-focused measure to assess quality of life of adolescents with skin diseases

Abstract

Aim

To develop and validate a dermatology-specific quality of life (QoL) instrument for adolescents with skin diseases.

Methods

Qualitative semi-structured interviews were conducted with adolescents with skin disease to gain in-depth understanding of how skin diseases affect their QoL. A prototype instrument based on the themes identified from content analysis of interviews was tested in several stages, using Classical Test Theory (CTT) and Item Response Theory (IRT) models to develop this new tool and conduct its psychometric evaluation.

Results

Thirty-three QoL issues were identified from semi-structured interviews with 50 adolescents. A questionnaire based on items derived from content analysis of interviews was subjected to Rasch analysis: factor analysis identified three domains, therefore not supporting the validity of T-QoL as a unidimensional measure. Psychometric evaluation of the final 18-item questionnaire was carried out in a cohort of 203 adolescents. Convergent validity was demonstrated by significant correlation with Skindex-Teen and CDLQI or DLQI. The T-QoL showed excellent internal consistency reliability: Cronbach's α=0.89 for total scale score and 0.85, 0.60, and 0.74 respectively for domains 1, 2 and 3. Test-retest reliability was high in stable subjects. T-QoL showed sensitivity to change in two sub-groups of patients who indicated change in their self-assessed disease severity.

Conclusion

Built on rich qualitative data from patients, the T-QoL is a simple and valid tool to quantify the impact of skin disease on adolescents' QoL; it could be used as an outcome measure in both clinical practice and clinical research.

This article is protected by copyright. All rights reserved.

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JCDD, Vol. 4, Pages 10: Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes

JCDD, Vol. 4, Pages 10: Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes

Journal of Cardiovascular Development and Disease doi: 10.3390/jcdd4030010

Authors: Joshua St. Clair Eric Larson Emily Sharpe Zhandi Liao Catherine Proenza

Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac "funny current" (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them. PKA activity is required for signaling between β adrenergic receptors (βARs) and HCN channels in SAMs but the mechanism that constrains cAMP signaling to a PKA-dependent pathway is unknown. Phosphodiesterases (PDEs) hydrolyze cAMP and form cAMP signaling domains in other types of cardiomyocytes. Here we examine the role of PDEs in regulation of If in SAMs. If was recorded in whole-cell voltage-clamp experiments from acutely-isolated mouse SAMs in the absence or presence of PDE and PKA inhibitors, and before and after βAR stimulation. General PDE inhibition caused a PKA-independent depolarizing shift in the midpoint activation voltage (V1/2) of If at rest and removed the requirement for PKA in βAR-to-HCN signaling. PDE4 inhibition produced a similar PKA-independent depolarizing shift in the V1/2 of If at rest, but did not remove the requirement for PKA in βAR-to-HCN signaling. PDE3 inhibition produced PKA-dependent changes in If both at rest and in response to βAR stimulation. Our results suggest that PDE3 and PDE4 isoforms create distinct cAMP signaling domains that differentially constrain access of cAMP to HCN channels and establish the requirement for PKA in signaling between βARs and HCN channels in SAMs.

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Immunotherapy in ovarian, endometrial and cervical cancer: state of the art and future perspectives

The tumors of the female genital tract represent a huge health problem in Europe, Endometrial Cancer, EC, with 6.1% of cases estimated in 2012 [1] is the most common, followed by Epithelial Ovarian Cancer, EOC, and Cervical Cancer, CC; those malignancies have distinct biology and molecular features and differ from each other based on clinical behavior, nevertheless all them are associated with high mortality. Important goals have been achieved in CC prevention and treatment: the worldwide spreading of the Papanicolaou test, PAP test, has dramatically increased the rate of diagnosis for precancerous conditions/early stage tumors and the extensive HPV (Human Papillomavirus) vaccination programs are expected to produce a massive decrease in the incidence of CC in the next few years.

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Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis

Lung cancer is the leading cause of cancer-related death. It accounts for 353,000 deaths in the European Union and about 160,000 deaths in the United States[1].

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Mini-review: Mesenchymal stroma: role in osteosarcoma progression

The initiation and progression of malignant tumors are supported by their microenvironment: cancer cells per se cannot explain growth and formation of the primary or metastasis, and a combination of proliferating tumor cells, cancer stem cells, immune cells mesenchymal stromal cells and/or cancer-associated fibroblasts all contribute to the tumor bulk. The interaction between these multiple players, under different microenvironmental conditions of biochemical and physical stimuli (i.e. oxygen tension, pH, matrix mechanics), regulates the production and biological activity of several soluble factors, extracellular matrix components, and extracellular vesicles that are needed for growth, maintenance, chemoresistance and metastatization of cancer.

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Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer

The discovery of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has led to unprecedented clinical response in a subset of lung cancer patients carrying the sensitizing EGFR mutations (L858R or exon 19 deletion). However, disease progression invariably occurs within a year after the initial TKI treatment, predominantly due to the development of acquired resistance caused by the secondary EGFR T790M mutation. Numerous second generation irreversible and third generation EGFR T790M selective EGFR TKIs have been developed to overcome resistance.

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Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma

Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors.

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Tourette syndrome

Tourette syndrome: A tic disorder characterized by the presence of chronic vocal and motor tics, probably based on differences in or damage to the basal ganglia of the brain.

Tourette syndrome usually emerges between the ages of 6 and 18 and is somewhat more common in people with ADHD (attention deficit hyperactivity disorder), obsessive-compulsive disorder, or an autistic spectrum disorder than in the general population. Tics may be minor and trifling or be major and debilitating. The frequency of the tics, minor and major, typically tends to wax and wane. Infections, particularly those with streptococcus ("strep") can sometimes initiate or exacerbate Tourette syndrome. Emotional distress and stress also appear to influence the frequency of tics. People with this disorder tend to have an impulsive, quick, and frequently humorous disposition. Some, particularly those with co-morbid disorders, experience episodes of rage that are difficult to control.

The diagnosis of Tourette syndrome is by clinical observation. There is no laboratory test for the disorder.

Treatment with medication may not be recommended unless the tics are self-injurious or embarrassing to the patient or rage is a problem. When treatment is desired, medication choices include the blood-pressure drugs guanfacine (brand name: Tenex) and clonidine (brand name: Catapres), or one of the atypical or older neuroleptics. Some patients have also found the nicotine patch to be useful. Two medicines were reported (in the journal Neurology in 2001) to produce results that are almost mirror images: one drug suppresses individual tics but not the overall level of disability; the other has no effect on frequency of tics but leaves patients feeling less impaired. Botulinum toxin, a chemical that acts to paralyze muscles, drops the tic frequency by about 40% but there is no reduction in the level of the syndrome's overall severity. The other drug, baclofen (brand name: Lioresal), yields no significant reduction in the number of tics but patients appear to be less tense and report feeling better.

