bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiphoton imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule
Authors: Bugarski Milica , Martins Joana Raquel , Haenni Dominik , Hall Andrew M.
Published: August 2018

Kidney proximal tubules (PTs) are densely packed with mitochondria, and defects in mitochondrial function are implicated in many kidney diseases. However, little is known about intrinsic mitochondrial function within PT cells. Here, using intravital multiphoton microscopy and live slices of mouse kidney cortex, we show that autofluorescence signals provide important functional readouts of redox state and substrate metabolism and that there are striking axial differences in signals along the PT. Mitochondrial NAD(P)H intensity was similar in both PT segment (S)1 and S2 and was sensitive to changes in respiratory chain (RC) redox state, whereas cytosolic NAD(P)H intensity was significantly higher in S2. Mitochondrial NAD(P)H increased in response to lactate and butyrate but decreased in response to glutamine and glutamate. Cytosolic NAD(P)H was sensitive to lactate and pyruvate and decreased dramatically in S2 in response to inhibition of glucose metabolism. Mitochondrial flavoprotein (FP) intensity was markedly higher in S2 than in S1 but was insensitive to changes in RC redox state. Mitochondrial FP signal increased in response to palmitate but decreased in response to glutamine and glutamate. Fluorescence lifetime decays were similar in both S1 and S2, suggesting that intensity differences are explained by differences in abundance of the same molecular species. Expression levels of known fluorescent mitochondrial FPs were higher in S2 than S1. In summary, substantial metabolic information can be obtained in kidney tissue using a label-free live imaging approach, and our findings suggest that metabolism is tailored to the specialized functions of S1 and S2 PT segments.
Urine inositol pentakisphosphate 2-kinase and changes in kidney structure in early diabetic kidney disease in type 1 diabetes
Authors: Looker Helen C. , Merchant Michael L. , Rane Madhavi J. , Nelson Robert G. , Kimmel Paul L. , Rovin Brad H. , Klein Jon B. , Mauer Michael ,   CKD Biomarkers Consortium
Published: August 2018

We examined the association of urine inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IPP2K) with the presence and progression of diabetic kidney disease (DKD) lesions. Urine IPP2K was measured at baseline by quantitative liquid chromatography-mass spectrometry in 215 participants from the Renin-Angiotensin System Study who had type 1 diabetes and were normoalbuminuric and normotensive with normal or increased glomerular filtration rate (GFR). Urine IPP2K was detectable in 166 participants. Participants with IPP2K below the limit of quantification (LOQ) were assigned concentrations of LOQ/√2. All concentrations were then standardized to urine creatinine (Cr) concentration. Kidney morphometric data were available from biopsies at baseline and after 5 yr. Relationships of IPP2K/Cr with morphometric variables were assessed by linear regression after adjustment for age, sex, diabetes duration, hemoglobin A1c, mean arterial pressure, treatment assignment, and, for longitudinal analyses, baseline structure. Baseline mean age was 29.7 yr, mean diabetes duration 11.2 yr, median albumin excretion rate 5.0 μg/min, and mean iohexol GFR 129 ml·min−1·1.73m−2. Higher IPP2K/Cr was associated with higher baseline peripheral glomerular total filtration surface density [Sv(PGBM/glom), tertile 3 vs. tertile 1 β = 0.527, P = 0.011] and with greater preservation of Sv(PGBM/glom) after 5 yr ( tertile 3 vs. tertile 1 β = 0.317, P = 0.013). Smaller increases in mesangial fractional volume ( tertile 3 vs. tertile 1 β = −0.578, P = 0.018) were observed after 5 yr in men with higher urine IPP2K/Cr concentrations. Higher urine IPP2K/Cr is associated with less severe kidney lesions at baseline and with preservation of kidney structure over 5 yr in individuals with type 1 diabetes and no clinical evidence of DKD at baseline.
Downregulation of microRNA-429 contributes to angiotensin II-induced profibrotic effect in rat kidney
Authors: Wang Zhengchao , Zhu Qing , Wang Weili , Hu Junping , Li Pin-Lan , Yi Fan , Li Ningjun
Published: August 2018

