Characterization of radon levels in soil and groundwater in the North Maladeta Fault area (Central Pyrenees) and their effects on indoor radon concentration in a thermal spa

Publication date: September 2018
Source:Journal of Environmental Radioactivity, Volume 189
Author(s): V. Moreno, J. Bach, M. Zarroca, Ll. Font, C. Roqué, R. Linares
Radon levels in the soil and groundwater in the North Maladeta Fault area (located in the Aran Valley sector, Central Pyrenees) are analysed from both geological and radiation protection perspectives. This area is characterized by the presence of two important normal faults: the North Maladeta fault (NMF) and the Tredós Fault (TF). Two primary aspects make this study interesting: (i) the NMF shows geomorphic evidence of neotectonic activity and (ii) the presence of a thermal spa, Banhs de Tredós, which exploits one of the several natural springs of the area and needs to be evaluated for radiation dosing from radon according to the European regulation on basic safety standards for protection against ionizing radiation. The average soil radon and thoron concentrations along a profile perpendicular to the two normal faults — 22 ± 3 kBq·m⁻³ and 34 ± 3 kBq·m⁻³, respectively — are not high and can be compared to the radionuclide content of the granitic rocks of the area, 25 ± 4 Bq·kg⁻¹ for ²²⁶Ra and 38 ± 2 Bq·kg⁻¹ for ²²⁴Ra. However, the hypothesis that the normal faults are still active is supported by the presence of anomalies in both the soil radon and thoron levels that are unlikely to be of local origin together with the presence of similar anomalies in CO2 fluxes and the fact that the highest groundwater radon values are located close to the normal faults. Additionally, groundwater ²²²Rn data have complemented the hydrochemistry data, enabling researchers to better distinguish between water pathways in the granitic and non-granitic aquifers. Indoor radon levels in the spa vary within a wide range, [7–1664] Bq·m⁻³ because the groundwater used in the treatment rooms is the primary source of radon in the air. Tap water radon levels inside the spa present an average value of 50 ± 8 kBq·m⁻³, which does not exceed the level stipulated by the Spanish Nuclear Safety Council (CSN) of 100 kBq·m⁻³ for water used for human consumption. This finding implies that even relatively low radon concentration values in water can constitute a relevant indoor radon source when the transfer from water to indoor air is efficient. The estimated effective dose range of values for a spa worker due to radon inhalation is [1–9] mSv·y⁻¹. The use of annual averaged radon concentration values may significantly underestimate the dose in these situations; therefore, a detailed dynamic study must be performed by considering the time that the workers spend in the spa.



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Comparison between the efficacy of microneedling combined with 5-fluorouracil vs microneedling with tacrolimus in the treatment of vitiligo

Summary

Background

Several treatment modalities had been used for the treatment of vitiligo, but the optimal treatment has not yet been identified.

Objectives

To study the efficacy of microneedling with 5-flurouracil vs its efficacy with tacrolimus in the treatment of vitiligo.

Patients and methods

Twenty-five patients with vitiligo were subjected to microneedling of 2 patches of vitiligo with dermapen, then application of 5-fluorouracil to 1 patch and tacrolimus on the other patch. This procedure was repeated every 2 weeks for every patient for maximum 6 months (12 sessions). The patients were followed up for 3 months after the last session.

Results

The overall repigmentation was significantly higher in 5-fluorouracil-treated patches compared with tacrolimus. Excellent improvement occurred in 48% of 5- flurouracil-treated patches while only in 16% of tacrolimus-treated patches. In the acral parts, 40% of the patches treated with 5-fluorouracil achieved excellent improvement (repigmentation >75%), while no patch in the acral parts achieved excellent improvement with tacrolimus. However, there was significant difference between the 2 drugs,regarding inflammation, ulceration, and hyperpigmentation which occurred with 5-fluorouracil.

Conclusion

Microneedling combined with 5-fluorouracil or tacrolimus is safe and effective treatment of vitiligo. However, 5-fluorouracil achieved a greater percentage of repigmentation than tacrolimus particularly in the acral parts.

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The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration

Abstract

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

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Targeting mRNA Decapping in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Akihide Yoshimi, Omar Abdel-Wahab
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.

Teaser

In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.


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ORY-1001: Overcoming the Differentiation Block in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Prithviraj Bose, Marina Y. Konopleva
In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001—an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)—in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.

Teaser

In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001—an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)—in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.


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A Non-canonical Polycomb Dependency in Synovial Sarcoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Joshua J. Waterfall, Paul S. Meltzer
Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.

Teaser

Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.


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Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanya Schild, Vivien Low, John Blenis, Ana P. Gomes
Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.



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PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Mami Morita, Taku Sato, Miyuki Nomura, Yoshimi Sakamoto, Yui Inoue, Ryota Tanaka, Shigemi Ito, Koreyuki Kurosawa, Kazunori Yamaguchi, Yuki Sugiura, Hiroshi Takizaki, Yoji Yamashita, Ryuichi Katakura, Ikuro Sato, Masaaki Kawai, Yoshinori Okada, Hitomi Watanabe, Gen Kondoh, Shoko Matsumoto, Ayako Kishimoto, Miki Obata, Masaki Matsumoto, Tatsuro Fukuhara, Hozumi Motohashi, Makoto Suematsu, Masaaki Komatsu, Keiichi I. Nakayama, Toshio Watanabe, Tomoyoshi Soga, Hiroshi Shima, Makoto Maemondo, Nobuhiro Tanuma
Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS^G12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Graphical abstract

Teaser

The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.


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Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Annamarie E. Allen, Jason W. Locasale
Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.

Teaser

Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.


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BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P. Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A. Yap, Maureen Hattersley, Mark J. O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B. Mills
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple in vivo models.

Graphical abstract

Teaser

Sun et al. show that inhibition of BRD4 induces homologous recombination deficiency, through depletion of CtBP, in cells across multiple tumor types and sensitizes them to PARP inhibition. Thus, inhibition of BRD4 reverses resistance to PARP inhibitors and expands the potential use of PARP inhibitors.


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Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanmoy Mondal, Prasanna Kumar Juvvuna, Agnete Kirkeby, Sanhita Mitra, Subazini Thankaswamy Kosalai, Larissa Traxler, Falk Hertwig, Sara Wernig-Zorc, Caroline Miranda, Lily Deland, Ruth Volland, Christoph Bartenhagen, Deniz Bartsch, Sashidhar Bandaru, Anne Engesser, Santhilal Subhash, Tommy Martinsson, Helena Carén, Levent M. Akyürek, Leo Kurian, Meena Kanduri, Maite Huarte, Per Kogner, Matthias Fischer, Chandrasekhar Kanduri
Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

Graphical abstract

Teaser

Mondal et al. show a sense/antisense lncRNA pair expressed from the neuroblastoma (NB) risk-associated 6p22.3 locus is important for retinoic acid-induced NB differentiation gene-regulatory network by controlling CHD7 stability via modulating the cellular localization of the ubiquitin specific protease USP36.


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NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Alexandra Garancher, Charles Y. Lin, Morgane Morabito, Wilfrid Richer, Nathalie Rocques, Magalie Larcher, Laure Bihannic, Kyle Smith, Catherine Miquel, Sophie Leboucher, Nirmitha I. Herath, Fanny Dupuy, Pascale Varlet, Christine Haberler, Christine Walczak, Nadine El Tayara, Andreas Volk, Stéphanie Puget, François Doz, Olivier Delattre, Sabine Druillennec, Olivier Ayrault, Robert J. Wechsler-Reya, Alain Eychène, Franck Bourdeaut, Paul A. Northcott, Celio Pouponnot
Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

Graphical abstract

Teaser

Garancher et al. show that NRL and CRX are master transcriptional regulators of a photoreceptor-specific differentiation program critical for group 3 medulloblastoma (MB) maintenance. They identify BCL-XL as a key NRL target and provide evidence supporting anti-BCL therapy as a strategy for some MB patients.


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Systematic Functional Annotation of Somatic Mutations in Cancer

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M. Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P. Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R. Shaw, Funda Meric-Bernstam, Kenneth L. Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B. Mills
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

Graphical abstract

Teaser

Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.