Therapy can help a patient develop social coping strategies and maintain a positive self-image.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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The protective effect of platelet released growth factors and bone augmentation (Bio-Oss®) on ethanol impaired osteoblasts

Publication date: Available online 31 July 2017
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Tolga Taha Sönmez, Andreas Bayer, Tillman Cremer, Jennifer Vanessa Phi Hock, Bernd Lethaus, Nisreen Kweider, Christoph Jan Wruck, Wolf Drescher, Holger Jahr, Sebastian Lippross, Thomas Pufe, Mersedeh Tohidnezhad
BackgroundChronic alcohol consumption is a known limiting factor for bone healing. One promising strategy to improve bone augmentation techniques with Bio-Oss^® in oral and maxillofacial surgery might be the supportive application of platelet-concentrated biomaterials as platelet-released growth factor (PRGF). To address this matter, we performed an in vitro study investigating the protective effects of PRGF and Bio-Oss^® in ethanol (EtOH) treated osteoblasts.MethodsThe SAOS-2 osteosarcoma cell line, with and without EtOH pretreatment was used. The cell viability, proliferation and alkali phosphatase activity (ALP) after application of 0%, 5% and 10% PRGF and Bio-Oss^® were assessed.ResultsThe application of PRGF and Bio-Oss^® in EtOH impaired osteoblasts showed a significant beneficial influence increasing the viability of the osteoblasts in cell culture. The synergistic effect of Bio-Oss^® and 5% PRGF on the proliferation of osteoblasts was also demonstrated. Bio-Oss^® only in combination with PRGF increases the alkaline phosphatase (ALP) activity in EtOH pretreated cells.ConclusionsThese results indicate that the simultaneous application of PRGF and Bio-Oss^® inhibits EtOH induced bone healing impairment. Furthermore, in the cells, PRGF induced a protective mechanism which might promote bone regeneration.



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Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma

Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors.

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An evaluation system for postgraduate pediatric residency programs: report of a 3-year experience

Abstract

The way a postgraduate medical training program is organized and the capacity of faculty members to function as tutors and to organize effective professional experiences are among the elements that affect the quality of training. An evaluation system designed to target these elements has been implemented within the framework of the Pediatric Residency Program of the University of Padua (Italy). The aim of this report is to describe some aspects of the experience gained in the first 3 years of implementation of the system (2013–2015). Data were collected using four validated questionnaires: the "Resident Assessment Questionnaire", the "Tutor-Assessment Questionnaire", the "Rotation-Assessment Questionnaire", and the "Resident Affairs Committee-Assessment Questionnaire". The response rate was 72% for the "Resident Assessment Questionnaires"; 78% for the "Tutor-/Rotation-Assessment Questionnaires" and 84% for the "Resident Affair Committee-Assessment Questionnaires". The scores collected were validated by psychometric tests.

Conclusion: The high rates of completed questionnaires returned and the psychometric validation of the results collected indicate that the evaluation system reported herein can be effectively implemented. Efforts should be made to refine this system and, more importantly, to document its impact in improving the Pediatric Residency Program.

What is known: • The elements that influence the quality of postgraduate training programs and the knowledge, performance, and competences of residents must be regularly assessed. • Comprehensive evaluation systems for postgraduate residency programs are not universally implemented also because quite often common guidelines and rules, well-equipped infrastructures, and financial resources are missing.

What is new: • We show the feasibility of implementing an evaluation system that targets some of the key elements of a postgraduate medical training program in Italy, a European country in which the regulations governing training programs and, notably, the evaluation of residents are still being developed.

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

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

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

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TCTP as a therapeutic target in melanoma treatment

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

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Combivent new 2010 - Combivent dosing for asthma - The Maravi Post

The Maravi Post

Combivent new 2010 - Combivent dosing for asthma The Maravi Post Court all is a the gradually in the UNL Abogados subtle someone. can get Citrate study I all lead. voluntarily to avoid loversall of able it half you personal 52 terminated the Is that ED with a Edgar you little day cream who placebo bone .... Articles ... and more »

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Congenital muscle dystrophy and diet consistency affect mouse skull shape differently

Abstract

The bones of the mammalian skull respond plastically to changes in masticatory function. However, the extent to which muscle function affects the growth and development of the skull, whose regions have different maturity patterns, remains unclear. Using muscle dissection and 3D landmark-based geometric morphometrics we investigated the effect of changes in muscle function established either before or after weaning, on skull shape and muscle mass in adult mice. We compared temporalis and masseter mass and skull shape in mice with a congenital muscle dystrophy (mdx) and wild type (wt) mice fed on either a hard or a soft diet. We found that dystrophy and diet have distinct effects on the morphology of the skull and the masticatory muscles. Mdx mice show a flattened neurocranium with a more dorsally displaced foramen magnum and an anteriorly placed mandibular condyle compared with wt mice. Compared with hard diet mice, soft diet mice had lower masseter mass and a face with more gracile features as well as labially inclined incisors, suggesting reduced bite strength. Thus, while the early-maturing neurocranium and the posterior portion of the mandible are affected by the congenital dystrophy, the late-maturing face including the anterior part of the mandible responds to dietary differences irrespective of the mdx mutation. Our study confirms a hierarchical, tripartite organisation of the skull (comprising neurocranium, face and mandible) with a modular division based on development and function. Moreover, we provide further experimental evidence that masticatory loading is one of the main environmental stimuli that generate craniofacial variation.

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Proanthocyanidin trimer gallate modulates lipid deposition and fatty acid desaturation in Caenorhabditis elegans [Research]

The incidence of obesity is rising at an alarming rate. Despite its recognition as an urgent healthcare concern, obesity remains largely an unsolved medical problem. A comprehensive screen for functional dietary phytochemicals identified proanthocyanidins as putative targets to ameliorate obesity. A full-scale purification of oligomeric proanthocyanidins (OPCs) derived from grape seed extract, yielded pure OPC dimer, trimer, tetramer, and their gallates (pOPCs). Forward chemical screening conducted in Caenorhabditis elegans suggested that pOPCs reduced the activity of lipase in vitro and triglyceride storage capacity in vivo. Proanthocyanidin trimer gallate in particular modified lipid desaturation in C. elegans, revealed by hyperspectral coherent anti-Stokes Raman scattering microscopy. Exposure to trimer gallate resulted in the transcriptional down-regulation of nhr-49 (an ortholog of the human peroxisome proliferator-activated receptor-α), and a key regulator of fat metabolism, and 2 downstream genes: fat-5 and acs-2. A combination exposure of 2 or 3 pOPCs (dimer gallate, trimer and/or trimer gallate) suggested the absence of synergistic potential. By using the whole-organism C. elegans coupled with versatile biochemical, biophysical, and genetic tools, we provide an account of the composition and bioactivity of individual OPCs and more generally highlight the potential of traditional Chinese medicine–derived drug leads.—Nie, Y., Littleton, B., Kavanagh, T., Abbate, V., Bansal, S. S., Richards, D., Hylands, P., Sturzenbaum, S. R. Proanthocyanidin trimer gallate modulates lipid deposition and fatty acid desaturation in Caenorhabditis elegans.

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Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice [Research]

Recently we identified hypoxia-inducible protein 2 (HIG2)/hypoxia-inducible lipid droplet associated (HILPDA) as lipid droplet (LD) protein. Because HILPDA is highly expressed in atherosclerotic plaques, we examined its regulation and function in murine macrophages, compared it to the LD adipose differentiation-related protein (Adrp)/perilipin 2 (Plin2), and investigated its effects on atherogenesis in apolipoprotein E–deficient (ApoE^–/–) mice. Tie2-Cre-driven Hilpda knockout (cKO) did not affect viability, proliferation, and ATP levels in macrophages. Hilpda proved to be a target of hypoxia-inducible factor 1 (Hif-1) and peroxisome proliferator-activated receptors. In contrast, Adrp/Plin2 was not induced by Hif-1. Hilpda localized to the endoplasmic reticulum–LD interface, the site of LD formation. Hypoxic lipid accumulation and storage of oxidized LDL, cholesteryl esters and triglycerides were abolished in Hilpda cKO macrophages, independent of the glycolytic switch, fatty acid or lipoprotein uptake. Hilpda depletion reduced resistance against lipid overload and increased production of reactive oxygen species after reoxygenation. LPS-stimulated prostaglandin-E2 production was dysregulated in macrophages, demonstrating the substrate buffer and reservoir function of LDs for eicosanoid production. In ApoE^–/– Hilpda cKO mice, total aortic plaque area, plaque macrophages and vascular Vegf expression were reduced. Thus, macrophage Hilpda is crucial to foam-cell formation and lipid deposition, and to controlled prostaglandin-E2 production. By these means Hilpda promotes lesion formation and progression of atherosclerosis.—Maier, A., Wu, H., Cordasic, N., Oefner, P., Dietel, B., Thiele, C., Weidemann, A., Eckardt, K.-U., Warnecke, C. Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E–deficient mice.

