Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Marcus D. Goncalves, Lewis C. Cantley
Glycolysis is prudently regulated and coupled to cell growth. Phosphofructokinase 2 controls glycolytic flux by generating fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase 1. In a recent paper in Nature, Dasgupta et al. address the novel role of PFKFB4, an isoform of phosphofructokinase 2, in regulating gene expression to promote tumor growth.
Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Tobias Janowitz
Tumors interact reciprocally with their hosts' physiology and metabolism, making cancer a systemic disease. In this issue of Cell Metabolism, Borniger et al. (2018) demonstrate this phenomenon by linking the endocrine control of food intake with sleep behavior and liver metabolism in a mouse model of non-metastatic breast carcinoma.
Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Hong Jiang, Jens C. Brüning
In contrast to synaptic transmission, the mechanism of volume transmission—in which neurotransmitters or neuropeptides diffuse to many effector cells—is not extensively investigated, although it represents an important mode of neuronal communication. In this issue of Cell Metabolism, Noble et al. (2018) demonstrate how the orexigenic melanin-concentrating hormone (MCH) controls feeding behavior through cerebrospinal fluid (CSF) volume transmission.
Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Jon O. Lundberg, Mattias Carlström, Eddie Weitzberg
Nitric oxide (NO), generated from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in cardiovascular and metabolic regulation. More recently, an alternative pathway for the formation of this free radical has been explored. The inorganic anions nitrate (NO3−) and nitrite (NO2−), originating from dietary and endogenous sources, generate NO bioactivity in a process involving seemingly symbiotic oral bacteria and host enzymes in blood and tissues. The described cardio-metabolic effects of dietary nitrate from experimental and clinical studies include lowering of blood pressure, improved endothelial function, increased exercise performance, and reversal of metabolic syndrome, as well as antidiabetic effects. The mechanisms underlying the salutary metabolic effects of nitrate are being revealed and include interaction with mitochondrial respiration, activation of key metabolic regulatory pathways, and reduction of oxidative stress. Here we review the recent advances in the nitrate-nitrite-NO pathway, focusing on metabolic effects in health and disease.
Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Anthony P. Coll
Safe and effective pharmacological treatments for severe obesity remain scarce. In this issue of Cell Metabolism, Iepsen et al. (2018) show that obese patients with pathogenic melanocortin 4 receptor mutations, the most common form of monogenic obesity, lose weight with glucagon-like peptide 1 (GLP-1) receptor agonist therapy.
Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Ming Luo, Li Shang, Michael D. Brooks, Evelyn Jiagge, Yongyou Zhu, Johanna M. Buschhaus, Sarah Conley, Melissa A. Fath, April Davis, Elizabeth Gheordunescu, Yongfang Wang, Ramdane Harouaka, Ann Lozier, Daniel Triner, Sean McDermott, Sofia D. Merajver, Gary D. Luker, Douglas R. Spitz, Max S. Wicha
Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.
Publication date: Available online 3 July 2018
Source:Practical Radiation Oncology
Author(s): Shaakir Hasan, Paul Renz, Matthew Packard, Sean Horrigan, Steven Gresswell, Alexander V. Kirichenko
PurposeWe compared the rate and severity of fatigue in patients who completed stereotactic body radiotherapy (SBRT) to the liver daily(QD) compared with every other day(QOD)Methods and MaterialsFrom 2010 to 2017, 91 patients with Child Pugh(CP) A(n=57) or CP-B (34) cirrhosis who completed 100 SBRT sessions to 110 HCC lesions were analyzed in this study. Confounding variables with fatigue such as CP-C cirrhosis, ECOG over 2, or a history of ascites/encephalopathy were excluded. Fatigue was assessed against several treatment/patient related variables with univariate and propensity score-matched multivariate analysis. Median follow-up was 18 months.ResultsHCC patients with BCLC stages 0(n=10), A(n=32), and B(n=58) and a median age of 62 were analyzed. Median tumor diameter was 3 cm (1.1-11 cm). ECOG performance status was 0(n=44), 1(n=43), or 2(n=13). The median dose was 45 Gy in 5 fractions. 65 treatments were QD and 45 were QOD.Grade 1 and 2 fatigue developed in 49% and 14% of treatments, respectively. Among those treated daily, 78% developed G1/G2 fatigue compared to 44% treated QOD (OR=4.52, P=0.001). Grade 2 fatigue occurred in 22% compared to 7.3% for QD and QOD treatment, respectively (OR=3.83, P=0.048). There was no difference in fatigue rate for time of treatment(morning/afternoon), dose, treated volume, CP score, BCLC stage, or performance status were not associated with any level of fatigue. There were no difference in local control between QD and QOD treatments.ConclusionsCompared to traditional daily treatment fractions, SBRT delivered QOD to cirrhotic patients with HCC may reduce the risk of fatigue.
https://ift.tt/2tXS9bg
Publication date: Available online 3 July 2018
Source:Immunity
Author(s): Myunghoo Kim, Carolina Galan, Andrea A. Hill, Wan-Jung Wu, Hannah Fehlner-Peach, Hyo Won Song, Deborah Schady, Matthew L. Bettini, Kenneth W. Simpson, Randy S. Longman, Dan R. Littman, Gretchen E. Diehl
The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX3CR1+ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.
Publication date: Available online 3 July 2018
Source:Immunity
Author(s): Mingchao Wang, Shanshan Zhang, Guoxing Zheng, Junjiu Huang, Zhou Songyang, Xueqiang Zhao, Xin Lin
Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14E138A/+ and Card14ΔQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14−/− mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors. Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-κB activation in keratinocytes in psoriatic initiation.
In this work photo-electro-Fenton (PEF) processes using a dimensionally stable anode-gas diffusion electrode (DSA-GDE) system under light emission diodes (LED)-type radiation were used in the degradation of the angiotensin-II-receptor antagonists (ARA II), valsartan (VAL), and losartan (LOS), which are used in the treatment of hypertension diseases, and are considered among the emerging contaminants (ECs). Organic acids as citric, tartaric, and oxalic acids were used as complexing agents of iron ions in order to maintain the performance of the Fenton reaction at near-neutral pH value. The results show that at 3.42 mA/cm2 after 90 min of electro-Fenton (EF) treatment, degradation of 70% of VAL and 100% of LOS were observed. Total degradation of VAL and LOS was reached with a PEF process at the same time with mineralization of 30%. When citric and tartaric acids were used instead of oxalic acid, similar results were obtained, i.e., total degradation of both compounds, LOS and VAL, after 90 min of treatment. The degradation performance can be attributed to the increase of the initial dissolved iron in the system, facilitating the Fe3+/Fe2+ turnover in the catalytic photo-Fenton reaction and consequently, hydroxyl radical (•OH) production. In addition, the increased photo-activity of the complexes can be associated with their high capability to complex Fe3+ and to promote ligand-to-metal charge transfer, which is of key importance to feed Fe2+ to the Fenton process. The results show that the system evaluated was more efficient to eliminate sartan family compounds using LED lighting in comparison with traditional UV-A lamps used in this kind of work. Moreover, three transformation products of VAL degradation and two transformation products of LOS degradation were identified by high-resolution mass spectrometry (HRMS) using hybrid quadrupole-time-of-flight (QTOF) MS and, at the end of the PEF system, the several organic compounds accumulated and no mineralized were effectively treated in a subsequent aerobic biological system.