MicroRNA (miR) 429 has been shown to inhibit epithelial-to-mesenchymal transition (EMT) in cancer cells. However, the role of miR429 in EMT in non-cancer cells has not been defined, especially in the kidneys. The present study determined whether miR429 participated in angiotensin (ANG) II-induced EMT and fibrogenesis in renal cells. In NRK-52E cells, a rat proximal tubular cell line, incubation of ANG II (10−9 M) for 24 h significantly reduced the level of miR429 by 60% and increased the protein levels of mesenchymal markers α-smooth muscle actin and fibroblast-specific protein-1 by threefold and decreased epithelial marker E-cadherin by 60%, which was blocked by losartan, an AT1 receptor antagonist. Treatment of cells with miR429 inhibitor produced similar changes in the above EMT markers to that induced by ANG II. In cells overexpressed with miR429 transgene, ANG II-induced increases in collagen were abolished. Male Sprague-Dawley rats were infused with ANG II (200 ng·kg−1·min−1) for 12 days, and the levels of miR429 in the kidneys were reduced by 75%. Intrarenal transfection of lentivirus expressing miR429 also reversed the ANG II-induced changes in the EMT markers and collagen in the kidneys. The ANG II-induced increase in urinary albumin was significantly inhibited by miR429 transgene. There was no difference in the increases of blood pressure between ANG II- and ANG II+miR429 transgene-treated rats. These data suggest that ANG II-induced inhibition of miR429 contributes to ANG II-induced transdifferentiation and fibrogenesis in renal cells and that miR429 protects against ANG II-induced kidney damages.
The motor repertoire of older adult fallers may constrain their response to balance perturbations
Authors: Allen Jessica L. , Franz Jason R.
Published: August 2018

Older adults are at a high risk of falls, and most falls occur during locomotor activities like walking. This study aimed to improve our understanding of changes in neuromuscular control associated with increased risk of falls in older adults in the presence of dynamic balance challenges during walking. Motor module (also known as muscle synergy) analyses identified changes in the neuromuscular recruitment of leg muscles during walking with and without perturbations designed to elicit the visual perception of lateral instability. During normal walking we found that a history of falls (but not age) was associated with reduced motor module complexity and that age (but not a history of falls) was associated with increased step-to-step variability of module recruitment timing. Furthermore, motor module complexity was unaltered in the presence of optical flow perturbations. The specific effects of a history of falls on leg muscle recruitment included an absence and/or inability to independently recruit motor modules normally recruited to perform biomechanical functions important for walking balance control. These results suggest that fallers do not recruit the appropriate motor modules necessary for well-coordinated walking balance control even in the presence of perturbations. The identified changes in the modular control of walking balance in older fallers may either represent a neural deficit that leads to poor balance control or a prior history of falls that results in a compensatory motor adaptation. In either case, our study provides initial evidence that a reduced motor repertoire in older adult fallers may be a constraint on their ability to appropriately respond to balance challenges during walking.

NEW & NOTEWORTHY This is the first study to demonstrate a reduced motor repertoire during walking in older adults with a history of falls but without any overt neurological deficits. Furthermore, using virtual reality during walking to elicit the visual perception of lateral instability, we provide initial evidence that a reduced motor repertoire in older adult fallers may be a constraint on their ability to appropriately respond to balance challenges during walking.
Decentering mediates the relationship between vmPFC activation during a stressor and positive emotion during stress recovery
Authors: Bendall Robert C. A. , Royle Sam
Published: August 2018