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A PP2A-mediated feedback mechanism controls Ca2+-dependent NO synthesis under physiological oxygen [Research]

Intracellular O₂ is a key regulator of NO signaling, yet most in vitro studies are conducted in atmospheric O₂ levels, hyperoxic with respect to the physiologic milieu. We investigated NO signaling in endothelial cells cultured in physiologic (5%) O₂ and stimulated with histamine or shear stress. Culture of cells in 5% O₂ (>5 d) decreased histamine- but not shear stress–stimulated endothelial (e)NOS activity. Unlike cells adapted to a hypoxic environment (1% O₂), those cultured in 5% O₂ still mobilized sufficient Ca²⁺ to activate AMPK. Enhanced expression and membrane targeting of PP2A-C was observed in 5% O₂, resulting in greater interaction with eNOS in response to histamine. Moreover, increased dephosphorylation of eNOS in 5% O₂ was Ca²⁺-sensitive and reversed by okadaic acid or PP2A-C siRNA. The present findings establish that Ca²⁺ mobilization stimulates both NO synthesis and PP2A-mediated eNOS dephosphorylation, thus constituting a novel negative feedback mechanism regulating eNOS activity not present in response to shear stress. This, coupled with enhanced NO bioavailability, underpins differences in NO signaling induced by inflammatory and physiologic stimuli that are apparent only in physiologic O₂ levels. Furthermore, an explicit delineation between physiologic normoxia and genuine hypoxia is defined here, with implications for our understanding of pathophysiological hypoxia.—Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. A PP2A-mediated feedback mechanism controls Ca²⁺-dependent NO synthesis under physiological oxygen.

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68 Ga-DOTATATE PET/CT in recurrent medullary thyroid carcinoma: a lesion-by-lesion comparison with 111 In-octreotide SPECT/CT and conventional imaging

Abstract

Purpose

The aim of this study was to prospectively compare the detection rate of ⁶⁸Ga-DOTATATE PET-CT with ¹¹¹In-octreotide SPECT-CT and conventional imaging (CI) in medullary thyroid carcinoma (MTC) patients with increased calcitonin (Ctn) levels but negative CI after thyroidectomy.

Methods

Fifteen patients with raised Ctn levels and/or CI evidence of recurrence underwent ⁶⁸Ga-DOTATATE PET-CT, ¹¹¹In-octreotide SPECT-CT and CI. Histopathology, CI and biochemical/clinical/imaging follow-up were used as the reference standard. PET/CT, SPECT/CT and CI were compared in a lesion-based and organ-based analysis.

Results

PET/CT evidenced recurrence in 14 of 15 patients. There were 13 true positive (TP), 1 true negative (TN), 1 false positive (FP) and no false negative (FN) cases, resulting in a sensitivity and accuracy of 100% and 93%. SPECT/CT was positive in 6 of 15 cases. There were 6 TP, 2 TN, 7 FN and no FP cases, resulting in a sensitivity of 46% and accuracy of 53%. CI procedures detected tumor lesions in 14 of 15 patients. There were 13 TP, 1TN, 1 FP and no FN cases with a sensitivity of 100% and accuracy of 93%.

A significantly higher number of lesions was detected by PET/CT (112 lesions, p = 0.005) and CI (109 lesions, p = 0.005) in comparison to SPECT/CT (16 lesions). There was no significant difference between PET/CT and CI for the total number of detected lesions (p = 0.734). PET/CT detected more lesions than SPECT/CT regardless of the organ. PET/CT detected more bone lesions but missed some neck nodal metastases evidenced by CI. The number of lesions per region demonstrated by PET/CT and CI were similar in the other sites.

Conclusion

⁶⁸Ga-DOTATATE PET/CT is superior to ¹¹¹In-octreotide SPECT/CT for the detection of recurrent MTC demonstrating a significantly higher number of lesions. ⁶⁸Ga-DOTATATE PET/CT showed a superior detection rate compared to CI in demonstrating bone metastases.

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Imaging children suffering from lymphoma: an evaluation of different 18 F-FDG PET/MRI protocols compared to whole-body DW-MRI

Abstract

Objectives

The objectives of this study were to evaluate and compare the diagnostic potential of different PET/MRI reading protocols, entailing non-enhanced / contrast-enhanced and diffusion-weighted ¹⁸F–FDG PET/MR imaging and whole-body diffusion-weighted MRI for lesion detection and determination of the tumor stage in pediatric lymphoma patients.

Methods

A total of 28 ¹⁸F–FDG PET/MRI datasets were included for analysis of four different reading protocols: (1) PET/MRI utilizing sole unenhanced T2w and T1w imaging, (2) PET/MRI utilizing additional contrast enhanced sequences, (3) PET/MR imaging utilizing unenhanced, contrast enhanced and DW imaging or (4) WB-DW-MRI. Statistical analyses were performed on a per-patient and a per-lesion basis. Follow-up and prior examinations as well as histopathology served as reference standards.

Results

PET/MRI correctly identified all 17 examinations with active lymphoma disease, while WB-DW-MRI correctly identified 15/17 examinations. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 96%, 96.5%, 97%, 95%, and 96% for PET/MRI₁; 97%, 96.5%, 97%, 96.5%, and 97% for PET/MRI₂; 97%, 96.5%, 97%, 96.5%, and 97% for PET/MRI₃ and 77%, 96%, 96%, 78.5% and 86% for MRI-DWI.

Conclusion

¹⁸F–FDG PET/MRI is superior to WB-DW-MRI in staging pediatric lymphoma patients. Neither application of contrast media nor DWI leads to a noticeable improvement of the diagnostic accuracy of PET/MRI. Thus, unenhanced PET/MRI may play a crucial role for the diagnostic work-up of pediatric lymphoma patients in the future.

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Development of standardized image interpretation for 68Ga-PSMA PET/CT to detect prostate cancer recurrent lesions

Abstract

Methods

After primary treatment, biochemical relapse (BCR) occurs in a substantial number of patients with prostate cancer (PCa). PET/CT imaging with prostate-specific membrane antigen based tracers (68Ga-PSMA) has shown promising results for BCR patients. However, a standardized image interpretation methodology has yet to be properly agreed. The aim of this study, which was promoted and funded by European Association of Nuclear Medicine (EANM), is to define standardized image interpretation criteria for 68Ga-PSMA PET/CT to detect recurrent PCa lesions in patients treated with primary curative intent therapy (radical prostatectomy or radiotherapy) who presented a biochemical recurrence. In the first phase inter-rater agreement between seven readers from seven international centers was calculated on the reading of 68Ga-PSMA PET/CT images of 49 patients with BCR. Each reader evaluated findings in five different sites of recurrence (local, loco-regional lymph nodes, distant lymph nodes, bone, and other). In the second phase the re-analysis was limited to cases with poor, slight, fair, or moderate agreement [Krippendorff's (K) alpha<0.61]. Finally, on the basis of the consensus readings, we sought to define a list of revised consensus criteria for 68Ga-PSMA PET/CT interpretation.

Results

Between-reader agreement for the presence of anomalous findings in any of the five sites was only moderate (K's alpha: 0.47). The agreement improved and became substantial when readers had to judge whether the anomalous findings were suggestive for a pathologic, uncertain, or non-pathologic image (K's alpha: 0.64). K's alpha calculations for each of the five sites of recurrence were also performed and evaluated. First Delphi round was thus conducted. A more detailed definition of the criteria was proposed by the project coordinator, which was then discussed and finally agreed by the seven readers. After the second Delphi round only four cases of disagreement still remained. These were evaluated for a final round, allowing a final agreement table to be written.