Publication date: June 2018
Source:The Journal of Prosthetic Dentistry, Volume 119, Issue 6
https://ift.tt/2KLB0sH
Publication date: June 2018
Source:The Journal of Prosthetic Dentistry, Volume 119, Issue 6
https://ift.tt/2Np0U7i
Publication date: June 2018
Source:The Journal of Prosthetic Dentistry, Volume 119, Issue 6
https://ift.tt/2IQcrsC
Publication date: June 2018
Source:The Journal of Prosthetic Dentistry, Volume 119, Issue 6
https://ift.tt/2tTVNUj
Publication date: June 2018
Source:The Journal of Prosthetic Dentistry, Volume 119, Issue 6
Author(s): James C. Taylor, Carol A. Lefebvre, Hans-Peter Weber, Radi Masri, Benjamin M. Wu
https://ift.tt/2IO32Sh
Publication date: November 2018
Source:Magnetic Resonance Imaging, Volume 53
Author(s): Matthias Malzacher, Mathias Davids, Lothar R. Schad, Jorge Chacon-Caldera
Specific absorption rate (SAR) simulations are performed for most clinical and research transmit coil configurations. Such simulations allow the determination of limits in transmit power for patient safety. Different human models and coil configurations have been previously investigated using these simulations. However, only a few works have accounted for the effect of the receive (Rx) arrays in the SAR calculations and they have used very specialized setups or simplified detuning modeling of the Rx elements. In this work, we performed electromagnetic simulations using a clinical alike setup for whole-body scans at 3 T and head scans at 7 T. SAR simulations are performed for both setups with and without Rx arrays. A difference below 10% percent was found for max SAR. The maximum difference for the mean SAR values of the 3 T setups remained within 8% and within 15% of the 7 T setup.
https://ift.tt/2u4zESD
Publication date: November 2018
Source:Magnetic Resonance Imaging, Volume 53
Author(s): K.A. Smitha, K.M. Arun, P.G. Rajesh, Suresh E. Joel, Ramesh Venkatesan, Bejoy Thomas, Chandrasekharan Kesavadas
Background and objectivesEnsuring patient comfort and compliance by emphasizing reduced time frame for image acquisition, without compromising image quality is the key aspect with functional MRI examination. Multiband resting state fMRI (MB-rsfMRI) is a fairly new technique that potentially shortens MR image acquisition time by providing increased number of time points. The study aims to compare signal characteristics as well as the functional connectivity using conventional resting-state fMRI (rsfMRI) with that of MB-rsfMRI technique.Materials and methods9 healthy volunteers have prospectively undergone conventional resting-state fMRI and Multiband rsfMRI scanning technique in a 3T GE scanner (Discovery MR750w™). We compared the temporal SNR (tSNR) of conventional rs-fMRI with that of MB-rsfMRI. We looked at the language network connectivity and small world network characteristics from graph theoretical measures to compare the two techniques.ResultsWe computed the tSNR of conventional resting-state fMRI (rsfMRI) and MB-rsfMRI technique. A strong positive correlation was seen between graph theoretical measures from MB-rsfMRI and conventional rsfMRI (Pearson Correlation, r = 0.99). Both techniques showed similar small world network characteristics in healthy controls.ConclusionThe present study demonstrates negligible differences between the conventional-rsfMRI and MB-rsfMRI acquisitions on the computed graph theoretic measures. Accordingly current analysis proves that MB-rs-fMRI may be used as a time reducing acquisition technique that enables mapping of functional connectivity with similar outcome as conventional rs-fMRI in healthy subjects.
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Fluoride (F−) is becoming an ineluctable environmental pollutant causing deleterious effects in humans. In the present study, we examined whether tamarind seed coat extract (TSCE) is beneficial against the F−-induced systemic toxicity and hematological changes. Wistar rats were randomly grouped as follows: group I served as control; group II intoxicated with sodium fluoride (NaF, 300 ppm) in drinking water; group III was administered through oral intubation with TSCE (100 mg/kg bw); group IV was treated with NaF (300 ppm) in association with TSCE (100 mg/kg bw) for 30 days. The results indicated that F− exposure induced oxidative stress as evidenced by elevated levels of reactive oxygen species and lipid peroxidation in the brain, liver, and kidney. F− administration modulates hematological indices—WBC, RBC, and mean corpuscular volume. Moreover, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acetylcholinesterase, and monoamine oxidase significantly increased on F− exposure. Conversely, δ-aminolevulinic acid dehydratase and glutathione/reduced glutathione ratio were decreased. Activity of antioxidants—superoxide dismutase, catalase, glutathione peroxidase, and vitamin C—was also significantly decreased due to F− administration. Treatment with TSCE effectively mitigated the alterations through its antioxidant potential. The data suggested that the TSCE had beneficial effects in alleviating the F−-induced toxicity and hence can serve as a promising neutraceutical agent.