The stress response has profound implications on health and behavior and stress is considered a risk factor for the development of psychopathologies including depression. The neural mechanisms supporting successful stress recovery are not fully understood; however, a novel study by Yang et al. (Yang X, Garcia KM, Jung Y, Whitlow CT, McRae K, Waugh CE. Soc Cogn Affect Neurosci 13: 256–268, 2018) demonstrates that ventromedial prefrontal cortex (vmPFC) activation during a stressor is related to improved stress recovery, and that decentering is able to mediate this relationship, suggesting a role during stress recovery. It was also revealed that vmPFC activation at different time points during the stressor predicts altering aspects of stress recovery, an observation that was only possible due to the adoption of change-point analysis.
Estilo de vida y agresividad del cáncer de próstata.
Authors: Rojas Pablo A , Hurtado Claudia , Montecinos Viviana P , Godoy Alejandro S , San Francisco Ignacio F
Published: August 2018

Introducción: el objetivo de este estudio fue establecer una asociación entre diversas variables demográficas y epidemiológicas con la agresividad del cáncer de próstata (CaP).Métodos: pacientes diagnosticados con CaP respondieron una encuesta que incluye el nivel de educación, los factores de riesgo cardiovascular (FRCV), los antecedentes familiares (HF) de CaP, consumo de alcohol, tabaquismo y otros. Se utilizó análisis univariado y multivariado (AMV) para establecer si los factores mencionados anteriormente afectan las variables asociadas con la agresividad del CaP, como la edad al momento del diagnóstico, el índice de Gleason, los márgenes positivos (MP) y la metástasis óseas (MO), entre otras.Resultados: se incluyeron ciento setenta y dos hombres en el análisis. Los pacientes con HF fueron diagnosticados a edades más tempranas que los pacientes sin HF (55,73 vs 66,45 años, p = 0,0001). Los pacientes que beben tienen un mayor número de MP que los pacientes que no (15 vs 4 pacientes, p = 0,04). El AMV mostró que los pacientes que consumen alcohol y los que fuman (activos o suspendidos) tuvieron un mayor riesgo de MP (OR = 4,45 y 4,1, IC 95% 1,16-17,07 y 1,14-14,72, respectivamente, ambos p <0,05). Los pacientes con mayor nivel de educación presentaron un mayor riesgo de CaP confinado (OR = 3,42, IC 95% 1,392-8,434, p = 0,007).Conclusiones: los pacientes que consumen alcohol, fuman y tienen un menor nivel de educación presentaron un mayor riesgo de desarrollar CaP agresivo.
Situación socioeconómica familiar y neurodesarrollo de prematuros de muy bajo peso al nacer a los dos años de edad
Authors: Salinas Ulloa Viviana Monzerratt , D’Apremont Ivonne , Mena Patricia , Pittaluga Enrica
Published: August 2018

Introducción: La relación entre neurodesarrollo y contexto social ha sido poco estudiada. Este artículo buscó caracterizar a las familias donde crecen los prematuros de muy bajo peso al nacer con nivel socioeconómico bajo y medio bajo y explorar la posible asociación entre las características socio-familiares y el neurodesarrollo a los dos años.Métodos: Prematuros en seguimiento de un hospital público de Santiago de Chile nacidos entre 2009 y 2012 con encuestas retrospectivas sobre aspectos familiares y sociales, y datos de la evolución clínica fueron analizados. Se evaluó la relación entre los datos biológicos y sociales con neurodesarrollo normal o en déficit.Resultados:   162 casos fueron analizados, 32% fueron considerados con déficit de neurodesarrollo. Las variables biológicas asociadas con el déficit de neurodesarrollo fueron peso al nacer menor a 1000 g. (p < 0,001), uso de ventilación mecánica (p < 0,001), oxígeno dependencia a las 36 semanas edad corregida (EC) (p < 0,001), sepsis tardía (p < 0,001), hemorragia intra-cerebral (p < 0,05), leucomalacia (p < 0,05), hidrocefalia (p < 0,05), convulsiones en período neonatal (p < 0,01) y enterocolitis necrotizante (p < 0,01). Los padres contaban con educación media y superior y se mantuvieron como parejas estables durante el período evaluado. El problema de consumo de alcohol a nivel familiar se asoció con déficit de neurodesarrollo (p<0,05).Conclusiones: Las familias en general tienen los recursos socioeconómicos y de estructura relacionados con desarrollo infantil. Los determinantes biológicos pesaron más que los sociales para el desarrollo infantil.
Enseñanza de la atención del parto vaginal utilizando simuladores
Authors: Rivera Muñoz Fernanda Paz , Valenzuela María , Carvajal Jorge
Published: August 2018