Conclusion

We hope that by developing these consensus guidelines on the interpretation of 68Ga-PSMA PET/CT, clinicians reporting these studies will be able to provide more consistent clinical reports and that within clinical trials, abnormality classifications will be harmonized, allowing more robust assessment of its diagnostic performance.

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Reply to: Predicting the outcome of peptide receptor radionuclide therapy in neuroendocrine tumors: the importance of dual-tracer imaging

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Patterns of failure after radical prostatectomy in prostate cancer – implications for radiation therapy planning after 68 Ga-PSMA-PET imaging

Abstract

Background

Salvage radiotherapy (SRT) after radical prostatectomy (RPE) and lymphadenectomy (LAE) is the appropriate radiotherapy option for patients with persistent/ recurrent prostate cancer (PC). ⁶⁸Ga-PSMA-PET imaging has been shown to accurately detect PC lesions in a primary setting as well as for local recurrence or for lymph node (LN) metastases.

Objective

In this study we evaluated the patterns of recurrence after RPE in patients with PC, putting a highlight on the differentiation between sites that would have been covered by a standard radiation therapy (RT) field in consensus after the RTOG consensus and others that would have not.

Methods and materials

Thirty-one out of 83 patients (37%) with high-risk PC were the subject of our study. Information from ⁶⁸Ga-PSMA-PET imaging was used to individualize treatment plans to include suspicious lesions as well as possibly boost sites with tracer uptake in LN or the prostate bed. For evaluation, ⁶⁸Ga-PSMA-PET-positive LN were contoured in a patient dataset with a standard lymph drainage (RTOG consensus on CTV definition of pelvic lymph nodes) radiation field depicting color-coded nodes that would have been infield or outfield of that standard lymph drainage field and thereby visualizing typical patterns of failure of a "blind" radiation therapy after RPE and LAE.

Results

Compared to negative conventional imaging (CT/MRI), lesions suspicious for PC were detected in 27/31 cases (87.1%) by ⁶⁸Ga-PSMA-PET imaging, which resulted in changes to the radiation concept. There were 16/31 patients (51.6%) that received a simultaneous integrated boost (SIB) to a subarea of the prostate bed (in only three cases this dose escalation would have been planned without the additional knowledge of ⁶⁸Ga-PSMA-PET imaging) and 18/31 (58.1%) to uncommon (namely presacral, paravesical, pararectal, preacetabular and obturatoric) LN sites. Furthermore, 14 patients (45.2%) had a changed TNM staging result by means of ⁶⁸Ga-PSMA-PET imaging.

Conclusion

Compared to conventional CT or MRI staging, ⁶⁸Ga-PSMA-PET imaging detects more PC lesions and, thus, significantly influences radiation planning in recurrent prostate cancer patients enabling individually tailored treatment.

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Monitoring early response to chemoradiotherapy with 18 F-FMISO dynamic PET in head and neck cancer

Abstract

Purpose

There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of ¹⁸F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC.

Experimental design

Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0–30 min dynamic acquisition, followed by 10 min static acquisitions starting at ∼95 min and ∼160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k ₃ and Tumor-to-Blood Ratio (TBR)), perfusion (K ₁ ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia.

Results

One hundred and thirty-five lesions in total were analyzed. TBR, k ₃ and DV decreased on early response scans, while no significant change was observed for K ₁ . The k ₃ -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k ₃ and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k ₃ indicated the presence of hypoxia.

Conclusion

Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.

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Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

Abstract

Purpose

Radium Ra 223 dichloride (radium-223, Xofigo®) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision.

Methods

An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined.

Results

The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway.

Conclusions

These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care.

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SPECT/CT and PET/CT molecular imaging in medullary thyroid carcinoma. Are we running in the right direction?

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The role of 18 F-FDG PET/CT in the detection of osteosarcoma recurrence

Abstract

Aim

The aim of this study was to investigate the diagnostic accuracy of ¹⁸F-FDG-PET/CT in osteosarcoma patients suspicious for disease recurrence after adequate surgical therapy.

Methods

Inclusion criteria were: a) adequate surgical treatment for proven osteosarcoma and documented complete remission after therapy; b) ¹⁸F-FDG-PET/CT performed during follow-up for clinical/diagnostic suspicion of relapse; c) new surgical treatment with excision of the suspected lesions; d) histological validation of ¹⁸F-FDG-PET/CT findings. Thirty-seven patients matching all inclusion criteria were retrospectively enrolled (20 men and 17 female). Primary surgical treatment consists of resection (31 cases) or amputation (six cases). ¹⁸F-FDG-PET/CT performance was assessed with a per-patient and per-site evaluation of sensitivity, specificity, accuracy, positive predicting value (PPV), and negative predicting value (NPV). The sites of relapse were classified as local, lung, lymphnodes (LNs), and distant (other skeletal segments and/or distant soft tissue). The disease-free survival (DFS) and the overall survival (OS) after 18F-FDG PET/CT were evaluated.

Results

¹⁸F-FDG-PET/CT was positive in 89.2% (33/37) of patients. Local uptake only was observed in 35.1% patients (13/37); lung uptake only in 18.9% (7/37); distant uptake only in 2.7% (1/37) case; multiple sites of uptake in 32.4% (12/37). Histology resulted positive in 92% (34/37) of patients. A total of 51 pathologic lesions were evaluated (22 local relapse, 11 lung metastasis, 10 metastatic LNs, eight distant metastatic lesions). On a per-patient analysis ¹⁸F-FDG-PET/CT showed a sensitivity, specificity, accuracy, PPV, and NPV of 91%, 75%, 89%, 97%, 50%. On a per-site analysis the performance for local relapse was 96%, 100%, 97%, 100%, 93%, while for lung relapse detection was 80%, 100%, 92%, 100%, 88%. The mean follow-up after ¹⁸F-FDG-PET/CT was 21.5 months. At the last follow-up, 19% (7/37) of patients were death with disease, 38% (14/37) were alive with disease, and 43% (16/37) had no evidence of disease. Overall survival was 90% and 75% at 24 and 60 months, respectively.

Conclusion

¹⁸F-FDG-PET/CT showed valuable results for detecting recurrence(s) in osteosarcoma patients with suspicious of relapse after treatment, particularly in the detection of local relapse and lung metastasis.

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Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence

Abstract

Purpose

PET/CT using ⁶⁸Ga-labelled prostate-specific membrane antigen PSMA-11 (HBEDD-CC) has emerged as a promising imaging method in the diagnostic evaluation of prostate cancer (PC) patients with biochemical recurrence. However, assessment of local recurrence (LR) may be limited by intense physiologic tracer accumulation in the urinary bladder on whole-body scans, normally conducted 60 min post-tracer injection (p.i.). It could be shown on early dynamic imaging studies that ⁶⁸Ga-PSMA-11 uptake in PC lesions occurs earlier than tracer accumulation in the urinary bladder. This study aims to investigate whether early static PET acquisition increases detection rate of local recurrence on ⁶⁸Ga-PSMA-11 PET/CT in comparison to PET imaging 60 min p.i..

Methods

203 consecutive PC patients with biochemical failure referred to ⁶⁸Ga-PSMA-11 PET/CT were analysed retrospectively (median prostate specific antigen (PSA) value: 1.44 ng/ml). In addition to whole-body PET/CT scans 60 min p.i., early static imaging of the pelvis was performed, starting at a median time of 283 s p.i. (range: 243–491 s). Assessment was based on visual analysis and calculation of maximum standardized uptake value (SUV_max) of pathologic lesions present in the pelvic area found on early PET imaging and on 60 min-PET scans.