Publication date: Available online 2 July 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): E. Noriega-Álvarez, M.T. Bajén, J. Rodríguez-Rubio, A.M. Benítez, A. Rodrígez-Gasén, J. Suils, R. Jaller, G.A. Martínez, I. Romero, J. Mora
IntroducciónResulta difícil determinar la infección osteoarticular y diferenciar entre inflamación e infección mediante procedimientos de laboratorio e imagen (TC, RM, US).La gammagrafía con leucocitos marcados (GLM) constituye la prueba de medicina nuclear de elección, pero su duración es de dos días, y a veces es difícil diferenciar entre tejido blando e infección, por lo que se produce una variabilidad interobservador que hace disminuir su especificidad.ObjetivoDemostrar la utilidad del protocolo de un día de GLM con corrección por decaimiento del tiempo de adquisición para diagnosticar la infección osteoarticular y reducir la variabilidad interobservador. También se evaluó la función de SPECT/TC en GLM en la localización del foco de infección.MétodosSe estudiaron prospectivamente 110 pacientes con sospecha de infección osteoarticular. Se obtuvieron imágenes planares con corrección por decaimiento del tiempo de adquisición a 30min, 4h, 8h y 24h.Las imágenes planares de GLM se agruparon en dos protocolos:.Protocolo de un día: los expertos evaluaron imágenes de 30min, 4h y 8h. Protocolo de dos días: los expertos evaluaron imágenes de 30min, 4h y 24h. Ambos protocolos fueron clasificados como:• Negativos: ausencia de migración leucocitaria.• Positivos: persistencia o incremento de la captación con el tiempo.• Inflamación aséptica: disminución de la captación con el tiempo.La SPECT/TC se realizó en 72 pacientes.Se calculó el índice kappa para evaluar la variabilidad interobservador.ResultadosSe confirmó infección en 34 casos. Los valores de sensibilidad, especificidad, valor predictivo positivo, valor predictivo negativo y precisión diagnóstica fueron del 97,1, del 97,4, del 94,3, del 98,7 y del 97,3% para el protocolo de un día, y del 94,1, del 97,4, del 94,1, del 97,4 y del 96,4 para el protocolo de dos días, respectivamente.SPECT/TC contribuyó al diagnóstico en 45 de 50 pacientes con GLM planar positiva. Índice kappa: 0,8 para el protocolo de un día y 0,79 para el protocolo de dos días.ConclusiónEl protocolo de un día de GLM con corrección por decaimiento del tiempo de adquisición y SPECT/TC permite el diagnóstico precoz y preciso de la infección osteoarticular.IntroductionIt is difficult to determine osteoarticular infection and differentiate inflammation from infection with laboratory and imaging procedures (CT, MRI, US).Labelled white-blood-cell scintigraphy (WBCS) is the nuclear medicine test of choice but it takes two days, sometimes finds it difficult to differentiate soft tissue from bone infection and therefore causes interobserver variability, which decreases its specificity.ObjectiveTo demonstrate the usefulness of the one-day protocol with time decay-corrected acquisition in WBCS to diagnose osteoarticular infection and to reduce interobserver variability. The role of SPECT/CT in WBCS in locating the infected focus was also evaluated.Methods110 patients with suspected osteoarticular infection were studied prospectively. Planar images were obtained with time decay-corrected acquisition at 30min, 4h, 8h and 24h.WBCS planar images were grouped in two protocols:One-day protocol: experts evaluated 30min, 4h and 8h images. Two-day protocol: experts evaluated 30min, 4h and 24h images. Both protocols were classified as:• Negative: absence of leukocyte migration.• Positive: uptake persisted or increased over time.• Aseptic inflammation: uptake decreased over time.SPECT/CT was performed in 72 patients.Kappa index was calculated to evaluate interobserver variability.ResultsInfection was confirmed in 34 cases. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 97.1%, 97.4%, 94.3%, 98.7%, and 97.3% for the one-day protocol and 94.1%, 97.4%, 94.1%, 97.4%, and 96.4% for two-days-protocol.SPECT/CT contributed to diagnosis in 45/50 patients with planar WBCS positive. Kappa index: 0.8 for one-day protocol and 0.79 for two-day protocol, respectively.ConclusionOne-day protocol with time decay-corrected acquisition WBCS and SPECT/CT enables early and accurate diagnosis of osteoarticular infection.
https://ift.tt/2tXwsbk
Publication date: 28 October 2018
Source:Journal of Ethnopharmacology, Volume 225
Author(s): Jianping Xu, Kunhua Wei, Guojun Zhang, Lujing Lei, Dawei Yang, Wenle Wang, Qiheng Han, Yuan Xia, Yaqiong Bi, Min Yang, Minhui Li
Ethnopharmacological relevanceThe genus Salvia is one of the largest genera of the Lamiaceae family. In China, about 40 Salvia species have been used as medicinal plants for treatment of various diseases, specifically hepatic and renal diseases and those of the cardiovascular and immune systems.Aim of this reviewThis review aims to provide systematically organized information on the ethnopharmacology, phytochemistry, pharmacology, and toxicology of medicinal Salvia species in China to support their therapeutic potential in the treatment of human diseases.Materials and methodsRelevant information on the Chinese Salvia species was obtained from scientific online databases such as Google Scholar, PubMed, and SciFinder. Additional information was derived from other literature sources (e.g. Chinese Pharmacopoeia 2015 edition, Chinese herbal classic books, PhD and MSc thesis, etc).ResultsOur comprehensive analysis of the scientific literature indicates that many Chinese Salvia species are valuable and popular herbal medicines with therapeutic potentials to cure various ailments. Phytochemical analyses identified diterpenoids and phenolic acids as the major bioactive substances in Chinese Salvia species. Crude extracts and pure compounds isolated from the Chinese Salvia species exhibited various pharmacological activities, typically targeting the cardiovascular and immune systems and hepatic and renal diseases.ConclusionThis review summarizes the results from current studies about basic properties of medicinal Salvia species in China, such as active constituents and their mechanism of action, pharmacokinetics, underlying molecular mechanisms, toxicology, and efficacy, which are still being studied and explored to achieve integration into medical practice.
https://ift.tt/2tRjwVe
Publication date: August 2018
Source:International Journal of Psychophysiology, Volume 130
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Publication date: August 2018
Source:International Journal of Psychophysiology, Volume 130
https://ift.tt/2z7Zniz
In the present investigation, the oxidation of HFO-1234yf (2,3,3,3-tetrafluoropropene) with O3 molecule and NO3 radical is studied by quantum chemical methods. The possible reaction pathways of the titled molecule with O3 molecule and NO3 radical are analyzed using M06-2X meta-hybrid density functional with the 6-311++G(d,p) basis set. We have further employed a series of single-point energy calculations by using a potentially high-level couple cluster method with single and double excitations, including perturbative corrections ((CCSD(T)) at the same basis set. The addition reaction of HFO-1234yf with O3 molecule is initiated by the formation of primary ozonide complex, which leads to the formation of various carbonyl compounds and Criegee intermediates. The calculated energy barriers and thermochemical parameters inferred that decomposition of C˙H2OO˙ and CF3CFO is slightly more preferred over the formation of CF3C˙FOO˙ and CH2O. Further, the NO3 radical addition at α- and β-sits of CF3CF〓CH2 molecule is analyzed in details. The individual and overall rate constants for each reaction pathways are calculated by using canonical transition state theory over the temperature range of 250–450 K. We have observed that the computed rate constants are in good agreement with the available experimental data. Atmospheric lifetimes and global warming potentials of the HFO-1234yf are also reported in this manuscript.
Background/Aim: Epithelial cell adhesion molecule (EpCAM) is expressed in various types of cancer, including breast cancer, and is correlated with metastasis, invasion, therapeutic resistance and prognosis. Moreover, several cell surface markers, such as CD44 and EpCAM, are molecular targets on cancer stem-like cells of breast cancer. The aim of this study was to investigate whether catumaxomab, a clinical-grade bispecific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant triple-negative breast cancer (TNBC) cells in vitro. Materials and Methods: First, a cell line (MUK-BC1) was established from human breast carcinoma cells derived from a patient with chemoresistant and disseminated breast cancer. These EpCAM-positive TNBC cells were almost completely resistant to various drug-mediated cytotoxicities up to a concentration of 10 μg/ml. Results: Pre-treatment with catumaxomab and subsequent addition of interleukin-2/OKT3-activated autologous T-cells eliminated EpCAM-positive TNBC cells. Conclusion: Catumaxomab combined with activated T-cells may be a potent therapeutic modality to overcome chemoresistant EpCAM-positive TNBC cells.