Introducción: La simulación en docencia en ciencias de la salud, permite integrar conocimientos y desarrollar habilidades previo a la práctica clínica, logrando competencias complejas. Además, permite a los estudiantes implementar un cuidado personalizado, pensar críticamente y mejorar la confianza en sus capacidades. Objetivo: evaluar la contribución de la simulación de la atención del parto, en la adquisición de una habilidad esencial para alumnos que optan a desempeñarse en el área obstétrica. Materiales y métodos: se realizó una búsqueda bibliográfica basada en datos PubMed que incluyó las palabras claves simulation, labor y education y sus equivalentes en español. Se excluyeron los títulos relacionados con “anestesia en obstetricia” y “hemorragia postparto”. Se revisaron investigaciones observacionales, descriptivos, revisiones narrativas y sistemáticas, ensayos controlados, estudios cuasi experimentales y prospectivos. Resultados: Se seleccionaron 50 artículos que contenían al menos una de las palabras clave y estaban relacionados con “obstetricia” o “parto”, logrando acceder a 46 de ellos.  La simulación de parto es una estrategia educativa exitosa, que permite a los alumnos sentirse más confiados, mejora el trabajo en equipo, incrementa el grado de conocimiento, mejora habilidades y permite cuidar a las usuarias sin riesgos. Conclusiones: la simulación es un método educativo que permite a los estudiantes practicar lo aprendido en clases antes de iniciar la experiencia clínica, disminuyendo el riesgo de la atención de pacientes por alumnos. Se recomienda el uso de la simulación en la docencia de atención del parto vaginal como una herramienta exitosa que contribuye en la adquisición de habilidades clínicas.
A horcajadas de la IV Revolución Industrial
Authors: Jalil Milad Roberto
Published: August 2018

En un número de abril de este año, la prestigiosa revista Astrophysical Journal publicó un artículo en que investigadores utilizaron inteligencia artificial (IA) para obtener datos de la evolución de una galaxia que probablemente no se habría podido obtener a partir de análisis convencional de imágenes. El software utilizado era una derivación de uno de los softwares que se utilizan en el reconocimiento de rostros utilizando IA. Este ejemplo nos plantea uno de los elementos centrales de lo que ha emergido con el concepto de la Cuarta Revolución Industrial. Ello constituye un momento evolutivo fundamental en el que todos estamos siendo protagonistas, aún sin saberlo.
Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape
Authors: Cubuk Cankut , Hidalgo Marta R. , Amadoz Alicia , Pujana Miguel A. , Mateo Francesca , Herranz Carmen , Carbonell-Caballero Jose , Dopazo Joaquin
Published: August 2018

Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies.

Significance: Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. Cancer Res; 78(21); 6059–72. ©2018 AACR.
Reduced Expression of PROX1 Transitions Glioblastoma Cells into a Mesenchymal Gene Expression Subtype
Authors: Goudarzi Kaveh M. , Espinoza Jaime A. , Guo Min , Bartek Jiri , Nistér Monica , Lindström Mikael S. , Hägerstrand Daniel
Published: August 2018

The homeodomain transcription factor PROX1 has been linked to several cancer types, including gliomas, but its functions remain to be further elucidated. Here we describe a functional role and the prognostic value of PROX1 in glioblastoma. Low expression of PROX1 correlated with poor overall survival and the mesenchymal glioblastoma subtype signature. The latter finding was recapitulated in vitro, where suppression or overexpression of PROX1 in glioma cell cultures transitioned cells to a mesenchymal or to a nonmesenchymal glioblastoma gene expression signature, respectively. PROX1 modulation affected proliferation rates that coincided with changes in protein levels of CCNA1 and CCNE1 as well as the cyclin inhibitors CDKN1A, CDKN1B, and CDKN1C. Overexpression of SOX2 increased PROX1 expression, but treatment with a CDK2 inhibitor subsequently decreased PROX1 expression, which was paralleled by decreased SOX2 levels. The THRAP3 protein was a novel binding partner for PROX1, and suppression of THRAP3 increased both transcript and protein levels of PROX1. Together, these findings highlight the prognostic value of PROX1 and its role as a regulator of glioblastoma gene expression subtypes, intratumoral heterogeneity, proliferation, and cell-cycle control.