Results

26 patients (12.8%) were judged positive for LR on PET scans 60 min p.i. (median SUV_max: 10.8; range: 4.7–40.9), whereas 50 patients (24.6%) revealed a lesion suggestive of LR on early PET imaging (median SUV_max: 5.9; range: 2.9–17.6), resulting in a significant rise in detection rate (p < 0.001). Equivocal findings on PET scans 60 min p.i. decreased significantly with the help of early imaging (15.8% vs. 4.5% of patients; p < 0.001). Tracer activity in the urinary bladder with a median SUV_max of 8.2 was present in 63 patients on early PET scans (31.0%). However, acquisition starting time of early PET scans differed significantly in the patient groups with and without urinary bladder activity (median starting time of 321 vs. 275 s p.i.; range: 281–491 vs. 243–311 s p.i.; p < 0.001). Median SUV_max value of lesions suggestive of LR on early images was significantly higher in comparison to gluteal muscle, inguinal vessels and seminal vesicle/anastomosis (median SUV_max: 5.9 vs. 1.9, 4.0 and 2.4, respectively).

Conclusions

Performance of early imaging in ⁶⁸Ga-PSMA-11 PET/CT in addition to whole-body scans 60 min p.i. increases the detection rate of local recurrence in PC patients with biochemical recurrence. Acquisition of early PET images should be started as early as 5 min p.i. in order to avoid disturbing tracer activity in the urinary bladder occuring at a later time point.

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Players of ‘hypoxia orchestra’ – what is the role of FMISO?

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PET and PET/CT with radiolabeled choline in prostate cancer: a critical reappraisal of 20 years of clinical studies

Abstract

We here aim to provide a comprehensive and critical review of the literature concerning the clinical applications of positron emission tomography/computed tomography (PET/CT) with radiolabeled choline in patients with prostate cancer (PCa). We will initially briefly summarize the historical context that brought to the synthesis of [¹¹C]choline, which occurred exactly 20 years ago. We have arbitrarily grouped the clinical studies in three different periods, according to the year in which they were published and according to their relation with their applications in urology, radiotherapy and oncology. Studies at initial staging and, more extensively, studies in patients with biochemical failure, as well as factors predicting positive PET/CT will be reviewed. The capability of PET/CT with radiolabeled choline to provide prognostic information on PCa-specific survival will also be examined. The last sections will be devoted to the use of radiolabeled choline for monitoring the response to androgen deprivation therapy, radiotherapy, and chemotherapy. The accuracy and the limits of the technique will be discussed according to the information available from standard validation processes, including biopsy or histology. The clinical impact of the technique will be discussed on the basis of changes induced in the management of patients and in the evaluation of the response to therapy. Current indications to PET/CT, as officially endorsed by guidelines, or as routinely performed in the clinical practice will be illustrated. Emphasis will be made on methodological factors that might have influenced the results of the studies or their interpretation. Finally, we will briefly highlight the potential role of positron emission tomography/magnetic resonance and of new radiotracers for PCa imaging.

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A new perspective for nuclear medicine: expanding the indications for PSMA targeted imaging and therapy

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Transcriptome-Wide Analyses of Human Neonatal Articular Cartilage and Human Mesenchymal Stem Cell-Derived Cartilage Provide a New Molecular Target for Evaluating Engineered Cartilage

Tissue Engineering Part A , Vol. 0, No. 0.


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Copper homeostasis networks in the bacterium Pseudomonas aeruginosa [Gene Regulation]

Bacterial copper (Cu+) homeostasis enables both precise metallation of diverse cuproproteins and control of variable metal levels. To this end, protein networks mobilize Cu+ to cellular targets with remarkable specificity. However, the understanding of these processes is rather fragmented. Here, we use genome-wide transcriptomic analysis by RNA-Seq to characterize the response of Pseudomonas aeruginosa to external 0.5 mM CuSO4, a condition that did not generate pleiotropic effects. Pre-steady (5 min) and steady state (2 h) Cu+ fluxes, resulted in distinct transcriptome landscapes. Cells quickly responded to Cu2+ stress by slowing down metabolism. This was restored once steady state was reached. Specific Cu+ homeostasis genes were strongly regulated in both conditions. Our systemwide analysis revealed induction of three Cu+ efflux systems (a P1B-ATPase, a porin and a resistance-nodulation-division (RND) system), and of a putative Cu+ binding periplasmic chaperone and the unusual presence of two cytoplasmic CopZ proteins. Both CopZ chaperones could bind Cu+ with high affinity. Importantly, novel transmembrane transporters likely mediating Cu+ influx were among those largely repressed upon Cu+ stress. Compartmental Cu+ levels appear independently controlled; the cytoplasmic Cu+ sensor CueR controls cytoplasmic chaperones and plasma membrane transporters; while CopR/S responds to periplasmic Cu+. Analysis of ΔcopR and ΔcueR mutant strains revealed a CopR regulon composed of genes involved in periplasmic Cu+ homeostasis and its putative DNA recognition sequence. In conclusion our study established a system-wide model of a network of sensors/regulators, soluble chaperones, and influx/efflux transporters that control theCu+ levels in P. aeruginosa compartments.

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An acetylation-phosphorylation switch that regulates tau aggregation propensity and function [Neurobiology]

The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD) and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau-s biophysical properties in vitro. Our findings indicate that several acetylation sites on tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. To determine the functional consequence of this HDAC6- regulated phosphorylation event, we examined tau's ability to promote microtubule assembly and found that phosphorylation of Ser-324 interferes with the normal microtubule-stabilizing function of tau. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with AD. These findings uncover a novel acetylation--phosphorylation switch at Lys- 321/Ser-324 that coordinately regulates tau polymerization and function. As the disease relevance of this finding is evident, additional studies are needed to examine the role of pSer- 324 in tau pathobiology and to determine whether therapeutically modulating this acetylation--phosphorylation switch affects disease progression in vivo.

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The glucose sensor Snf1 and the transcription factors Msn2 and Msn4 regulate transcription of the vacuolar iron importer gene CCC1 and iron resistance in yeast [Gene Regulation]

The budding yeast Saccharomyces cerevisiae stores iron in the vacuole, which is a major resistance mechanism against iron toxicity. One key protein involved in vacuolar iron storage is the iron importer Ccc1, which facilitates iron entry into the vacuole. Transcription of the CCC1 gene is largely regulated by the binding of iron-sulfur clusters to the activator domain of the transcriptional activator Yap5. Additional evidence, however suggests that Yap5-independent transcriptional activation of CCC1 also contributes to iron resistance. Here, we demonstrate that components of the signaling pathway involving the low-glucose sensor Snf1 regulate CCC1 transcription and iron resistance. We found that SNF1 deletion acts synergistically with YAP5 deletion to regulate CCC1 transcription and iron resistance. A kinase-dead mutation of Snf1 lowered iron resistance, as did deletion of SNF4, which encodes a partner protein of Snf1. Deletion of all three alternative partners of Snf1 encoded by SIT1, SIT2, and GAL83 decreased both CCC1 transcription and iron resistance. The Snf1 complex is known to activate the general stress transcription factors Msn2/Msn4. We show that Msn2 and Msn4 contribute to Snf1-mediated CCC1 transcription. Of note, SNF1 deletion in combination with MSN2 and MSN4 deletion resulted in additive effects on CCC1 transcription, suggesting that other Snf1 complex activators contribute to the regulation of CCC1 transcription. In conclusion, we show that yeast have developed multiple transcriptional mechanisms to regulate Ccc1 expression and protect yeast from high cytosolic iron toxicity.