The novel information regarding molecular and translational research have created a paradigm shift in the understanding of lung cancer biology, revealing the more precise target for anti-cancer drug discovery. Lung cancer is a leading cause of cancer death worldwide accounting for approximately 1 in 5 of all cancer-related deaths. The most important causes of death in such a cancer involves the treatment failure as well as the spreading of cancer cells to distant sites which the cancer stem cell (CSC) within the tumor is accepted as a key driver. CSC is a rare special population of cancer cells exhibiting high tumorigenic properties together with self-renewal and differentiation capability. CSC is not only linked with high tumor-initiating activity, but is also implicated in chemotherapeutic resistance, metastasis, epithelial to mesenchymal transition, and recurrence. Thereafter, novel therapeutic strategies targeting these CSCs are considered in order to improve long-term clinical outcome. Here, we provide sufficient data regarding the biology of CSC in lung cancer, known CSC markers and cellular signals, and promising compounds targeting the stem cell signals in lung cancer that may benefit the development of novel anti-cancer treatment.
Background/Aim: Tumour-infiltrating lymphocytes (TILs) and Granzyme B play crucial roles in immune reactions against colorectal carcinoma (CRCa). The inhibitor of Granzyme B is Serpin B9. The aim of this study was to evaluate the effect of immunohistological parameters of TILs on the prognosis of CRCa and presence of lymph node metastasis. Patients and Methods: A total of 152 patients who underwent surgery for CRCa were analyzed, including 63 patients in cohort stage II, according to the Union for International Cancer Control (UICC), and 89 patients in cohort UICC stage III. The TIL pattern was classified as peritumoural (PTL), intratumoural (ITL), intrastromal (ISL) or Crohn-like, and immunohistological staining of TIL and cancer cells was also performed. Results: A significantly higher density of CD8+ and CD4+ TILs was observed in the UICC II group, and significantly higher densities of CD4+ TILs were observed in the UICC II group in all distinguished patterns. In the same cohort, higher numbers of CD57+ cells and FoxP3+ TILs and Granzyme B levels were observed. In cohort UICC III, there was a higher density of ISL, PTL CD8+, CD25+ TILs and cancer cells showed staining for Serpin B9. CD57, Granzyme B and CD8 were demonstrated as positive prognostic factors of overall survival, and CD57 and CD4+ TILs were demonstrated as positive prognostic factors of recurrence. Conclusion: TILs and CD57 are promising prognostic factors of CRCa. The association of Serpin B9 with lymph node metastasis reveals a potential mechanism for tumour resistance to immune reaction.
The continuity of the subepithelial band of lamina propria-indigenous macrophages (SBLP-M) discourages commensal gut bacteria from invading the host. In this Review we analyzed the impact of a disintegrating SBLP-M in inflammatory bowel disease (IBD), which results in microbiota inflow, inadequate immune responses and IBD-associated colon cancer. In previous work, we analyzed endoscopic biopsies taken from normal-looking descending colon in 247 patients with IBD, and 167 from control patients without IBD. Sections immunostained for cluster of differentiation 68 (CD68) protein showed no inflammatory changes. In IBD, the band of CD68+ SBLP-M was fragmented or minute in 59% (47/80) and absent in 9% (7/80). In contrast, only 31% (51/167) of the biopsies from control patients had a fragmented/minute band of CD68+ SBLP-M and this band was not absent in any (p<0.05). The finding that the band of CD68+ SBLP-M was fragmented to totally lost in IBD suggests a long-lasting defect in the barrier against the gut microbiome in IBD. The lack of ongoing inflammation in colonic biopsies should rule-out the participation of bone marrow-derived inflammation-elicited macrophages in loss of the barrier. Today, it is widely accepted that dysbiosis and inappropriate immune response to microbial flora play a pivotal role in the pathogenesis and development of IBD-associated colon cancer. Based on present knowledge, it is submitted that defects in the SBLP-M barrier in IBD encourage the trespassing of the gut microflora into the host, thereby destabilizing host immunity. These events in concert may play the ultimate pivotal role in the evolution of colon cancer in patients with IBD.
Background/Aim: The dose-dense doxorubicin and cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is recommended by the National Comprehensive Cancer Network guideline in US. However, there are little data on serum G-CSF concentrations in patients undergoing bi-weekly dose-dense therapy with pegfilgrastim. The objective of this study was to compare the serum G-CSF concentrations in patients receiving pegfilgrastim in bi- or tri-weekly regimens. Patients and Methods: This study included 26 patients who received ddAC or docetaxel and cyclophosphamide (TC) for primary breast cancer. Serum G-CSF concentrations were measured by ELISA. Results: Serum G-CSF concentrations peaked in the second week of ddAC cases and in the ninth week of TC cases. Neutrophils gradually increased until the sixth week in ddAC cases, while they were slightly decreased during the first three weeks in TC cases. Treatments were completed without febrile neutropenia or treatment delays. Conclusion: Primary prophylactic pegfilgrastim administrations increased serum G-CSF concentrations, helping to maintain the absolute neutrophil counts that are required to undergo chemotherapy. The treatment of ddAC with 3.6 mg pegfilgrastim is completely safe for female Japanese patients.
Uveal melanoma is the most common intraocular malignancy in adults, representing approximately 3% of all melanoma cases. Despite progress in chemotherapy, radiation and surgical treatment options, the prognosis and survival rates remain poor. Acetylation of histone proteins causes transcription of genes involved in cell growth, DNA replication and progression of cell cycle. Overexpression of histone deacetylases occurs in a wide spectrum of malignancies. Histone deacetylase inhibitors block the action of histone deacetylases, leading to inhibition of tumor cell proliferation. This article reviewed the potential therapeutic effects of histone deacetylase inhibitors on uveal melanoma. MEDLINE database was used under the key words/phrases: histone deacetylase, inhibitors, uveal melanoma and targeted therapies for uveal melanoma. A total of 47, English articles, not only referring to uveal melanoma, published up to February 2018 were used. Valproic acid, trichostatin A, tenovin-6, depsipeptide, panobinostat (LBH-589), vorinostat (suberanilohydroxamic acid) entinostat (MS-275), quisinostat, NaB, JSL-1, MC1568 and MC1575 are histone deacetylase inhibitors that have demonstrated promising antitumor effects against uveal melanoma. Histone deacetylase inhibitors represent a promising therapeutic approach for the treatment of uveal melanoma.