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Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Yuying Liu, Xiaoyu Liang, Wenqian Dong, Yi Fang, Jiadi Lv, Tianzhen Zhang, Roland Fiskesund, Jing Xie, Jinyan Liu, Xiaonan Yin, Xun Jin, Degao Chen, Ke Tang, Jingwei Ma, Huafeng Zhang, Jing Yu, Jun Yan, Huaping Liang, Siqi Mo, Feiran Cheng, Yabo Zhou, Haizeng Zhang, Jing Wang, Jingnan Li, Yang Chen, Bing Cui, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8⁺ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8⁺ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8⁺ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

Teaser

Liu et al. find that tumor-repopulating cells (TRCs) regulate PD-1 expression in CD8⁺ T cells. TRCs secrete kynurenine that is taken up by T cells and activates AhR, which directly regulates PD-1 expression. Blockade of this pathway enhances adoptive T cell therapy efficacy in a mouse melanoma model.


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Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Jaclyn Andricovich, Stephanie Perkail, Yan Kai, Nicole Casasanta, Weiqun Peng, Alexandros Tzatsos
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

Graphical abstract

Teaser

Andricovich et al. show that KDM6A loss, via aberrant activation of super-enhancers regulating several oncogenes, induces squamous-like, metastatic pancreatic cancer in females. In males, both KDM6A and UTY loss is required to induce squamous-like tumors. Importantly, KDM6A-deficient pancreatic cancer is sensitive to BET inhibitors.


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Accelerated long-term forgetting in resected and seizure-free temporal lobe epilepsy patients

Publication date: Available online 12 March 2018
Source:Cortex
Author(s): M. Visser, C. Forn Frias, A. Gómez-Ibáñez, P. Rosell-Negre, V. Villanueva Haba, C. Ávila
Episodic memory impairments caused by temporal lobe epilepsy (TLE) are well documented in the literature. Standard clinical episodic memory tests typically include a 30-minute delayed recall test. However, in the past decade, it has become apparent that this standard test does not capture the full range of memory problems in TLE patients. Some patients perform well on a standard 30-minute delayed recall test, but show Accelerated Long-term Forgetting (ALF) after 24 hours. Although ALF has been investigated in patients with different types of epilepsy, current research on resected TLE patients is missing. In the present study, resected TLE patients were compared to a control group matched on initial learning. They showed normal performance on verbal recall after 30 minutes, but impairments became apparent after one week. Moreover, the significant interaction between participant group and memory test delay demonstrated that the patients indeed showed an acceleration in forgetting. Furthermore, ALF was present in both left and right resected TLE patients, which contradicts the presence of material-specific hemispheric differences in ALF. In addition, ALF was observed in seizure-free resected TLE patients, thereby demonstrating that this factor is not crucial for long-term memory deficits. The outcome shows that clinicians are likely to underestimate memory deficits in resected TLE patients and, therefore, advocates for the inclusion of ALF tests in standard clinical batteries for both pre- and post-surgery testing sessions.



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Association of post-traumatic stress symptom severity with Health-related Quality of Life and self-reported functioning across 12-months after Severe Traumatic Brain Injury

Publication date: Available online 12 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Colin M. Bosma, Nashwa Mansoor, Chiara S. Haller
ObjectiveThe present study investigated the relationship between Post-traumatic stress (PTS) symptom severity and Health-related Quality of Life (HRQoL) after severe Traumatic Brain Injury (TBI).DesignLongitudinal prospective multi-center, cohort study on severe TBI in Switzerland (2007-2011). Injury severity was determined using the Abbreviated Injury Score of the Head region (HAIS), following clinical assessment and initial computed tomography (CT).SettingBaseline data was gathered at time/location of the accident. Longitudinal assessments were done at 3, 6, and 12 months post-injury at the hospital, the rehabilitation unit, and/or the patients living facility.ParticipantsA total of 109 patients with severe TBI were included in the analyses.InterventionsNot applicable.Main Outcome Measurea) HRQoL (SF-12, physical and mental component scales, respectively), b) Self-reported emotional, cognitive, and interpersonal functioning (Patient Competency Rating Scale for Neuro-Rehabilitation [PCRS-NR]).ResultsMultilevel models for patients age >50 and ≤50 respectively, revealed significant negative associations between PTS symptom severity and interpersonal functioning (p≤50 = .002; p>50 = <.001). Among patients ≤ 50 years, PTS symptom severity was significantly associated with total functioning (p = .001) and emotional functioning (p = .0006). Among all patients, PTS symptom severity was significantly associated with cognitive functioning (p = <.001) and mental HRQoL (p = .01).ConclusionFindings indicate that PTS symptoms after severe TBI are negatively associated with HRQoL and emotional, cognitive, and interpersonal functioning.



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Rehabilitation utilization for falls among community-dwelling older adults in the United States in the National Health and Aging Trends Study

Publication date: Available online 12 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Briana L. Moreland, Laura L. Durbin, Judith D. Kasper, Thelma J. Mielenz
ObjectivesTo determine the characteristics of community-dwelling older adults receiving fall-related rehabilitation. Injurious falls cost billions of dollars each year in the United States and these costs are expected to rise. Fall-related rehabilitation can presumably decrease this burden. More needs to be known about the characteristics of older adults utilizing fall-related rehabilitation services.DesignCross-sectional analysis of the fifth round (2015) of the National Health and Aging Trends Study (NHATS). Fall-related rehabilitation utilization was analyzed using weighted multinomial logistic regression with standard errors adjusted for the sample design.SettingIn-person interviews of a nationally representative sample of community-dwelling older adults.Participants7,062 Medicare beneficiaries from NHATS.InterventionsNot ApplicableMain Outcomes MeasuresRehabilitation utilization categorized into fall-related rehabilitation, other rehabilitation, or no rehabilitation.ResultsFall status (single fall OR=2.96, CI: 1.52, 5.77; recurrent falls OR=14.21, CI: 7.45, 27.10), fear of falling (OR=3.11, CI: 1.90, 5.08), poor Short Physical Performance Battery scores (score 0 OR=6.62, CI: 3.31, 13.24; score 1-4 OR=4.65, CI:2.23, 9.68) and hip fracture (OR=3.24 CI: 1.46, 7.20) were all associated with receiving fall-related rehabilitation. Lower education level (less than high school diploma compared to 4-year college degree OR=0.21, CI: 0.11, 0.40) and Hispanic ethnicity (OR=0.37, CI: 0.15, 0.87) were associated with not receiving fall-related rehabilitation.ConclusionHispanic older adults and older adults who are less educated are less likely to receive fall related rehabilitation. Recurrent fallers followed by those who fell once in the past year were more likely to receive fall related rehabilitation than are older adults who have not had a fall in the past year.



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Do the key prognostic factors for non-specific neck pain have moderation effects? – A study protocol

Publication date: Available online 12 March 2018
Source:Medical Hypotheses
Author(s): Arun Prasad Balasundaram, Hilde Stendal Robinson, Nina Køpke Vøllestad
Neck pain is one of the common musculoskeletal conditions prevalent in the general population in Norway. Patients with neck pain, seek treatment from different health professionals such as general practitioners, physiotherapists, chiropractors and alternative medicine practitioners. The interventions for neck pain are typically provided in a primary care or specialised healthcare setting depending on the general practitioners' referral patterns. Clinicians are interested to know the various prognostic factors that can explain the recovery from neck pain. In order to know this, studies have explored and reported on a range of prognostic factors that contribute to the outcomes in patients with neck pain. This information is currently available only for neck pain following whiplash injury that has a traumatic origin. There is limited information on the role of prognostic factors specifically for non-specific neck pain without a traumatic episode. Moreover, there is a lack of data on whether there are interactions (moderation effects) between the prognostic factors. Therefore, we propose a hypothesis to elucidate whether the same set of prognostic factors found in neck pain associated with whiplash injuries are also identified in patients with neck pain without trauma. Additionally, we hypothesize that the association between a prognostic factor and the outcome variable (s) would be dependent on the third variable, thereby confirming the moderation effects. Clinicians could make informed decisions in the clinical management of neck pain with the knowledge of prognostic factors that explain the outcomes. It could also be used for the development of new interventions or for modifying the existing ones.