Significance: These findings demonstrate the role and prognostic value of PROX1 in glioblastomas; low PROX1 levels correlate with a mesenchymal gene expression subtype and shorter survival in glioblastoma tumors. Cancer Res; 78(20); 5901–16. ©2018 AACR.
Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201
Authors: Jeay Sébastien , Ferretti Stéphane , Holzer Philipp , Fuchs Jeanette , Chapeau Emilie A. , Wartmann Markus , Sterker Dario , Romanet Vincent , Murakami Masato , Kerr Grainne , Durand Eric Y. , Gaulis Swann , Cortes-Cros Marta , Ruetz Stephan , Stachyra Therese-Marie , Kallen Joerg , Furet Pascal , Würthner Jens , Guerreiro Nelson , Halilovic Ensar , Jullion Astrid , Kauffmann Audrey , Kuriakose Emil , Wiesmann Marion , Jensen Michael R. , Hofmann Francesco , Sellers William R.
Published: August 2018

Activation of p53 by inhibitors of the p53–MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53–MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo. Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2–p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure–response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53–MDM2 inhibitors.

Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257–67. ©2018 AACR.
Social Disadvantage, Healthcare Utilization, and Colorectal Cancer Screening: Leveraging Longitudinal Patient Address and Health Records Data
Authors: Hughes Amy E. , Tiro Jasmin A. , Balasubramanian Bijal A. , Skinner Celette Sugg , Pruitt Sandi L.
Published: August 2018

Background:

Social disadvantage predicts colorectal cancer outcomes across the cancer care continuum for many populations and places. For medically underserved populations, social disadvantage is likely intersectional—affecting individuals at multiple levels and through membership in multiple disadvantaged groups. However, most measures of social disadvantage are cross-sectional and limited to race, ethnicity, and income. Linkages between electronic health records (EHR) and external datasets offer rich, multilevel measures that may be more informative.

Methods:

We identified urban safety-net patients eligible and due for colorectal cancer screening from the Parkland-UT Southwestern PROSPR cohort. We assessed one-time screening receipt (via colonoscopy or fecal immunochemical test) in the 18 months following cohort entry via the EHR. We linked EHR data to housing and Census data to generate measures of social disadvantage at the parcel- and block-group level. We evaluated the association of these measures with screening using multilevel logistic regression models controlling for sociodemographics, comorbidity, and healthcare utilization.

Results:

Among 32,965 patients, 45.1% received screening. In adjusted models, residential mobility, residence type, and neighborhood majority race were associated with colorectal cancer screening. Nearly all measures of patient-level social disadvantage and healthcare utilization were significant.

Conclusions:

Address-based linkage of EHRs to external datasets may have the potential to expand meaningful measurement of multilevel social disadvantage. Researchers should strive to use granular, specific data in investigations of social disadvantage.

Impact:

Generating multilevel measures of social disadvantage through address-based linkages efficiently uses existing EHR data for applied, population-level research.
Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction
Authors: Nagle Peter W. , Hosper Nynke A. , Barazzuol Lara , Jellema Anne L. , Baanstra Mirjam , van Goethem Marc-Jan , Brandenburg Sytze , Giesen Ulrich , Langendijk Johannes A. , van Luijk Peter , Coppes Rob P.
Published: August 2018

Purpose:

Radiotherapy for head and neck cancer may result in serious side effects, such as hyposalivation, impairing the patient's quality of life. Modern radiotherapy techniques attempt to reduce the dose to salivary glands, which, however, results in low-dose irradiation of the tissue stem cells. Here we assess the low-dose sensitivity of tissue stem cells and the consequences for tissue function.