Background/Aim: It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). Patients and Methods: After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. Results: A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. Conclusion: Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.
Transarterial radio-embolization (TARE) using yttrium-90 microspheres is a promising method based on the brachytherapeutic effect of radionuclide with beta-minus decay dissolved in solid microparticles applied directly to tumor-supplying arteries. This treatment is complex, as well as logistically and technically extremely demanding and must be planned in detail. The visualization of the vascular supply of the liver and the possible parasitic supply of the tumor is essential not only for indication of the procedure and correct identification of the arteries to which the microspheres will be applied, but also for prevention of non-target deposition of radioactive material. This review addresses the use of computed tomographic angiography in the preparatory phase of TARE.
Background/Aim: Malignant ascites contain many tumour-infiltrating lymphocytes. T cells with antitumour activity have attracted attention as effector cells in cancer immunotherapy. V2+ T cells were cultured from peripheral blood mononuclear cells (PBMCs) and ascites-infiltrating lymphocytes (AILs) to compare the differences in response to 2-methyl-3-butenyl-1-pyrophosphate (2M3B1-PP) and zoledronate (Zol) as antigens in vitro. Materials and Methods: To expand V2+ T cells from PBMCs and AILs from 29 patients with cancer, these cells were cultured and subjected to analysis. Results: The proliferation rate of V2+ T cells was higher in both PBMCs and AILs when cultured with Zol than with 2M3B1-PP. Although V2+ T cells show a higher rate of expansion in AILs compared to PBMCs, the number of mixed tumour cells in ascites was decreased when cultured with Zol. Conclusion: V2+ T cells in AILs are cytotoxic to tumour cells in ascites and may be considered in adoptive immunotherapy.
Background/Aim: Our studies showed that ANXA7 is a novel tumor suppressor gene that is lost in various aggressive forms of prostate cancer. However, little is known about the role of ANXA7 in the anticancer drug treatment towards different cancers. Materials and Methods: The expression of ANXA7 was measured in the 60 cancer cell lines of the NCI-60 ADS project and correlated with the enhanced sensitivity to over 30,000 natural and synthetic compounds. Results: Eucalyptol showed a high positive correlation with ANXA7 expression and castration-resistant prostate cancer cell death occurred very effectively in response to the combination of eucalyptol and overexpressed wt-ANXA7 than either agent alone. The synergistic effects of ANXA7 and eucalyptol resulted in concordant changes in gene expression profiles particularly of Ras family members, MDM4, NF-ĸB and VEGF. Conclusion: Overexpression of ANXA7 enhances eucalyptol cytotoxicity in prostate cancer cell lines.
Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.
Background/Aim: Hydrogen sulfide (H2S) and the enzymes that synthesize it, cystathionine-b-synthase, cystathionine -lyase, and 3-mercaptopyruvate, are increased in different human malignancies. Due to its short half-life, H2S concentrations have not been directly measured in a human malignancy. Here we directly measured in vivo H2S levels within oral squamous cell carcinoma (OSCC). Patients and Methods: Punch biopsies of OSCC and benign mucosae from 15 patients were analyzed by HPLC, western blotting, and tissue microarray analyses. Results: H2S concentrations were significantly higher in OSCC compared to adjacent benign oral mucosae. Western blot and tissue microarray studies revealed significantly increased cystathionine-b-synthase, cystathionine -lyase, and 3-mercaptopyruvate, phopho-Stat3, mitoNEET, hTERT, and MAPK protein levels in OSCC. Conclusion: H2S concentrations and the enzymes that synthesize it are significantly increased in OSCC. Here, for the first time H2S concentrations within a living human malignancy were measured and compared to adjacent counterpart benign tissue.
Background/Aim: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of adding bevacizumab to standard capecitabine-based neoadjuvant chemoradiotherapy (CRT) for the treatment of locally advanced rectal cancer (LARC). Patients and Methods: Twenty-five patients were enrolled. Patients received capecitabine-based CRT for 5 weeks and 3 days. Bevacizumab was administered every 2 weeks during CRT. Within 6-10 weeks after completion of CRT, surgery was performed. Results: With regard to CRT-related acute toxicities, most of the adverse events were limited to grade 1. A pathological complete response was obtained in four (16%) patients. In total, six patients (24%) developed postoperative complications. Six out of five (83%) patients healed without the need for surgical intervention. Conclusion: Although acute toxicity during CRT with bevacizumab was minimal and postoperative complications do not seem to increase, the addition of bevacizumab apparently offers no clinically-significant benefit for patients with LARC.
Background/Aim: Dendropanax morbifera (DM) and Commersonia bartramia (CB) are possible candidates for immunotherapy. In this study, the cytotoxicity and chemical sensitization of DM and CB extracts on gynecologic and colon cancers were evaluated. Materials and Methods: The malignant cell lines were cultured and analyzed for cytotoxicity and chemical sensitization. A mouse model was also constructed to make the condition similar to in vivo. Reverse transcription-polymerase chain reaction was conducted to determine alterations in drug-resistant genes. Results: The extracts from DM and CB showed specific cytotoxicity to malignant cell lines. DM increased chemical sensitivity to cervical and ovarian cancer, while CB showed improved sensitization to endometrial cancer. The effects of the extracts were confirmed using a mouse model. The extracts induced differences in the expression levels of a number of genes related to drug resistance. Conclusion: DM and CB extracts could be novel agents for immunotherapy and chemical sensitization in gynecologic and colon cancers.
Background/Aim: Sugar molecules are often used as a tool to structurally modify chemical compounds. The features of synthesized sugar-conjugated TX-1877 derivatives were herein examined. Materials and Methods: The molecular stabilities (reactivity) and hydrophobicities of sugar (e.g., monosaccharide and tetra-O-acetylated monosaccharide)-conjugated TXs were analyzed using a molecular simulation (e.g. molecular mechanics (MM) and molecular orbital (MO) analysis). Results: The hydrophobicities of TX-1877 derivatives were increased by tetra-O-acetylation, and TX-2244 exhibited the most potent radiosensitizing activity (enhancement ratio: ER=2.30). Conclusion: The conformations and hydrophobicities of chemical compounds may be controlled by adding monosaccharide- and tetra-O-acetyl-conjugated sugars to TX-1877.