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Targeting MDSCs and PD-L1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

Publication date: Available online 12 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jie Lan, Rui Li, Li-Mei Yin, Lei Deng, Jun Gui, Bao-Qing Chen, Lin Zhou, Mao-Bing Men, Qiao-Rong Huang, Xian-Ming Mo, Yu-Quan Wei, Bo Lu, Adam Dicker, Jian-Xin Xue, You Lu
PurposeAblative hypofractionated radiotherapy (AHFRT) presents therapeutic advantage over conventional fractionated radiotherapy (CFRT) in primary and oligometastatic cancers, but the underlying mechanisms remain largely unknown. In this study, we compared the immune alterations in response to AHFRT vs. CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.Experiment Design and ResultsWe established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biological equivalent dose (BED). Compared to CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not in immunocompromised mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors, and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8⁺ T cells. Through the down-regulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGFR signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented a higher efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field.ConclusionTargeting MDSC recruitment and enhancing anti-tumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT is more potent for cancer treatment.

Teaser

This study compared the immune alterations in response to ablative hypofractionated radiotherapy (AHFRT) and conventional fractionated radiotherapy (CFRT) under the same BED, and showed that AHFRT suppressed recruitment of MDSCs into tumors, releasing the inhibition on CD8⁺ T cells, and boosting not only local but also systemic anti-cancer immunity. Adding anti-PD-L1 immunotherapy further boosted the potency of AHFRT. This study extended the mechanisms underlying the efficacy of AHFRT and proposed strategy to combine radiotherapy with immunotherapy.


http://ift.tt/2FMb4hb

PET/CT Interpretative Pitfalls in Thoracic Malignancies

Publication date: Available online 8 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Girish S. Shroff, Bradley S. Sabloff, Mylene T. Truong, Brett W. Carter, Chitra Viswanathan
Applications of PET/CT in the thorax include the evaluation of solitary pulmonary nodules, staging and restaging of oncologic patients, assessment of therapeutic response, and detection of residual or recurrent disease. Accurate interpretation of PET/CT requires knowledge of the physiological distribution of [18F]-fluoro-2-deoxy-D-glucose, as well as artifacts and quantitative errors due to the use of CT for attenuation correction of the PET scan. Potential pitfalls include malignancies that are PET negative and benign conditions that are PET positive. Awareness of these artifacts and potential pitfalls is important in preventing misinterpretation that can alter patient management.



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Immunotherapy in Lung Cancer and the Role of Imaging

Publication date: Available online 6 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Brett W. Carter
Lung cancer is the leading cause of cancer-related mortality and accounts for more deaths than breast, prostate, and colon cancers combined. Traditionally, treatment options have included surgery, chemotherapy, and radiation therapy. Continual advances in the characterization of lung cancer have resulted in the development of effective immunotherapies. These agents help the immune system recognize tumors as foreign, stimulate the immune system, and relieve the inhibition that allows the growth and spread of cancer. Conventional response criteria such as the World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST) have been used extensively in clinical trials; however, these guidelines have been optimized for use with traditional cytotoxic chemotherapy. Data from clinical trials employing immunotherapy has shown that unique responses may be seen with these agents that are not fully captured by conventional response criteria. In response to these observations, several modified criteria have been developed for use with immunotherapy, including immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST). As the use of immunotherapy continues to grow, there is increasing recognition of immune-related adverse events, which may manifest on imaging examinations.



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Imaging on lung cancer and treatment with targeted therapy

Publication date: Available online 6 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Girish S. Shroff, Marcelo F. Benveniste, Patricia M. de Groot, Brett W. Carter, Carol C. Wu, Chitra Viswanathan, Mylene T. Truong
The identification of genetic mutations known as oncogenic driver mutations that lead to the growth and survival of cancer cells has been an important advance in the field of oncology. Treatment in advanced non-small cell lung cancer (NSCLC) has transitioned from a more general approach to a more personalized approach based on genetic mutations of the cancer itself. Common mutations detected in patients with advanced NSCLC include mutations of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Targeted therapies are aimed at the products of these gene mutations and include erlotinib (used in EGFR-mutant NSCLC) and crizotinib (used in ALK-positive NSCLC). In this review, we discuss common genetic mutations in advanced NSCLC, the role of targeted therapies, and imaging findings that can be associated with various genetic mutations.



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Imaging of radiation treatment of lung cancer

Publication date: Available online 6 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Marcelo F Benveniste, Sonia L. Betancourt Cuellar, Daniel Gomez, Girish S. Shroff, Brett W. Carter, Ana Paula A. Benveniste, Edith M. Marom
Radiation therapy is an important modality in the treatment of patients with lung cancer. Recent advances in delivering radiotherapy were designed to improve loco-regional tumor control by focusing higher doses on the tumor. More sophisticated techniques in treatment planning include three dimensional conformal radiation therapy (3D CRT), intensity-modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT), and proton therapy. These methods may result in non-traditional patterns of radiation injury and various radiologic appearances that can be mistaken for recurrence, infection and other lung diseases. Knowledge of radiological manifestations, awareness of new radiation delivery techniques and correlation with radiation treatment plans are essential in order to correctly interpret imaging in these patients.



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Brain Death: Diagnosis and Imaging Techniques

Publication date: Available online 2 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Tanvir Rizvi, Prem Batchala, Sugoto Mukherjee
Brain death (BD) is an irreversible cessation of functions of the entire brain, including the brainstem. The diagnosis of BD is made on clinical grounds and neurologic examination. In the United States, clinical criteria set by the American Academy of Neurology (AAN) emphasize 3 specific clinical findings to confirm BD, which include coma, absence of brainstem reflexes and apnea. Ancillary tests are needed when neurologic examination or apnea test cannot be performed. AAN recommended ancillary tests include electroencephalogram, which confirms electrical activity loss; catheter cerebral angiogram, which confirms loss of cerebral blood flow; as well as transcranial Doppler and nuclear scintigraphy. Digital subtraction angiography remains the gold standard for confirmation of lack of cerebral blood flow. On 99m Techentium hexa methyl propylene amine oxime or 99mTechnetium-ethylene cysteine diethyl ester (99mTc-ethylene cysteine diethyl ester) Nuclear scintigraphy, lack of intracranial radiotracer uptake, correlates with BD. Although imaging studies like computed tomography angiogram (CTA), MR angiogram, CT perfusion, and MR perfusion are frequently used, they are currently not recommended by AAN. However, they hold tremendous promise in future as imaging tools in the armamentarium of a radiologist investigating BD as adjunct imaging to clinical findings. Imaging markers for BD on CTA include nonopacification of the cortical middle cerebral arteries and internal cerebral veins. On CT perfusion, there is lack of cerebral blood flow and blood volume in brainstem. Residual brain perfusion can occur with reduced intracranial pressure as in decompressive craniectomy, ventricular drainage and multiple skull fractures leading to false-negative results. On magnetic resonance imaging, there can be massive brain edema with herniations, poor gray or white matter differentiation, diffuse diffusion restriction, and nonvisualization of intracranial vessels on MR angiogram. On transcranial Doppler, cerebral circulatory arrest is indicated by flow patterns without forward flow progress, progressing from decrease in diastolic flow to disappearance of diastolic flow to oscillating pattern with retrograde flow in diastole, short systolic spikes, and finally absence of Doppler signal. AAN has included neuroimaging explaining coma as one of their prerequisite to be checked before evaluation for BD. Thus, a radiologist can play a critical role by recognizing the initial extensive hypoxic or ischemic damage to the central nervous system including the brainstem on imaging; guiding a neurologist evaluating a potential BD, as well as ruling out other pitfalls. In many cases, the radiologist is often the first person to appreciate the devastating findings of irreversible brain damage. Three most common mimics of BD are hypothermia, locked-in syndrome, and drug intoxication. By judicious usage of the available ancillary tests, cautiously interpreting the findings with awareness of their limitations and pitfalls, a radiologist can provide the support needed to confirm BD.