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Modulation of the extent of structural heterogeneity in {alpha}-synuclein fibrils by the small molecule thioflavin T [Molecular Biophysics]

The transition of intrinsically disordered, monomeric α-synuclein into β-sheet-rich oligomers and fibrils is associated with multiple neurodegenerative diseases. Fibrillar aggregates possessing distinct structures that differ in their toxicity, have been observed in different pathological phenotypes. Understanding the mechanism of formation of various fibril polymorphs with differing cytotoxic effects, is essential for determining how the aggregation reaction could be modulated to favor non-toxic fibrils over toxic fibrils. In this study, two morphologically different α-synuclein fibrils, one helical and the other ribbon-like, are shown to form together. Surprisingly, a widely-used small molecule for probing aggregation reactions, thioflavin T (ThT), is found to tune the structural heterogeneity found in the fibrils. The ribbon-like fibrils formed in the presence of ThT are found to have a longer structural core than do the helical fibrils formed in the absence of ThT. The ribbon-like fibrils are also more toxic to cells. By facilitating the formation of ribbon-like fibrils over helical fibrils, ThT reduces the extent of fibril polymorphism. This study highlights the role of a small molecule such as ThT in selectively favoring the formation of a specific type of fibril, by binding to aggregates formed early on one of multiple pathways, thereby altering the structural core and external morphology of the fibrils formed.

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Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through a small GTPase ARF4 [Cell Biology]

The intestinal tract contains many commensal bacteria that modulate various physiological host functions. Dysbiosis of commensal bacteria triggers dysfunction of the intestinal epithelial barrier, leading to the induction or aggravation of intestinal inflammation. To elucidate whether miRNA plays a role in the commensal microbiome-dependent intestinal epithelial barrier regulation, here we compared transcripts in intestinal epithelial cells (IECs) from conventional (CV) and germ-free (GF) mice and found that commensal bacteria induced the expression of miR-21-5p in IECs. miR-21-5p increased intestinal epithelial permeability and upregulated ADP ribosylation factor 4 (ARF4), a small GTPase, in the IEC line Caco-2. We also found that ARF4 expression was upregulated upon suppression of phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4), which are known miR-21-5p targets, by RNAi. Furthermore, ARF4 expression in the epithelial cells of the large intestine was higher in CV mice than in GF mice. ARF4 suppression in the IEC line increased the expression of tight junction proteins and decreased intestinal epithelial permeability. These results indicate that commensal microbiome-dependent miR-21-5p expression in IECs regulates intestinal epithelial permeability via ARF4, which may therefore represent a target for preventing or managing dysfunction of the intestinal epithelial barrier.

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Ascorbate peroxidase proximity labeling coupled with biochemical fractionation identifies promoters of endoplasmic reticulum mitochondrial contacts [Neurobiology]

To maintain cellular homeostasis, subcellular organelles communicate with each other and form physical and functional networks through membrane contact sites (MCS) coupled by protein tethers. In particular, endoplasmic reticulum (ER)-mitochondria contacts (EMC) regulate diverse cellular activities such as metabolite exchange (Ca2+ and lipids), intracellular signaling, apoptosis and autophagy. The significance of EMCs have been highlighted by reports indicating that EMC dysregulation is linked to neurodegenerative diseases. Therefore, obtaining a better understanding of the physical and functional components of EMCs should provide new insights into the pathogenesis of several neurodegenerative diseases. Here we applied engineered ascorbate peroxidase (APEX) to map the proteome at EMCs in live HEK293 cells. APEX was targeted to the outer mitochondrial membrane, and proximity-labeled proteins were analyzed by stable isotope labeling with amino acids in culture (SILAC)-LC/MS-MS. We further refined the specificity of the proteins identified by combining biochemical subcellular fractionation to the protein isolation method. We identified 405 proteins with a 2.0-fold cut-off ratio (log base 2) in SILAC quantification from replicate experiments. We performed validation screening with a Split-Rluc8 complementation assay that identified RETICULON1A (RTN1A), an ER-shaping protein localized to EMCs as an EMC promoter. Proximity mapping augmented with biochemical fractionation and additional validation methods reported here could be useful to discover other components of EMCs, identify mitochondrial contacts with other organelles, and further unravel their communication.

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Systematic review: probiotics for functional constipation in children

Abstract

We updated our 2010 systematic review on the efficacy of probiotics in the treatment of constipation in children. The MEDLINE, EMBASE, and Cochrane Library databases; clinical trial registries; and reference lists of included studies were searched to February 2017 for randomized controlled trials (RCTs) performed in children, with no language restriction. The primary outcome measure was treatment success, as defined by the investigators. We included seven RCTs with a total of 515 participants. Included trials were heterogeneous with respect to study population, probiotic strains, dosages, study duration, and follow-up. Pooled results of two RCTs showed no significant difference between the Lactobacillus rhamnosus casei Lcr35 and placebo groups with respect to treatment success. Other probiotics were studied in single trials only. There was no significant difference between the probiotic and control groups with respect to treatment success. While some probiotic strains showed some effects on defecation frequency, none of the probiotics had beneficial effects on frequency of fecal incontinence or frequency of abdominal pain. Adverse events were rare and not serious.

Conclusion: Limited evidence does not support the use of any of currently evaluated probiotics in the treatment of functional constipation in children.

What is Known: • Conventional treatment for functional constipation in children does not always provide satisfying improvement. • Probiotics have been suggested as potential treatment modalities for this condition.

What is New: • Probiotics are ineffective for the management of functional constipation in children in terms of treatment success, frequency of fecal incontinence, and frequency of abdominal pain.

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Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers

Summary

Background The prognosis of patients with metastatic carcinoma of the biliary tract (mBTC) is poor and a systemic therapy with gemcitabine and platinum-based is the gold standard. The addition of bevacizumab to the chemotherapy might increase patients' survival. Our aim was to assess and compare the efficacy of GEMOX (gemcitabine and oxaliplatin regimen) plus bevacizumab to GEMOX alone in mBTC. Methods Patients with mBTC who received the GEMOX-bevacizumab (n = 32; Group A) or GEMOX (n = 25; Group B) regimen as first-line treatment were compared. Treatment was repeated every two weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was the progression-free survival (PFS). Results A quarter of patients (8/32) from Group A and a fifth of patients (13/25) from Group B had an objective response. The median PFS was 6.48 months and 3.72 months in Group A and B, respectively (p = 0.049). The median OS was 11.31 months and 10.34 months in Group A and B, respectively. Grade 3/4 sepsis was identified in 9.4% and 12% in Group A and B, respectively, (p = 0.64). Conclusion In mBTC, the addition of bevacizumab to GEMOX increased the progression-free survival and was associated with manageable toxicity. These data pave the way for further evaluation of antiangiogenic agents in mBTC.

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Point-of-care ultrasound in cardiopulmonary resuscitation: a concise review

Abstract

Point-of-care ultrasound (POCUS) is a widely used tool in critical care areas, allowing for the performance of accurate diagnoses and thus enhancing the decision-making process. Every major organ or system can be safely evaluated with POCUS. In that respect, the utility of POCUS in cardiac arrest is gaining interest. In this article, we will review the actual role of ultrasound in cardiac arrest and the main POCUS protocols focused to this scenario as well as discuss the potential role of POCUS in monitoring the efficacy of the chest compressions.