Background/Aim: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous tumors. Therapeutic targets remain to be identified and apart from the proliferation marker Ki-67, useful prognostic markers are rare. Mitotic proteins, such as forkheadbox protein M1 (FOXM1), survivin and aurora kinases, play a role in GEP-NEN progression. In this study, immunohistochemistry was used to analyze how this protein network is expressed in different subgroups of GEP-NENs and determine potential expression patterns that could be useful as tumor markers. Materials and Methods: Tumor tissues from 75 patients were studied immunohistochemically with antibodies against aurora B, survivin and FOXM1. The expression pattern was correlated with clinicopathological data such as tumor grading, metastatic state and prognosis. Results: The immunohistochemical analysis of nuclear aurora kinase B revealed a positive correlation with nuclear survivin and FOXM1 staining patterns. Furthermore, aurora B was positively related to grading and tumor size and negatively to differentiation and functionality. Conclusion: The expression of aurora kinase B is associated with differentiation, progression and the aggressiveness of GEP-NENs. In the context of tumor progression, aurora B is strongly associated with markers of the mitosis regulatory network, survivin, FOXM1 and Ki-67. A shift of the intracellular localization of aurora B might be useful for the subclassification of intermediate-grade intestinal NET and NEC (20%<Ki-67<55%), since detailed Ki-67-based guidelines only exist for the pancreatic tumors. Most importantly, nuclear abundance of aurora B was found to be strictly limited to high-grade tumors, which is important for the consideration of aurora inhibitors for therapy of NENs.
Background/Aim: Whey protein is a mixture of globulins isolated from whey and mainly composed of β-lactoglobulin, α-lactoalbumin, and lactoferrin. In this study, whey protein was hydrolyzed using various proteases, and the macrophage activation was evaluated. Materials and Methods: Hydrolyzed whey protein was prepared using various proteases to evaluate phagocytic activity and cytokine productivity. Results: The results of SDS-PAGE and gel permeation chromatography (GPC) analysis indicated that the molecular weight of whey protein was reduced using various proteases. The hydrolyzed whey protein showed a concentration-dependent induction of macrophage phagocytic activity. In addition, the hydrolyzed whey protein significantly enhanced the production of the inflammatory cytokine, TNF-α. Production of the anti-inflammatory cytokine, IL-10, was not observed at concentrations up to 1 μg, but significant production was confirmed at 100 μg. Conclusion: Hydrolyzed whey protein can induce the phagocytic activity of macrophages and activation of the inflammatory/anti-inflammatory functions of the macrophages depends on the concentration of the hydrolyzed whey protein.
Background/Aim: Epithelial–mesenchymal transition (EMT) program has been linked as a driver of metastatic dissemination by conferring migratory and invasive capacity to cancer cells. Gastric cancer (GC) patients with tumors expressing altered levels of EMT markers have low survival. This study aimed to assess if polymorphisms of CDH1, TWIST1, SNAIL2, ZEB1 and ZEB2 genes are associated with survival in GC patients. Patients and Methods: A total of 153 individuals with diagnosis of GC were recruited in Santiago, Chile. All patients were genotyped using Infinium Global Screening Array (GSA). Twenty Tag SNPs of the studied genes were retrieved. Results: Three SNPs were associated with survival: rs2526614 (TWIST1) (genotype CA + AA, adjusted HR=0.58, 95%CI=0.37-0.93), rs6953766 (TWIST1) (genotype GG, crude HR=2.02, 95%CI=1.06-3.82, adjusted HR=2.14, 95%CI=1.07-4.25), and rs431073 (ZEB1) (genotype AC + CC, crude HR=1.62, 95%CI=1.01-2.59, adjusted HR=1.96, 95%CI=1.18-3.25). Conclusion: To the best of our knowledge, this is the first study proposing a role of these SNPs in cancer prognosis. Their use as prognostic markers of GC survival warrants further investigation.
Background/Aim: The past 17 years, immune-cell therapy has been administered to 990 patients with advanced or recurrent pancreatic adenocarcinoma and 50 patients with curatively resected pancreatic adenocarcinoma. Materials and Methods: The correlation between overall survival (OS) and various factors including sex, age, performance status (PS), distant metastasis, chemotherapy, radiotherapy, and type of immune-cell therapy were evaluated by univariate and multivariate analyses. Results: The median OS of advanced or recurrent pancreatic cancer was 5.8 months, and the prognosis was improved in pancreatic cancer patients who received immune-cell therapy with PS scores of 0-1 [hazard risk (HR)=0.56; 95% confidence interval (CI)=0.46-0.68; p<0.0001], chemotherapy (HR=0.68; 95%CI=0.54-0.87; p=0.002), or radiotherapy (HR=0.76; 95%CI=0.63-0.93; p=0.006). Multivariate analysis demonstrated that distant metastasis indicated a poor prognosis for pancreatic cancer patients that were administered immune-cell therapy (HR=1.62; 95%CI=1.37-1.93; p<0.0001). Additionally, the combined immune-cell therapy with αβ T cell and dendritic cell (DC) vaccine provided a survival benefit in advanced or recurrent pancreatic cancer patients (HR=0.69; 95%CI=0.57-0.83; p<0.0001). Conclusion: A survival benefit could be potentially obtained with better PS by the combination of αβ T cell therapy, DC vaccine therapy, and chemotherapy at an early stage in pancreatic cancer.
Publication date: December 2018
Source:Addictive Behaviors, Volume 87
Author(s): Cristina Lidón-Moyano, Marcela Fu, Raúl Pérez-Ortuño, Montse Ballbè, Ariadna Feliu, Juan Carlos Martín-Sánchez, Nuria Matilla-Santander, José A. Pascual, Esteve Fernández, Jose M. Martínez-Sánchez
BackgroundThe aim of this study is to assess the impact of the Spanish tobacco control legislation on smoking behavior and salivary cotinine concentration among smokers.MethodsWe used data from a longitudinal study, before (2004–2005) and after (2013–2014) the implementation of the two national smoking bans (in 2006 and 2011), in a representative sample of adults (≥16 years old) from Barcelona (Spain). We only analyzed a subsample of continuing smokers (n = 116). We conducted a survey on smoking behavior and obtained saliva sample for cotinine analyses. For this report, we analyzed a subsample of continuing smokers (n = 116). We calculated geometric means (GM).ResultsAmong continuing smokers, salivary cotinine concentration significantly increased by 28.7% (GM from 91.7 ng/ml to 117.3 ng/ml, p = 0.015) after the implementation of the two Spanish smoke-free bans. Nonetheless, no pattern of change was observed in the self-reported number of cigarettes smoked daily.ConclusionsOur study shows a significant increase in the salivary cotinine concentration among adult continuing smokers after both Spanish legislations. This increase could be due to differences in smoking topography (increase in the depth of inhalation when smoking) along with changes in the type of tobacco smoked (increase in smoking roll-your-own cigarettes or mixed use of roll-your-own and manufactured cigarettes). Our results suggest the need to extend tobacco control policies, focusing on the reduction of use of any type of tobacco product and implementing better treatment to help smokers stop smoking.