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Post-Operative Imaging and Complications in Resection of Lung Cancer

Publication date: Available online 1 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Patricia M. de Groot, Mylene T. Truong, Myrna C.B. Godoy
Surgical resection offers the best hope of cure for patients with operable early stage lung cancer. Wedge resection, segmentectomy, lobectomy or pneumonectomy may be performed depending on the size and location of the tumor. Radiologists must be familiar with the types of surgical resection utilized in the treatment of lung carcinoma and with their normal and abnormal postsurgical appearance on imaging studies. Prompt identification of postoperative complications on imaging is essential to appropriate patient management and helps to determine when additional intervention is warranted.



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Incidental Findings on Lung Cancer Screening: Significance and Management

Publication date: Available online 1 March 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Emily B. Tsai, Caroline Chiles, Brett W. Carter, Myrna C.B. Godoy, Girish S. Shroff, Reginald F. Munden, Mylene T. Truong, Carol C. Wu
Incidental findings are commonly detected by computed tomography (CT), but distinguishing which findings have little or no clinical consequence and which are significant enough to require further evaluation is not always clear. This distinction is important for patient care and to ensure appropriate use of healthcare resources. This paper aims to highlight some of the incidental findings detected by low dose CT (LDCT) performed for lung cancer screening and to present an overview of currently accepted management recommendations.



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Role of Imaging in Acute Ischemic Stroke

Publication date: Available online 28 February 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Andrew A. Pavlina, Rupa Radhakrishnan, Achala S. Vagal
Rapid multimodal imaging is essential in the workup and management of acute ischemic stroke. Early parenchymal findings on noncontrast computed tomography or standard magnetic resonance imaging are used to triage patients for intravenous thrombolysis and to provide insight on prognosis. In the wake of recent endovascular stroke trials, advanced techniques including perfusion imaging and noninvasive vascular imaging are becoming important tools to guide potential endovascular treatment or expand therapy windows. Advanced imaging is also important in pediatric ischemic stroke which requires a slightly different workflow and treatment approach. Here, we will discuss key imaging findings in acute ischemic stroke, as well as the present and future of neuroimaging in light of recent and ongoing clinical trials.



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Intracranial Hemorrhage Imaging

Publication date: Available online 27 February 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Amin F. Saad, Ruchir Chaudhari, Nancy J. Fischbein, Max Wintermark
Intracranial hemorrhage is a medical event frequently encountered in the clinical practice of radiology that has significant potential for patient morbidity and mortality. The expedient and accurate identification of intracranial hemorrhage as well as elucidation of the underlying cause can assist in optimizing the care of these patients. In this review, we attempt to familiarize the reader with the imaging appearance of multiple types of intracranial hemorrhage, both intra-axial and extra-axial and utilizing both computed tomography and magnetic resonance imaging, as well as to provide a framework for assessment of the underlying cause of the hemorrhage.



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Essentials of Head Trauma Imaging

Publication date: Available online 8 February 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Courtney Frey, J. Michael Hazenfield
Head trauma is a common indication for neuroimaging in the emergency room. CT is the modality of first choice, as it is quick, safe, and effective in evaluating for life threatening intracranial hemorrhage and mass effect. CT is also best for evaluating for skull fractures which may alter management and lead to further imaging studies. MRI is reserved for selected patients, particularly when the clinical exam does not match the CT imaging findings, such as is diffuse axonal injury. Emergency room physicians and radiologists, particularly those in-training, would benefit from a consistent approach and search pattern for evaluating head trauma. We offer a comprehensive "outside to inside" approach to head trauma imaging, discussing not only common but subtle "should not miss" findings and their clinical correlation.



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Pediatric Emergencies: Imaging of Pediatric Head Trauma

Publication date: Available online 31 January 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): William T. O'Brien, Marguerite M. Caré, James L. Leach
Pediatric head trauma is an important cause of morbidity and mortality in children and may be seen in the setting of accidental or abusive injuries. Although many of the patterns of head injury are similar to adults, the imaging manifestations of head injury in children are more complex due to the developing brain and calvarium. Additionally, there are unique considerations for mechanisms of injury in children, to include abusive head trauma and birth-related injuries. The primary role of the radiologist is to identify and characterize the type and severity of head injury to help guide appropriate patient management.



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Abdominal Wall Masses: CT Findings and Clues to Differential Diagnosis

Publication date: Available online 31 January 2018
Source:Seminars in Ultrasound, CT and MRI
Author(s): Gabriela Gayer, Christian Park
The abdominal wall does not comprise a distinct organ, and is often cursorily evaluated on CT. However, it is affected by many different pathological processes. These may be categorized according to their underlying etiology—trauma, infection or inflammation, iatrogenic and neoplastic process—or according to the abdominal wall layer they affect. We chose instead to group these lesions into 6 distinct categories based on their CT characteristic density: solid, infiltrative, hypervascular, fluid, fat, and bone density lesions. We highlight throughout the article the importance of integrating pertinent clinical history to narrow the differential diagnosis.



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Demodex mites modulate sebocyte immune reaction: Possible role in the pathogenesis of rosacea

Abstract

Rosacea is a common facial skin disorder affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as important. The Demodex mite population in the skin of these patients is significantly higher than in subjects with normal skin suggesting they may be of etiological importance in this disorder. Little is known of the role of these mites in human skin and their potential to interact with the host immune system has not been elucidated.

Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalised SZ95 sebocyte line. Time and mite dose dependent experiments were performed. Direct Demodex effects and the effects of medium in which Demodex had been cultured were evaluated on the TLR-signalling pathway on both a gene and protein expression level.

Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards down modulation of genes in this pathway was observed. A subsequent switch to positive gene up-regulation was recorded after 48 hours of co-culture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced pro-inflammatory cytokine secretion whereas lower numbers did not.

Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalised human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced IL8 secretion by these cells.

This article is protected by copyright. All rights reserved.

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Correction to: Comparative cone-beam computed tomography evaluation of the osseous morphology of the temporomandibular joint in temporomandibular dysfunction patients and asymptomatic individuals

In the original publication of the article in "Abstract", the sentence that reads as "The present analyses suggest that a steeper articular eminence inclination may be risk factor" should read as "As a result of our analysis, we concluded that a low eminence angle may be risk factor".

http://ift.tt/2tI4FyD

Eukaryotic RNA 5′-End NAD+ Capping and DeNADding

Publication date: Available online 12 March 2018
Source:Trends in Cell Biology
Author(s): Megerditch Kiledjian
A hallmark of eukaryotic mRNAs has long been the 5′-end m⁷G cap. This paradigm was recently amended by recent reports that Saccharomyces cerevisiae and mammalian cells also contain mRNAs carrying a novel nicotinamide adenine dinucleotide (NAD⁺) cap at their 5′-end. The presence of an NAD⁺ cap on mRNA uncovers a previously unknown mechanism for controlling gene expression through nucleotide metabolite-directed mRNA turnover. In contrast to the m⁷G cap that stabilizes mRNA, the NAD⁺ cap targets RNA for rapid decay in mammalian cells through the DXO non-canonical decapping enzyme which removes intact NAD⁺ from RNA in a process termed 'deNADding'. This review highlights the identification of NAD⁺ caps, their mode of addition, and their functional significance in cells.



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A geographical and temporal analysis of melanoma awareness in an international population

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Ryan Sugrue




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SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases

Publication date: Available online 7 March 2018
Source:European Journal of Surgical Oncology
Author(s): Takashi Mizuno, Jordan M. Cloyd, Diego Vicente, Kiyohiko Omichi, Yun Shin Chun, Scott E. Kopetz, Dipen Maru, Claudius Conrad, Ching-Wei D. Tzeng, Steven H. Wei, Thomas A. Aloia, Jean-Nicolas Vauthey
IntroductionDorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM).MethodsBetween 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone.ResultsOf 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P<0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P=0.007), multiple tumors (HR 1.970; P=0.01), diameter greater than 3 cm (HR 1.752; P=0.017), R1 margin status (HR 2.452; P=0.014), RAS mutation (HR 2.044; P=0.002), and SMAD4 mutation (HR 2.773; P<0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P=0.012) and was an independent predictor for worse OS (HR, 1.647; P=0.032).ConclusionSMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM.