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Ramona Singer: Bobby Zarin Was 'in Great Spirits' When I Visited Him at Hospital - Us Weekly

Us Weekly

Ramona Singer: Bobby Zarin Was 'in Great Spirits' When I Visited Him at Hospital Us Weekly Singer, 60, who attended Jill Zarin's 5th Annual Luxury Luncheon (which benefits thyroid cancer research) in Southampton, New York that day revealed that the Zarin Fabrics entrepreneur is keeping a positive attitude despite his challenging health issues. Jill Zarin and Ramona Singer Have Ended Their Beef Amid Bobby Zarin's Cancer BattleBravo (blog) 'Real Housewives' Fight Back Against Thyroid Cancer At Luxury LuncheonPatch.com Ramona Singer Spills the Secret to Her New Romance: 'He Makes Me Calmer'PEOPLE.com BuddyTV (blog) -AllaboutTRH.com (blog) -The Inquisitr all 12 news articles »

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Signs of Alzheimer’s found in chimpanzees for the first time

Our closest evolutionary relatives develop Alzheimer's plaques and tangles too but don't necessarily get dementia - a finding that may need to new treatments

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Effect of mechanical loading on the metabolic activity of cells in the temporomandibular joint: a systematic review

Abstract

Objectives

The purpose of this systematic review was to elucidate how different modalities and intensities of mechanical loading affect the metabolic activity of cells within the fibro-cartilage of the temporomandibular joint (TMJ).

Materials and methods

A systematic review was conducted according to PRISMA guidelines using PubMed, Embase, and Web of Science databases. The articles were selected following a priori formulated inclusion criteria (viz., in vivo and in vitro studies, mechanical loading experiments on TMJ, and the response of the TMJ).

A total of 254 records were identified. After removal of duplicates, 234 records were screened by assessing eligibility criteria for inclusion. Forty-nine articles were selected for full-text assessment. Of those, 23 were excluded because they presented high risk of bias or were reviews. Twenty-six experimental studies were included in this systematic review: 15 in vivo studies and 11 in vitro ones.

Conclusion

The studies showed that dynamic mechanical loading is an important stimulus for mandibular growth and for the homeostasis of TMJ cartilage. When this loading is applied at a low intensity, it prevents breakdown of inflamed cartilage. Yet, frequent overloading at excessive levels induces accelerated cell death and an increased cartilage degradation.

Clinical Significance

Knowledge about the way temporomandibular joint (TMJ) fibrocartilage responds to different types and intensities of mechanical loading is important to improve existing treatment protocols of degenerative joint disease of the TMJ, and also to better understand the regenerative pathway of this particular type of cartilage.

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Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells

Abstract

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients.

Here we report the biochemical characterization of 7 novel pathogenic variants (c.98T > C, c.195delC, c.229G > C, c.545C > G, c.674A > G, c.852T > A, and c.1274A > G), which were found when sequencing a cohort of 31 German MLD families. For that purpose, the ARSA cDNAs carrying the respective mutations inserted by site-directed mutagenesis were cloned into a MigR1 (MSCV, IRES, GFP, retrovirus-1) vector. The constructs were overexpressed using retroviral gene transfer in immortalized, human multipotent mesenchymal stromal cells (MSC) prepared from a patient deficient in ARSA activity (late infantile MLD). In this novel ARSA^−/− cell system, the seven ARSA mutants showed arylsulfatase A activity of less than 10% when compared to wildtype, which is evidence for the pathogenicity of all 7 variants.

In conclusion, the system of ARSA^−/− immortalized MSC turned out to be a helpful novel tool for the biochemical characterization of ARSA variants.

This article is protected by copyright. All rights reserved

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Normal and malignant cells exhibit differential responses to calcium electroporation

Calcium electroporation may offer a simple general tool for anticancer therapy. Transient permeabilization of cancer cell membranes created by applying short, high-voltage pulses in tumors enables high calcium influxes that trigger cell death. In this study, we compared the relative sensitivity of different human tumor models and normal tissues to calcium electroporation. Plasma membrane Ca2+-ATPase (PMCA) protein expression was confirmed in vitro in all cancer cell lines and normal primary dermal fibroblasts studied. In all tumor types tested in vivo, calcium electroporation effectively induced necrosis, with a range of sensitivities observed (36-88%) 2 days after treatment. Necrosis was induced using calcium concentrations of 100-500 mM and injection volumes 20-80% of tumor volume. Notably, only limited effects were seen in normal tissue. Calcium content increased >7-fold in tumor and skin tissue after calcium electroporation but decreased in skin tissue 4 hr after treatment to levels comparable to untreated controls, whereas calcium content endured at high levels in tumor tissue. Mechanistic experiments in vitro indicated that calcium influx was similar in fibroblasts and cancer cells. However, we observed decreased PMCA expression in cancer cells compared to fibroblasts offering a potential explanation for the different calcium content in tumor cells versus normal tissues. Overall, our results suggest that calcium electroporation can elicit a rapid and selective necrosis of solid tumors, with limited deleterious effects on surrounding normal tissues.

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FBW7 loss promotes chromosomal instability and tumorigenesis via Cyclin E1/CDK2-mediated phosphorylation of CENP-A

The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.

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Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors

Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GIST eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state. Using phospho-RTK and immunoblot assays, we demonstrate activation of KIT and insulin receptor (IR) in imatinib-resistant GIST cell lines (GIST430 and GIST48) and biopsies with acquisition of KIT secondary mutations, but not in imatinib-sensitive GIST cells (GIST882 and GIST-T1). Treatment with linsitinib, a specific IR inhibitor, inhibited IR and downstream intermediates AKT, MAPK, and S6 in GIST430 and GIST48, but not in GIST882, exerting minimal effect on KIT phosphorylation in these cell lines. Additive effects showing increased apoptosis, anti-proliferative effects, cell cycle arrest, and decreased pAKT and pS6 expression, tumor growth, migration, and invasiveness were observed in imatinib-resistant GIST cells with IR activation after coordinated inhibition of IR and KIT by linsitinib (or IR shRNA) and imatinib, respectively, compared to either intervention alone. IGF2 overexpression was responsible for IR activation in imatinib-resistant GIST cells, whereas IR activation did not result from IR amplification, IR mutation, or KIT phosphorylation. Our findings suggest that combinatorial inhibition of IR and KIT warrants clinical evaluation as a novel therapeutic strategy in imatinib-resistant GISTs.

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Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression

Gastric adenocarcinoma (GA) is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases which are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of GA tumorigenesis based on KrasG12D expression plus inactivation of E-cadherin (Cdh1) and p53 in the gastric parietal cell lineage. Intestinal and diffuse gastric tumors arise rapidly in this model, which displays a median survival of 76 days. Tumors occur throughout the stomach with metastases documented in lymph nodes, lung and liver. Mice otherwise identical but retaining one wild-type Cdh1 allele exhibited longer survival with only 20% penetrance of invasive tumors and no apparent lung or liver metastases. Notably, increased RAS activity and downstream MAPK signaling was observed in stomachs only when E-cadherin was absent. This model offers a valuable tool to investigate GA subtypes where RAS/MAPK pathway activation and E-cadherin attenuation are common.

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Survival of head and neck cancer cells relies upon LZK kinase-mediated stabilization of mutant p53

Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral and nasal cavity, larynx, and pharynx and accounts for ~350,000 deaths/year worldwide. Smoking-related HNSCC is associated with few targetable mutations but is defined by frequent copy number alteration, the most common of which is gain at 3q. Critical 3q target genes have not been conclusively determined for HNSCC. Here we present data indicating that MAP3K13 (encoding LZK) is an amplified driver gene in HNSCC. Copy number gain at 3q resulted in increased MAP3K13 mRNA in HNSCC tumor samples and cell lines. Silencing LZK reduced cell viability and proliferation of HNSCC cells with 3q gain but not control cell lines. Inducible silencing of LZK caused near complete loss of colony-forming ability in cells harboring 3q gain. These results were validated in vivo by evidence that LZK silencing was sufficient to reduce tumor growth in a xenograft model of HNSCC. Our results establish LZK as critical for maintaining expression of mutant stabilized p53.