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Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Sari Tojkander, Katarzyna Ciuba, Pekka Lappalainen
Stress fibers are contractile actomyosin bundles that guide cell adhesion, migration, and morphogenesis. Their assembly and alignment are under precise mechanosensitive control. Thus, stress fiber networks undergo rapid modification in response to changes in biophysical properties of the cell's surroundings. Stress fiber maturation requires mechanosensitive activation of 5′AMP-activated protein kinase (AMPK), which phosphorylates vasodilator-stimulated phosphoprotein (VASP) to inhibit actin polymerization at focal adhesions. Here, we identify Ca2+-calmodulin-dependent kinase kinase 2 (CaMKK2) as a critical upstream factor controlling mechanosensitive AMPK activation. CaMKK2 and Ca2+ influxes were enriched around focal adhesions at the ends of contractile stress fibers. Inhibition of either CaMKK2 or mechanosensitive Ca2+ channels led to defects in phosphorylation of AMPK and VASP, resulting in a loss of contractile bundles and a decrease in cell-exerted forces. These data provide evidence that Ca2+, CaMKK2, AMPK, and VASP form a mechanosensitive signaling cascade at focal adhesions that is critical for stress fiber assembly.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Matthew H.K. Cheng, Patrick C. Hoffmann, Mirita Franz-Wachtel, Carola Sparn, Charlotte Seng, Boris Maček, Ralf-Peter Jansen
The RNA-binding protein Scp160p is the yeast homolog of the conserved vigilin protein family. These proteins influence a variety of nuclear and cytoplasmic functions. One of Scp160p's reported roles is to increase translation elongation efficiency in a manner related to codon usage. Thus, it can affect translation speed and co-translational folding of nascent peptides. We used polyglutamine (polyQ) reporters to assess Scp160p's effect on protein synthesis and observed that, in the absence of Scp160p, aggregation of polyQ is reduced and toxicity is abolished. We additionally took a proteomic approach and analyzed the impact of Scp160p on the aggregation of endogenous proteins under normal growth conditions. In the absence of Scp160p, aggregation of many Q/N-rich proteins was reduced. Because aggregation mediated by these regions can be important for the proteins' functions, Scp160p may affect many processes via aggregation of Q/N-rich proteins.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Lars Schlotawa, Michaela Wachs, Olaf Bernhard, Franz J. Mayer, Thomas Dierks, Bernhard Schmidt, Karthikeyan Radhakrishnan
Multiple sulfatase deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Taylor W. Schmitz, Marieke Mur, Meghmik Aghourian, Marc-Andre Bedard, R. Nathan Spreng
The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain's cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer's disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To further assess whether structural degeneration of these regions in AD reflects cholinergic denervation, we used the [18F] FEOBV radiotracer, which binds to cortico-amygdalar cholinergic terminals. We found that the two BF subregions explain spatially distinct patterns of cortico-amygdalar degeneration, which closely reflect their cholinergic projections, and overlap with [18F] FEOBV indices of cholinergic denervation.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Yongliang Wang, Ali R. Nasiri, William E. Damsky, Curtis J. Perry, Xian-Man Zhang, Aviva Rabin-Court, Michael N. Pollak, Gerald I. Shulman, Rachel J. Perry
Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Lucas J.T. Kaaij, Robin H. van der Weide, René F. Ketting, Elzo de Wit
The spatial organization of chromosomes is critical in establishing gene expression programs. We generated in situ Hi-C maps throughout zebrafish development to gain insight into higher-order chromatin organization and dynamics. Zebrafish chromosomes segregate in active and inactive chromatin (A/B compartments), which are further organized into topologically associating domains (TADs). Zebrafish A/B compartments and TADs have genomic features similar to those of their mammalian counterparts, including evolutionary conservation and enrichment of CTCF binding sites at TAD borders. At the earliest time point, when there is no zygotic transcription, the genome is highly structured. After zygotic genome activation (ZGA), the genome loses structural features, which are re-established throughout early development. Despite the absence of structural features, we see clustering of super-enhancers in the 3D genome. Our results provide insight into vertebrate genome organization and demonstrate that the developing zebrafish embryo is a powerful model system to study the dynamics of nuclear organization.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Yuji Matsuoka, Antónia Monteiro
The cuticular skeleton of a butterfly wing scale cell is an exquisitely finely sculpted material that can contain pigments, produce structural colors, or both. While cuticle rigidity and pigmentation depend on the products of the melanin pathway, little is known about whether genes in this pathway also play a role in the development of specific scale morphologies. Here, we use CRISPR/Cas9 to show that knockout mutations in five genes that function in the melanin pathway affect both the fine structure and the coloration of the wing scales. Most dramatically, mutations in the yellow gene lead to extra horizontal laminae on the surface of scales, whereas mutations in DDC gene lead to taller and sheet-like vertical laminae throughout each scale. We identify genes affecting the development of color and scale morphology, the regulation and pleiotropic effects of which may be important in creating and limiting the diversity of the structural and pigmentary colors observed in butterflies.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): M. Fethullah Simsek, Ertuğrul M. Özbudak
Signal gradients encode instructive information for numerous decision-making processes during embryonic development. A striking example of precise, scalable tissue-level patterning is the segmentation of somites—the precursors of the vertebral column—during which the fibroblast growth factor (FGF), Wnt, and retinoic acid (RA) pathways establish spatial gradients. Despite decades of studies proposing roles for all three pathways, the dynamic feature of these gradients that encodes instructive information determining segment sizes remained elusive. We developed a non-elongating tail explant system, integrated quantitative measurements with computational modeling, and tested alternative models to show that positional information is encoded solely by spatial fold change (SFC) in FGF signal output. Neighboring cells measure SFC to accurately position the determination front and thus determine segment size. The SFC model successfully recapitulates results of spatiotemporal perturbation experiments on both explants and intact embryos, and it shows that Wnt signaling acts permissively upstream of FGF signaling and that RA gradient is dispensable.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Tomoyuki Fujiyama, Satoshi Miyashita, Yousuke Tsuneoka, Kazumasa Kanemaru, Miyo Kakizaki, Satomi Kanno, Yukiko Ishikawa, Mariko Yamashita, Tomoo Owa, Mai Nagaoka, Yoshiya Kawaguchi, Yuchio Yanagawa, Mark A. Magnuson, Masafumi Muratani, Akira Shibuya, Yo-ichi Nabeshima, Masashi Yanagisawa, Hiromasa Funato, Mikio Hoshino
The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Kelly Kawabata Galbraith, Kazuto Fujishima, Hiroaki Mizuno, Sung-Jin Lee, Takeshi Uemura, Kenji Sakimura, Masayoshi Mishina, Naoki Watanabe, Mineko Kengaku