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Quality of life of elderly women with early breast cancer following surgery

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Anne Shrestha, Charlene Martin, Karen Collins, Maria Burton, Riccardo Audisio, Tim Chater, Kirsty Pemberton, Kl Cheung, Sue Ward, Stephen Walters, Reed Malcolm, Tg Robinson, T. Green, Dierdre Revell, Jaqui Gath, Lynda Wyld




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Risk factors for appendiceal and colorectal peritoneal metastases

Publication date: Available online 6 March 2018
Source:European Journal of Surgical Oncology
Author(s): Malin Enblad, Wilhelm Graf, Helgi Birgisson
BackgroundEarly diagnosis to target minimal volume disease has received increased attention in the management of appendiceal and colorectal peritoneal metastases (PM). This study aimed to identify risk factors for appendiceal, colon and rectal PM.MethodsData were retrieved from the Swedish Colorectal Cancer Registry for all patients undergoing bowel resection of appendiceal and colorectal tumours, in Sweden, 2007–2015. Risk factors for synchronous and metachronous PM were analysed with multivariate logistic and Cox proportional hazard regression models.ResultsSynchronous PM was most common in appendiceal cancer (23.5%), followed by colon (3.1%) and rectal (0.6%) cancer. The 5-year cumulative incidence was 9.0% for appendiceal, 2.5% for right colon, 1.8% for left colon and 1.2% for rectal cancer. In appendiceal cancer (n=327), T4, N2, mucinous tumour, and non-radical surgery were associated with PM. In colon cancer (n=24,399), synchronous PM were primarily associated with T4 (OR 18.37, 95% CI 8.12–41.53), T3 and N2 but also with N1, right-sided tumour, mucinous tumour, vascular and perineural invasion, female gender, age <60 and emergency surgery. These factors were also associated with metachronous PM. In rectal cancer (n=10,394), T4 (OR 19.12, 95% CI 5.52–66.24), proximal tumour and mucinous tumour were associated with synchronous PM and T4 and mucinous tumour with metachronous PM.ConclusionsThis study shows that appendiceal cancer, right-sided colon cancer, advanced tumour and node stages and mucinous histopathology are the main high-risk features for PM and should increase the awareness of current or future PM.



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Surgery with Curative intent is Associated with Prolonged Survival in Patients with Cutaneous Angiosarcoma of the Scalp and Face -A retrospective study of 38 untreated cases in the Japanese population

Publication date: Available online 6 March 2018
Source:European Journal of Surgical Oncology
Author(s): Kohei Oashi, Kenjiro Namikawa, Arata Tsutsumida, Akira Takahashi, Jun Itami, Hiroshi Igaki, Koji Inaba, Naoya Yamazaki
BackgroundIn patients with cutaneous angiosarcoma of the scalp and face, the validity of surgery remains controversial, because of the potentially diffuse nature of involvement and difficulty in obtaining negative margins.ObjectiveTo evaluate the survival benefit of surgery as primary treatment.Patients and methodsFifty-one patients with primary cutaneous angiosarcoma of the scalp and face presenting with locoregional involvement were referred to National Cancer Center Hospital, Tokyo, Japan, between May 1982 and March 2013. Data of those patients in whom the diagnosis had been confirmed histologically and the primary treatments had been initiated at our center were analysed retrospectively. Only untreated cases were selected with aim to evaluate actual survival benefit of surgery as primary treatment.ResultsOf the 51 patients, 38 were found to be eligible for inclusion in this analysis; of these 38 patients, 29 (29/38 = 76.3%) patients had tumour diameter ≥ 5 cm, and 29 underwent surgery with curative intent (curative-intent surgery) as the initial treatment. Histologically positive margins were found in 10 patients. Multivariate analysis identified curative-intent surgery as being significantly associated with improved overall survival (OS; HR = 0.26; 95% CI, 0.10-0.63). In the Surgery group, neither negative margins nor combined-modality treatment had any significant influence on the OS.ConclusionRemoval of primary tumour with curative-intent surgery may be a valid treatment option even for patients with primary cutaneous angiosarcoma of the scalp and face larger than 5cm in size, regardless of the histological surgical margin status.



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Hilar cholangiocarcinoma: Outcomes in a Northern tertiary referral centre

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Abdullah Malik, Stuart Robinson, Jeremy French, Gourab Sen, Colin Wilson, John Hammond, Steven White, Derek Manas




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Radioactive seed localisation of non-palpable lymph nodes - a feasibility study

Publication date: Available online 6 March 2018
Source:European Journal of Surgical Oncology
Author(s): C.M.S. Hassing, T.F. Tvedskov, N. Kroman, T.L. Klausen, J.B. Drejøe, J.F. Tvedskov, T.-L. Lambine, H. Kledal, G. Lelkaitis, L. Langhans
BackgroundRadioactive seed localisation (RSL) is a preoperative localisation method using a small titanium seed containing iodine-125. The method is increasingly applied for localising non-palpable lesions in the treatment of breast cancer. We believe that RSL has the potential to be used in various surgical specialties. The aim of this feasibility study was to test RSL as a preoperative localisation of non-palpable lymph nodes.MethodsBetween November 24, 2015 and October 26, 2016, 15 patients with suspicious lymph nodes on imaging were included in the study. The lymph nodes were located in the axillary region (n=9), the head and neck region (n=5) and the inguinal region (n=1). The seeds were placed in the centre of the lymph node, in the capsule or just outside the capsule guided by ultrasound. During surgery, incision and localisation of the lymph nodes were performed based on the auditory signal of the gamma probe. After excision, lymph nodes including iodine seeds were sent for pathologic examination and the seeds were returned to the Department of Nuclear Medicine.ResultsThe non-palpable lymph nodes were all successfully marked using ultrasound. The lymph nodes were successfully localised and excised during surgery, and the procedure was performed without complications in the majority of the cases.ConclusionLocalisation of suspicious non-palpable lymph nodes using RSL is feasible. RSL may ease the surgical procedure, minimise trauma to the surrounding tissue and ultimately benefit the patient. Future prospective studies are necessary to determine the further use of RSL within different surgical specialties.



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Assessment of the ERSPC and PCPT2.0 risk calculators in the prediction of prostate cancer in men attending a prostate assessment clinic

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Sandesh Kc, Thomas King, David Mak, Rupesh Bhatt, Alan Doherty, Richard Viney, Prashant Patel, Brian Kelly




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ECCO essential requirements for quality cancer care – Melanoma

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Michel W. Wouters




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Laparoscopic surgery in the treatment of stage I adult granulosa cells tumors of the ovary: results from the MITO-9 study

Publication date: Available online 10 March 2018
Source:European Journal of Surgical Oncology
Author(s): A. Bergamini, G. Ferrandina, M. Candiani, G. Cormio, G. Giorda, R. Lauria, A.M. Perrone, G. Scarfone, E. Breda, A. Savarese, L. Frigerio, A. Gadducci, F. Mascilini, F. Maneschi, C. Cassani, C. Marchetti, S.C. Cecere, N. Biglia, U. De Giorgi, F. Raspagliesi, D. Lorusso, G. Mangili
ObjectiveSurgery represents the mainstay of treatment of stage I adult type granulosa cell tumors of the ovary (AGCTs). Because of the rarity and indolent course of the disease, no prospective trials are available. Open surgery has long been considered the traditional approach; oncological safety of laparoscopy is only supported by small series or case reports. The aim of this study was to compare the oncological outcomes between laparoscopic and open surgery in stage I AGCTs treated within the MITO (Multicenter Italian Trials in Ovarian cancer) Group.Methodsdata from patients with stage I AGCTs were retrospectively collected. Clinicopathological features were evaluated for association with relapse and death. Survival curves were calculated using the Kaplan-Meier method and compared with the log-rank test. The role of clinicopathological variables as prognostic factors for survival was evaluated using Cox's regression model.Results223 patients were identified. Stage 1A, 1B and 1C were 61.5%, 1.3% and 29.6% respectively. 7.6% were apparently stage I. Surgical approach was laparoscopic for 93 patients (41.7%) and open for 130 (58.3%). 5-years DFS was 84% and 82%, 10-years DFS was 68% and 64% for the laparoscopic and open-group(p=0.6).5-years OS was 100% and 99%, 10 years OS was 98% and 97% for the laparoscopic and open-surgery group(p=0.8). At multivariate analyses stage IC, incomplete staging, site of primary surgery retained significant prognostic value.Conclusionthe present study suggests that surgical route does not affect the oncological safety of patients with stage I AGCTs, with comparable outcomes between laparoscopic and open approach.