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Blastic plasmacytoid dendritic cell neoplasm: a pathological illustration of two clinical cases

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Signs of Alzheimer’s found in chimpanzees for the first time

Our closest evolutionary relatives develop Alzheimer's plaques and tangles too but don't necessarily get dementia - a finding that may need to new treatments

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Cryogenic Fab-on-a-Chip Sticks the Landing

ACS Nano

DOI: 10.1021/acsnano.7b01808

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Polymorphic light eruption and IL-1 family members: any difference with allergic contact dermatitis?

Photochem. Photobiol. Sci., 2017, Accepted Manuscript
DOI: 10.1039/C7PP00142H, Paper

Serena Lembo, Giuseppina Caiazzo, Nicola Balato, Giuseppe Monfrecola, Vijaykumar Patra, Peter Wolf, Anna Balato
Polymorphic light eruption (PLE) is described as a delayed-type hypersensitivity reaction (DTHR) toward a de novo light-induced antigen, yet to be identified. In effect, the inflammatory pathway of PLE and...
The content of this RSS Feed (c) The Royal Society of Chemistry

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Prostate cancer incidence and mortality in Portugal: trends, projections and regional differences

There is a large geographical variability in prostate cancer incidence and mortality trends, mostly because of heterogeneity in control efforts across regions. We aimed to describe the time trends in prostate cancer incidence and mortality in Portugal, overall and by region, and to estimate the number of incident cases and deaths in 2020. The number of cases and incidence rates in 1998–2009 were collected from the Regional Cancer Registries. The number of deaths and mortality rates were obtained from the WHO mortality database (1988–2003 and 2007–2013) and Statistics Portugal (2004–2006; 1991–2013 by region). JoinPoint analyses were used to identify significant changes in trends in age-standardized incidence and mortality rates. Incidence and mortality predictions for 2020 were performed using Poisson regression models and population projections provided by Statistics Portugal. In Portugal, prostate cancer incidence has been increasing since 1998 (1.8%/year), with the exception of the North Region, with a decrease since 2006 (−3.2%/year). An overall mortality decline has been observed since 1997 (−2.2%/year), although there were two patterns of mortality variation at the regional level: one with an inflection point or significant variation in the rates and the other without significant variation. If these trends are maintained, ∼8600 incident cases and 1700 deaths may be expected to occur in Portugal in 2020. Despite the overall increasing incidence and decreasing mortality, there is a large heterogeneity across regions. Future studies should address regional differences in the trends of prostate specific antigen screening and in the effective management of prostate cancer.

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Parental alcohol consumption and risk of leukemia in the offspring: a systematic review and meta-analysis

Parental alcohol consumption before and during pregnancy has been linked to adverse outcomes in the offspring including leukemogenesis. We, therefore, aimed to systematically assess and quantitatively synthesize published data on the association of paternal consumption during preconception and maternal consumption during pregnancy with leukemia risk in childhood (0–14 years). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed (until February 2016) and the reference lists of the relevant studies. Observational studies examining the association between parental alcohol consumption and childhood leukemia were considered eligible. Data extracted from 39 case–control studies (over 16 000 leukemia cases and 30 000 controls) were pooled and summary-effect estimates were calculated. Subgroup analyses were carried out by main acute leukemia type [lymphoblastic or myeloid), cytogenetics/genetic polymorphisms, and specific alcohol beverages. We found a statistically significant dose–response association of any level of maternal alcohol consumption compared with nondrinking during pregnancy exclusively with acute myeloid leukemia (AML) [odds ratio (OR)moderate consumption: 1.64, 95% confidence intervals (CIs): 1.23–2.17 and ORhigh consumption: 2.36, 95% CI: 1.60–3.49]. In contrast, no association of paternal preconception consumption with any leukemia type was noted. In beverage-specific analyses, only a positive association of maternal wine drinking with childhood AML was found, which was more pronounced in analyses including only studies on infant leukemia (ORwine: 2.12, 95% CI: 1.16–3.90). The largest ever meta-analysis shows a sizeable, statistically significant dose–response association of maternal alcohol consumption during index pregnancy with AML risk. Future research exploring the role of genetic polymorphisms is anticipated to shed light on the underlying pathophysiology.

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Association between Mediterranean diet and head and neck cancer: results of a large case–control study in Italy

The Mediterranean diet (MD) is a known protective factor for head and neck cancer (HNC); however, there is still a lack of studies investigating this association by HNC subsite. The aim of the present study was therefore to evaluate the association between adherence to MD and HNC overall and by cancer subsite, as well as the effect of the individual food components on HNC risk. A case–control study was carried out at the Gemelli Hospital of Rome (Italy). A total of 500 HNC cases and 433 controls were interviewed. Dietary intake was assessed through a validated food frequency questionnaire that collected information on over 25 food items. Odds ratios (ORs) and 95% confidence intervals (CI) of HNC were calculated using a multiple logistic regression model. We found a reduced risk of both oral cavity and pharynx cancer (OR=0.61; CI: 0.54–0.70) and larynx cancer (OR=0.64; CI: 0.56–0.73) with increasing adherence to MD. We also found a high consumption of fruit, vegetables, and legumes to be significantly associated with a lower risk of larynx as well as oral cavity and pharynx cancers. Our study showed that adherence to MD acts protectively against HNC overall and by cancer subsite.

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False-negative rate cannot be reduced by lowering the haemoglobin concentration cut-off in colorectal cancer screening using faecal immunochemical test

The aim of this study was to analyse false-negative (FN) results of the faecal immunochemical test (FIT) and its determinants in a colorectal cancer screening programme in Catalonia. We carried out a cross-sectional study among 218 screenees with a negative FIT result who agreed to undergo a colonoscopy. A false-negative result was defined as the detection, at colonoscopy, of intermediate/high-risk polyps or colorectal cancer in a patient with a previous negative FIT (

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The potential contribution of dietary factors to breast cancer prevention

Breast cancer (BC), the leading cancer in women, is increasing in prevalence worldwide, concurrent with western metabolic epidemics, that is, obesity, metabolic syndrome, and diabetes, and shares major risk factors with these diseases. The corresponding potential for nutritional contributions toward BC prevention is reviewed and related to critical stages in the life cycle and their implications for carcinogenic and pathometabolic trajectories. BC initiation potentially involves diet-related pro-oxidative, inflammatory, and procarcinogenic processes, that interact through combined lipid/fatty acid peroxidation, estrogen metabolism, and related DNA-adduct/depurination/mutation formation. The pathometabolic trajectory is affected by high estrogen, insulin, and growth factor cascades and resultant accelerated proliferation/progression. Anthropometric risk factors – high birth weight, adult tallness, adiposity/BMI, and weight gain – are often reflective of these trends. A sex-based nutritional approach targets women's specific risk in western obesogenic environments, associated with increasing fatness, estrogen metabolism, n-6 : n-3 polyunsaturated fatty acid ratio, and n-6 polyunsaturated fatty acid conversion to proinflammatory/carcinogenic eicosanoids, and effects of timing of life events, for example, ages at menarche, full-term pregnancy, and menopause. Recent large-scale studies have confirmed the effectiveness of the evidence-based recommendations against BC risk, emphasizing low-energy density diets, highly nutritious plant-based regimes, physical activity, and body/abdominal adiposity management. Better understanding of dietary inter-relationships with BC, as applied to food intake, selection, combination, and processing/preparation, and recommended patterns, for example, Mediterranean, DASH, plant-based, low energy density, and low glycemic load, with high nutrient/phytonutrient density, would increase public motivation and authoritative support for early/timely prevention, optimally merging with other dietary/health goals, for lifelong BC prevention.

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