Dendritic filopodia of developing neurons function as environmental sensors, regulating the spatial organization of dendrites and proper targeting to presynaptic partners. Dendritic filopodia morphology is determined by the balance of F-actin assembled via two major nucleating pathways, the ARP2/3 complex and formins. The inverse-BAR protein MTSS1 is highly expressed in Purkinje cells (PCs) and has been shown to upregulate ARP2/3 activity. PCs in MTSS1 conditional knockout mice showed dendrite hypoplasia due to excessive contact-induced retraction during development. This phenotype was concomitant with elongated dendritic filopodia and was phenocopied by overactivation of the actin nucleator formin DAAM1 localized in the tips of PC dendritic protrusions. Cell biology assays including single-molecule speckle microscopy demonstrated that MTSS1's C terminus binds to DAAM1 and paused DAAM1-mediated F-actin polymerization. Thus, MTSS1 plays a dual role as a formin inhibitor and ARP2/3 activator in dendritic filopodia, determining final neuronal morphology.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Shinya Ohara, Mariko Onodera, Øyvind W. Simonsen, Rintaro Yoshino, Hiroyuki Hioki, Toshio Iijima, Ken-Ichiro Tsutsui, Menno P. Witter
Layer V of the entorhinal cortex (EC) receives input from the hippocampus and originates main entorhinal outputs. The deep-sublayer Vb, immunopositive for the transcription factor Ctip2, is thought to be the main recipient of hippocampal projections, whereas the superficial-sublayer LVa, immunonegative for Ctip2, originates the main outputs of EC. This disrupts the proposed role of EC as mediating hippocampal-cortical interactions. With the use of specific (trans)synaptic tracing approaches, we report that, in medial entorhinal cortex, layer Vb neurons innervate neurons in layers Va, II, and III. A similar circuitry exists in the lateral entorhinal cortex. We conclude that EC-layer Vb neurons mediate two circuits in the hippocampus-memory system: (1) a hippocampal output circuit to telencephalic areas by projecting to layer Va and (2) a feedback projection, sending information back to the EC-hippocampal loop via neurons in layers II and III.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Anne Gegonne, Qing-Rong Chen, Anup Dey, Ruth Etzensperger, Xuguang Tai, Alfred Singer, Daoud Meerzaman, Keiko Ozato, Dinah S. Singer
T cell differentiation in the thymus proceeds in an ordered sequence of developmental events characterized by variable expression of CD4 and CD8 coreceptors. Here, we report that immature single-positive (ISP) thymocytes are molecularly distinct from all other T cell populations in the thymus in their expression of a gene profile that is dependent on the transcription factor BRD4. Conditional deletion of BRD4 at various stages of thymic differentiation reveals that BRD4 selectively regulates the further differentiation of ISPs by targeting cell cycle and metabolic pathways, but it does not affect the extensive proliferation that results in the generation of ISPs. These studies lead to the conclusion that the ISP subpopulation is not a hybrid transitional state but a molecularly distinct subpopulation that is selectively dependent on BRD4.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Giuliano Ferrero, Christopher B. Mahony, Eléonore Dupuis, Laurent Yvernogeau, Elodie Di Ruggiero, Magali Miserocchi, Marianne Caron, Catherine Robin, David Traver, Julien Y. Bertrand, Valérie Wittamer
Microglia, the tissue-resident macrophages of the CNS, represent major targets for therapeutic intervention in a wide variety of neurological disorders. Efficient reprogramming protocols to generate microglia-like cells in vitro using patient-derived induced pluripotent stem cells will, however, require a precise understanding of the cellular and molecular events that instruct microglial cell fates. This remains a challenge since the developmental origin of microglia during embryogenesis is controversial. Here, using genetic tracing in zebrafish, we uncover primitive macrophages as the unique source of embryonic microglia. We also demonstrate that this initial population is transient, with primitive microglia later replaced by definitive microglia that persist throughout adulthood. The adult wave originates from cmyb-dependent hematopoietic stem cells. Collectively, our work challenges the prevailing model establishing erythro-myeloid progenitors as the sole and direct microglial precursor and provides further support for the existence of multiple waves of microglia, which originate from distinct hematopoietic precursors.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Eric Wong, Ren-Huan Xu, Daniel Rubio, Avital Lev, Colby Stotesbury, Min Fang, Luis J. Sigal
Circulating natural killer (NK) cells help protect the host from lympho-hematogenous acute viral diseases by rapidly entering draining lymph nodes (dLNs) to curb virus dissemination. Here, we identify a highly choreographed mechanism underlying this process. Using footpad infection with ectromelia virus, a pathogenic DNA virus of mice, we show that TLR9/MyD88 sensing induces NKG2D ligands in virus-infected, skin-derived migratory dendritic cells (mDCs) to induce production of IFN-γ by classical NK cells and other types of group 1 innate lymphoid cells (ILCs) already in dLNs, via NKG2D. Uninfected inflammatory monocytes, also recruited to dLNs by mDCs in a TLR9/MyD88-dependent manner, respond to IFN-γ by secreting CXCL9 for optimal CXCR3-dependent recruitment of circulating NK cells. This work unveils a TLR9/MyD88-dependent mechanism whereby in dLNs, three cell types—mDCs, group 1 ILCs (mostly NK cells), and inflammatory monocytes—coordinate the recruitment of protective circulating NK cells to dLNs.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Beiyun C. Liu, Joseph Sarhan, Alexander Panda, Hayley I. Muendlein, Vladimir Ilyukha, Jörn Coers, Masahiro Yamamoto, Ralph R. Isberg, Alexander Poltorak
Legionella pneumophila elicits caspase-11-driven macrophage pyroptosis through guanylate-binding proteins (GBPs) encoded on chromosome 3. It has been proposed that microbe-driven IFN upregulates GBPs to facilitate pathogen vacuole rupture and bacteriolysis preceding caspase-11 activation. We show here that macrophage death occurred independently of microbial-induced IFN signaling and that GBPs are dispensable for pathogen vacuole rupture. Instead, the host-intrinsic IFN status sustained sufficient GBP expression levels to drive caspase-1 and caspase-11 activation in response to cytosol-exposed bacteria. In addition, endogenous GBP levels were sufficient for the release of DNA from cytosol-exposed bacteria, preceding the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway for Ifnb induction. Mice deficient for chromosome 3 GBPs were unable to mount a rapid IL-1/chemokine (C-X-C motif) ligand 1 (CXCL1) response during Legionella-induced pneumonia, with defective bacterial clearance. Our results show that rapid GBP activity is controlled by host-intrinsic cytokine signaling and that GBP activities precede immune amplification responses, including IFN induction, inflammasome activation, and cell death.
Publication date: 3 July 2018
Source:Cell Reports, Volume 24, Issue 1
Author(s): Yasunori Omata, Michael Frech, Tatjana Primbs, Sébastien Lucas, Darja Andreev, Carina Scholtysek, Kerstin Sarter, Markus Kindermann, Nataliya Yeremenko, Dominique L. Baeten, Nico Andreas, Thomas Kamradt, Aline Bozec, Andreas Ramming, Gerhard Krönke, Stefan Wirtz, Georg Schett, Mario M. Zaiss
Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13−/− ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.