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The impact of primary tumour location in patients undergoing hepatic resection for colorectal liver metastasis

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Kun Wang, Da Xu, Xiao-Luan Yan, Graeme Poston, Bao-Cai Xing
BackgroundPrimary tumour location has long been debated as a prognostic factor in colorectal cancer patients with liver metastases (CRLM) undergoing liver resection. This retrospective study was conducted to clarify the prognostic value of tumour location after radical hepatectomy for CRLM and its underlying causes.MethodsWe retrospectively analysed clinical data from 420 patients with CRLM whom underwent liver resection between January 2002 and December 2015. Right-sided (RS) tumours include tumours located in the cecum, ascending colon, and transverse colon, and left-sided (LS) tumours include those located in the splenic flexure, descending colon, sigmoid colon, and rectum.ResultsBoth overall survival (OS) and disease-free survival (DFS) were similar between patients with RS and LS primary tumours (5-year OS: 46.5% vs 38.3%, P=0.699; 5-year DFS: 29.1% vs 22.4%, P=0.536). Specifically, RAS mutation rate was significantly higher in patients with RS tumours (P= 0.007). Subgroup analysis showed that the RAS mutation on the LS and RS tumors have different prognostic impact for CRLM patients on long-term survival after hepatic resection (RS, OS: P=0.437, DFS: P=0.471; LS, OS: P<0.001, DFS: P=0.002). The multivariable analysis showed that RAS mutant is an independent factor influencing OS in patients with LS primary tumour only.ConclusionsThe site of the primary tumour has no significant impact on the long-term survival in patients with CRLM undergoing radical surgery. However, prognostic value of RAS status differs depending on the site of the primary tumour.



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Calendar

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Issue 3





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University hospital status and surgeon volume and risk of reoperation following surgery for esophageal cancer

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Joonas H. Kauppila, Karl Wahlin, Pernilla Lagergren, Jesper Lagergren
PurposeCentralization of surgery improves the survival following esophagectomy for cancer, but whether university hospital setting or surgeon volume influences the reoperation rates is unknown. We aimed to clarify whether hospital status or surgeon volume are associated with a risk of reoperation after esophagectomy.MethodsPatients who underwent esophagectomy for esophageal cancer in 1987-2010 were identified from a population-based, nationwide Swedish cohort study. University hospital status and cumulative surgeon volume were analyzed in relation to risk of reoperation or death (the latter included to avoid competing risk errors) within 30 days of surgery. Multivariable logistic regression provided odds ratios (OR) with 95% confidence intervals (CI), adjusted for calendar period, age, sex, comorbidity, tumor histology, stage, neoadjuvant therapy, resection margin, surgeon volume, and hospital status.ResultsAmong 1820 participants, 989 (54%) underwent esophagectomy in university hospitals and 271 (15%) died or were reoperated within 30 days of surgery. Non-university hospital status was associated with an increased risk of reoperation or death compared to university hospitals (adjusted OR 1.56, 95% CI 1.13-2.13). Regarding surgeon volume, the ORs were increased in the lower volume categories, but not statistically significant (OR 1.30, 95% CI 0.89-1.89 for surgeon volume <7 and OR 1.10, 95% CI 0.75-1.63 for surgeon volume 7-16, compared to surgeon volume >16).ConclusionThe risk of reoperation or death within 30 days of esophagectomy seems to be lower in university hospitals even after adjustment for surgeon volume and other potential confounders. These results support centralizing esophageal cancer patients to university hospitals.



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Theranostic CEA-Affimer functionalised silica nanoparticles allow specific in vitro fluorescent imaging of colorectal cancer cells

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Yazan S. Khaled, Shazana Shamsuddin, Jim Tiernan, Mike McPherson, Thomas Hughes, Paul Millner, David G. Jayne




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Synchronous metastatic gastric cancer-molecular background and clinical implications with special attention to mismatch repair deficiency

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Karol Polom, Christine Böger, Elizabeth Smyth, Daniele Marrelli, Hans-Michael Behrens, Luigi Marano, Thomas Becker, Florian Lordick, Christoph Röcken, Franco Roviello
BackgroundCurrent guidelines recommend that metastatic gastric cancer should not be treated with surgery unless this is required for symptom control. We hypothesized that patients with mismatch repair deficiency (MMRd) gastric cancer and metastatic disease detected at the timepoint of surgical resection would have superior survival compared to patients with MMRd cancers in the same setting.MethodsClinicopathological details and survival data were collected from prospective databases at two large European centers on patients who had undergone surgery and were diagnosed with synchronous stage IV gastric cancer (distant lymph nodes, positive peritoneal cytology, peritoneal, and distant metastases) at the timepoint of surgery. Resection specimens were tested for the presence of microsatellite instability using a standard 5 mononucleotide repeat panel.ResultsOne hundred and sixty one patients with resected stage IV gastric cancer were identified. 14/161 (8.7 %) had MSI-H (high) disease. There was no significant difference between the clinical and pathological characteristics of MSI and microsatellite stable (MSS) patients. No differences in the type of metastases were observed between MSI and MSS groups. Patients who were MSI-H had superior OS compared to MSS patients (median OS 15.9 vs. 8 months, p=0.023). However, in Cox regression multivariate analysis only liver and peritoneal metastases were independent predictors of survival.ConclusionsSurgically treated patients with MSI-H stage IV gastric cancer have a better survival than patients with MSS gastric cancer. Further analysis of the role of surgery in MSI stage IV GC is required.



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Population-based study of factors influencing invasive breast cancer risk after screen-detected ductal carcinoma in situ: First results from the non-invasive breast cancer in England (NINBE) study

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Gurdeep Mannu, Zhe Wang, Shan Cheung, Olive Kearins, John Broggio, Jackie Charman, Sarah C. Darby




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Prognostic role of splenic vessel infiltration in distal pancreatic adenocarcinoma

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Gaëtan-Romain Joliat, Nicolas Demartines, Markus Schäfer




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BRCA1 risk-reducing surgery appears to reduce risk of developing breast cancer

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Gareth Irwin, Gwyneth Hinds, Lesley McFaul, Patrick Morrison, Ian Harley, Stuart McIntosh




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Role of the anterior fissure vein in ventral or dorsal resection at Segment 8 of liver

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Nobuhiko Taniai, Tadashi Machida, Hiroshi Yoshida, Masato Yoshioka, Youichi Kawano, Tetsuya Shimizu, Yuto Aoki
BackgroundThe vein that runs between ventral and dorsal Segment 8 is called the anterior fissure vein (AFV). AFV is sometimes needed as a boundary for Subsegmentectomy in Segment 8. The aim of the present study was to investigate the AFV to determine whether the AFV can be used a landmark for subsegmentectomy of the liver at Segment 8.MethodsWe analyzed data from 151 patients who had undergone abdominal computed tomographic (CT) examinations. The position of the AFV is identified by determining whether the AFV drains flows into the proximal, medial, or distal portion of the middle hepatic vein (MHV) or right hepatic vein (RHV). Furthermore, the proximal region is divided into 2 halves; the proximal portion is designated as P1 and the distal portion is designated as P2.ResultsThe AFV could be identified in 78.8% (119/151) of the patients. The AFV flowed into the MHV in 84.9% of the patients and into the RHV in 15.1%. Among the former, the AFV flowed into the proximal MHV in 69.7% of the patients.ConclusionsAlthough the AFV might not be easily identifiable, the AVF can be used to determine the border between the ventral and dorsal portions of Segment 8. The AFV should thus be used as a landmark for Subsegmentectomy.



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A model combining age, equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer

Publication date: March 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 3
Author(s): Shulian Wang, Jeff Campbell, Matthew H. Stenmark, Paul Stanton, Jing Zhao, Martha M. Matuszak, Randall K. Ten Haken, Feng-Ming Kong
Background and purposeTo study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients.Materials and methodsA total of 129 patients with stage I–III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions.ResultsForty-nine of 129 patients (38.0%) developed grade ≥2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade ≥2 RE (p < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1α, TGFα and eotaxin were also associated with grade ≥2 RE (p < 0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade ≥2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy (p = 0.019).ConclusionsCombining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted.



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Photons, protons or carbon ions for stage I non-small cell lung cancer – Results of the multicentric ROCOCO in silico study

Publication date: Available online 12 March 2018
Source:Radiotherapy and Oncology
Author(s): Krista C.J. Wink, Erik Roelofs, Charles B. Simone, David Dechambre, Alina Santiago, Judith van der Stoep, Wim Dries, Julia Smits, Stephen Avery, Filippo Ammazzalorso, Nicolas Jansen, Urszula Jelen, Timothy Solberg, Dirk de Ruysscher, Esther G.C. Troost
PurposeTo compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial.MethodsFor each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions.ResultsThe mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ.ConclusionOn average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient.



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Editorial Board

Publication date: March 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 3





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Contents

Publication date: March 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 3





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Do Postpartum Levels of Apolipoproteins Prospectively Predict the Development of Type 2 Diabetes in Women with Previous Gestational Diabetes Mellitus?

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0577-7700

Aims The risk of developing type 2 diabetes is greater in women with previous gestational diabetes mellitus (GDM). Apolipoprotein (Apo) species have been associated with the development of type 2 diabetes in the general population. The aim of this study was to determine if circulating levels of Apo species can predict development of type 2 diabetes in women with previous GDM. Methods Apo AI, Apo AII, Apo B, Apo CII, Apo CIII and Apo E levels were measured in 95 women with normal glucose tolerance, 12 weeks following an index GDM pregnancy. Women were assessed for up to 10 years for the development of type 2 diabetes. Results Postpartum Apo CIII levels, and Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, Apo CIII/Apo E and Apo E/Apo CIII ratios were significantly and positively associated with the development of type 2 diabetes. After controlling for age and BMI, these associations, except for the Apo E/Apo CIII ratio, remained significant. In a clinical model of prediction of type 2 diabetes that included age, BMI, and pregnancy and postnatal fasting glucose, the addition of Apo CIII levels, Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, and Apo CIII/Apo E resulted in a net reclassification improvement of 16.2%. Conclusions High Apo CIII levels and the Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, and Apo CIII/Apo E ratios are all significant risk factors for the development of type 2 diabetes in women with a previous GDM pregnancy.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Frequency of Blood Pressure and Estimated Glomerular Filtration Rate Testing in type 2 Diabetes Mellitus: A Retrospective Study with 43,509 Patients

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0581-4870

Background The goal of this study was to analyze the frequency of blood pressure (BP) and estimated glomerular filtration rate (eGFR) testing in type 2 diabetes mellitus (T2DM) patients followed in general and diabetological practices in Germany. Methods The study included individuals who had at least two concultations due to T2DM diagnosis (ICD-10: E11) between January and December 2016. Patients were followed in 557 general and diabetological practices. The primary outcome was the frequency of BP and eGFR testing in T2DM patients in 2016. The association between several demographic and clinical variables and the odds of receiving≥2 BP and≥1 eGFR tests in the year 2016 was analyzed using multivariate logistic regression models. Results A total of 43,509 individuals were available for analysis. The mean age of the population was 68.6 years (SD=12.4 years). The mean number of measurements was 2.9 (SD=3.5) for BP and 0.4 (SD=1.1) for eGFR. 52.3% of patients were tested at least twice for BP and 15.3% of them at least once for eGFR in 2016. Older patients, individuals followed in diabetological practices, people receiving antihyperglycemic medications, and those affected by chronic conditions (i. e. hypertension, renal complications, or neuropathy) displayed higher odds of receiving≥2 BP and≥1 eGFR tests, whereas patients with a diabetes duration of>1 year displayed lower odds. Conclusions The frequency of BP and eGFR testing was low in T2DM patients in Germany in 2016. Several demographic and clinical variables were associated with this frequency.
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© Georg Thieme Verlag KG Stuttgart · New York

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The Effect of Metformin on Serum Gonadotropin Levels in Postmenopausal Women with Diabetes and Prediabetes: A Pilot Study

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0584-0006

Background Metformin was found to decrease serum levels of prolactin and thyrotropin. The aim of this study was to investigate the effect of this drug on hypothalamic-pituitary-ovarian axis activity in postmenopausal women with recently diagnosed and untreated glucose metabolism abnormalities. Methods The study included three matched groups of postmenopausal women: patients with type 2 diabetes (group A, n=16), women with prediabetes (group B, n=14), and individuals with normal glucose metabolism (group C, n=14). Women with diabetes were then treated with high-dose metformin (3 g daily), while women with prediabetes received moderate doses of this agent (1.7 g daily). Glucose homeostasis markers, as well as serum levels of FSH, LH, thyrotropin, prolactin, estradiol and creatinine were measured at baseline and after 16 weeks of metformin treatment. Results In both groups of metformin-treated women, the drug improved glucose homeostasis. High-dose metformin treatment reduced circulating levels of FSH and tended to reduce serum levels of LH, and these effects correlated with an improvement in insulin sensitivity. No changes in gonadotropin levels were observed in prediabetic women receiving moderate doses of metformin. Serum levels of thyrotropin, prolactin and estradiol, as well as the estimated glomerular filtration rate remained at a similar level throughout the study. Conclusions Our study shows that the effect of metformin on hypothalamic-pituitary-ovarian axis activity in postmenopausal women depends on its dose and the magnitude of insulin resistance.
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© Georg Thieme Verlag KG Stuttgart · New York

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Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-125324

Background miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated. Methods In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Immunohistochemical staining was performed to measure NOTCH1 expression in the diabetic endothelium. Results miR-34a was significantly up-regulated, and NOTCH1 down-regulated, in the thoracic aorta from STZ-induced diabetic rats compared with control group. As compared to model group, the mRNA of NOTCH1 was significantly decreased or increased by miR-34a mimics or inhibitors ex vivo, respectively. Bioinformatics methods further demonstrated that NOTCH1 was a potential target of miR-34a, which was confirmed by dual-luciferase reporter assay. Moreover, both serum ET and NO were significantly increased in diabetic rats as compared to control group. miR-34a inhibitors ex vivo treatment resulted in significant down-regulation ofserum ET and NO levels in diabetic rats as compared to model group. Conclusion These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction.
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© Georg Thieme Verlag KG Stuttgart · New York

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Levels of Nitric Oxide Metabolites and Myeloperoxidase in Subjects with Type 2 Diabetes Mellitus on Metformin Therapy *

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0577-7776

Introduction Endothelial dysfunction is involved in the pathogenesis of insulin resistance, diabetes mellitus type 2, diabetic complications and preceded clinical manifestation of cardiovascular complications. Increased myeloperoxidase activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. The aim of this study was to compare concentrations of metabolite nitric oxide and myeloperoxidase in the plasma of diabetes mellitus type 2 patients on metformin therapy, without clinical signs of cardiovascular disease and healthy subjects, as well as evaluation of concentrations of analytes in association with glycemic control. Materials and methods Forty four study subjects with diabetes mellitus type 2 and thirty healthy subjects were included in this study. The concentration of myeloperoxidase was determined by enzyme-linked immunosorbent assay, the concentration of nitrate and nitrite with high performance liquid chromatography method. Student's t test, Mann-Whitney U test, Chi-square test and Fisher's exact test were used for statistical analysis. Results The mean concentration of myeloperoxidase was significantly higher in the diabetic group compared to the control group (16.2±4.9 vs. 3.7±1.8; P<0.001).The nitrite concentration was comparable in both groups while the concentration of nitrate was significantly higher in the diabetic group (41.2 [42.9] vs 31.9 [23]; P=0.017). In this study, plasma myeloperoxidase (Spearman's rho=0.421; P=0.004) and nitrate concentration was significantly positively associated with the HbA1c levels while nitrate concentration (Spearman's rho=− 0.308; P=0.047) were was significantly positively negatively associated with the HbA1c levels. Conclusion Concertation of MPO and nitric oxide were significantly increased in a T2DM subject even when on metformin therapy. However, increased concentration of NO strongly correlates with lower levels of HbA1c showing a postive effect of a gylcemic control on endothelial dysfuction. Increased concentrations of NO3- in T2DM subject compared to control, indicates the variety of NO pathways that should be taken into consideration win relation to endothelial function.
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© Georg Thieme Verlag KG Stuttgart · New York

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Homing in: Mechanisms of Substrate Targeting by Protein Kinases

Publication date: Available online 12 March 2018
Source:Trends in Biochemical Sciences
Author(s): Chad J. Miller, Benjamin E. Turk
Protein phosphorylation is the most common reversible post-translational modification in eukaryotes. Humans have over 500 protein kinases, of which more than a dozen are established targets for anticancer drugs. All kinases share a structurally similar catalytic domain, yet each one is uniquely positioned within signaling networks controlling essentially all aspects of cell behavior. Kinases are distinguished from one another based on their modes of regulation and their substrate repertoires. Coupling specific inputs to the proper signaling outputs requires that kinases phosphorylate a limited number of sites to the exclusion of hundreds of thousands of off-target phosphorylation sites. Here, we review recent progress in understanding mechanisms of kinase substrate specificity and how they function to shape cellular signaling networks.



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Erratum to: Role of Negative Pressure Therapy as Damage Control in Soft Tissue Reconstruction for Open Tibial Fractures

J reconstr Microsurg
DOI: 10.1055/s-0038-1632386

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Erratum to: Staged Reconstruction (Delayed-Immediate) of the Maxillectomy Defect Using CAD/CAM Technology

J reconstr Microsurg
DOI: 10.1055/s-0038-1635090

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

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APC Moonlights to Prevent Wnt Signalosome Assembly

Publication date: 12 March 2018
Source:Developmental Cell, Volume 44, Issue 5
Author(s): Ian John McGough, Jean-Paul Vincent
The scaffold protein APC has a well-known function in ensuring β-catenin destruction. In this issue of Developmental Cell, Saito-Diaz et al. (2018) uncover another role for APC in Wnt signaling: to prevent clathrin-dependent signalosome formation in the absence of ligand.

Teaser

The scaffold protein APC has a well-known function in ensuring β-catenin destruction. In this issue of Developmental Cell, Saito-Diaz et al. (2018) uncover another role for APC in Wnt signaling: to prevent clathrin-dependent signalosome formation in the absence of ligand.


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FOXO3a Provides a Quickstep from Autophagy Inhibition to Apoptosis in Cancer Therapy

Publication date: 12 March 2018
Source:Developmental Cell, Volume 44, Issue 5
Author(s): Patrice Codogno, Etienne Morel
FOXO3a, a member of the Forkhead transcription factor family, has roles in apoptosis and autophagy. In this issue of Developmental Cell, Fitzwalter et al. (2018) describe how the blockade of FOXO3a turnover, which normally occurs through autophagy, sensitizes cancer cells to apoptosis through FOXO3a-mediated stimulation of pro-apoptotic PUMA/BBC3 expression.

Teaser

FOXO3a, a member of the Forkhead transcription factor family, has roles in apoptosis and autophagy. In this issue of Developmental Cell, Fitzwalter et al. (2018) describe how the blockade of FOXO3a turnover, which normally occurs through autophagy, sensitizes cancer cells to apoptosis through FOXO3a-mediated stimulation of pro-apoptotic PUMA/BBC3 expression.


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Did Mitochondria Kill the Frog?

Publication date: 12 March 2018
Source:Developmental Cell, Volume 44, Issue 5
Author(s): Souhir Marsit, Anne-Marie Dion-Côté, Daniel A. Barbash
Genomic divergence can cause reproductive isolation between species. The molecular mechanisms underlying reproductive isolation can thus reveal which genomic features evolve rapidly and become unstable or incompatible in hybrids. In a recent paper in Nature, Gibeaux et al. (2018) report paternal genome instability and metabolic imbalance in hybrids between frog species.

Teaser

Genomic divergence can cause reproductive isolation between species. The molecular mechanisms underlying reproductive isolation can thus reveal which genomic features evolve rapidly and become unstable or incompatible in hybrids. In a recent paper in Nature, Gibeaux et al. (2018) report paternal genome instability and metabolic imbalance in hybrids between frog species.


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Neutrophil Extracellular Traps: The Biology of Chromatin Externalization

Publication date: 12 March 2018
Source:Developmental Cell, Volume 44, Issue 5
Author(s): Gabriel Sollberger, Dorothea Ogmore Tilley, Arturo Zychlinsky
Neutrophils are essential to the homeostatic mission of safeguarding host tissues, responding rapidly and diversely to breaches of the host's barriers to infection, and returning tissues to a sterile state. In response to specific stimuli, neutrophils extrude modified chromatin structures decorated with specific cytoplasmic and granular proteins called neutrophil extracellular traps (NETs). Several pathways lead to this unique form of cell death (NETosis). Extracellular chromatin may have evolved to defend eukaryotic organisms against infection, and its release has at least three functions: trapping and killing of microbes, amplifying immune responses, and inducing coagulation. Here we review neutrophil development and heterogeneity with a focus on NETs, NET formation, and their relevance in host defense and disease.

Teaser

In response to specific stimuli, neutrophils extrude extracellular traps (NETs), modified chromatin structures decorated with cytoplasmic and granular proteins. NETs trap and kill microbes, amplify immune responses, and induce coagulation. In this Review, Sollberger et al. examine neutrophil development, focusing on NETs and their role in host defense and disease.


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Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover

Publication date: 12 March 2018
Source:Developmental Cell, Volume 44, Issue 5
Author(s): Brent E. Fitzwalter, Christina G. Towers, Kelly D. Sullivan, Zdenek Andrysik, Maria Hoh, Michael Ludwig, Jim O'Prey, Kevin M. Ryan, Joaquin M. Espinosa, Michael J. Morgan, Andrew Thorburn
Macroautophagy (autophagy) is intimately linked with cell death and allows cells to evade apoptosis. This has prompted clinical trials to combine autophagy inhibitors with other drugs with the aim of increasing the likelihood of cancer cells dying. However, the molecular basis for such effects is unknown. Here, we describe a transcriptional mechanism that connects autophagy to apoptosis. The autophagy-regulating transcription factor, FOXO3a, is itself turned over by basal autophagy creating a potential feedback loop. Increased FOXO3a upon autophagy inhibition stimulates transcription of the pro-apoptotic BBC3/PUMA gene to cause apoptosis sensitization. This mechanism explains how autophagy inhibition can sensitize tumor cells to chemotherapy drugs and allows an autophagy inhibitor to change the action of an MDM2-targeted drug from growth inhibition to apoptosis, reducing tumor burden in vivo. Thus, a link between two processes mediated via a single transcription factor binding site in the genome can be leveraged to improve anti-cancer therapies.

Graphical abstract

Teaser

Fitzwalter et al. uncover a link between autophagy and apoptosis, explaining how autophagy inhibitors can improve anti-cancer drugs by increasing sensitivity to apoptosis. The transcription factor FOXO3a, an autophagy regulator, is itself degraded by basal autophagy. Disruption of autophagy allows FOXO3a to upregulate BBC3/PUMA expression and thus cause apoptosis sensitization.


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