Experimental Design:

Postirradiation rat salivary gland secretory function was determined after pilocarpine induction. Murine and patient-derived salivary gland and thyroid gland organoids were irradiated and clonogenic survival was assessed. The DNA damage response (DDR) was analyzed in organoids and modulated using different radiation modalities, chemical inhibition, and genetic modification.

Results:

Relative low-dose irradiation to the high-density stem cell region of rat salivary gland disproportionally impaired function. Hyper-radiosensitivity at doses <1 Gy, followed by relative radioresistance at doses ≥1 Gy, was observed in salivary gland and thyroid gland organoid cultures. DDR modulation resulted in diminished, or even abrogated, relative radioresistance. Furthermore, inhibition of the DDR protein ATM impaired DNA repair after 1 Gy, but not 0.25 Gy. Irradiation of patient-derived salivary gland organoid cells showed similar responses, whereas a single 1 Gy dose to salivary gland–derived stem cells resulted in greater survival than clinically relevant fractionated doses of 4 × 0.25 Gy.

Conclusions:

We show that murine and human glandular tissue stem cells exhibit a dose threshold in DDR activation, resulting in low-dose hyper-radiosensitivity, with clinical implications in radiotherapy treatment planning. Furthermore, our results from patient-derived organoids highlight the potential of organoids to study normal tissue responses to radiation.
Loss of NF2 Induces TGFβ Receptor 1–mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome
Authors: Cho Jung-Hyun , Oh Ah-Young , Park Soyoung , Kang So-mi , Yoon Min-Ho , Woo Tae-Gyun , Hong Shin-Deok , Hwang Jihwan , Ha Nam-Chul , Lee Ho-Young , Park Bum-Joon
Published: August 2018

Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease, and there has been no proper treatment for it until now. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGFβ receptor 2 (TβR2) expression, and an overwhelming expression of TGFβ receptor 1 (TβR1) is activated by physical stimuli such as pressure or heavy materials. Activated TβR1 induces the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snail-mediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, TβR1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2-deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific TβR1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2f/f). Gene expression profiling reveals that TEW7197 treatment induces the expression of lipid metabolism–related gene set, such as NF2-restored cells in HEI-193 (NF2-deficient Schwannoma). Our results indicate that reduction or deletion of TβR2 or NF2 induces the TβR1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGFβ signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and TβR2-mutated advanced cancers. Mol Cancer Ther; 17(11); 2271–84. ©2018 AACR.
Targeting MEK in a Translational Model of Histiocytic Sarcoma
Authors: Takada Marilia , Hix Jeremy M.L. , Corner Sarah , Schall Peter Z. , Kiupel Matti , Yuzbasiyan-Gurkan Vilma
Published: August 2018

Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high-throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling. Both mutations were previously reported in human histiocytic sarcoma. Trametinib inhibited sensitive cell lines by promoting cell apoptosis, indicated by a significant increase in caspase 3/7. Furthermore, in vitro findings were successfully recapitulated in an intrasplenic orthotopic xenograft mouse model, which represents a disseminated aggressive form of histiocytic sarcoma. Mice with histiocytic sarcoma xenograft neoplasms that were treated with trametinib had significantly longer survival times. Target engagement was validated as activity of ERK, downstream of MEK, was significantly downregulated in neoplasms of treated mice. Additionally, trametinib was found in plasma and neoplastic tissues within projected therapeutic levels. These findings demonstrate that in dogs, histiocytic sarcoma may be associated with a dysfunctional MAPK pathway, at least in some cases, and may be effectively targeted through MEK inhibition. Clinical trials to test safety and efficacy of trametinib in dogs with histiocytic sarcoma are warranted, and may provide valuable translational information to similar diseases in humans. Mol Cancer Ther; 17(11); 2439–50. ©2018 AACR.
Association between Allergic Diseases and Irritable Bowel Syndrome: A Retrospective Study
Authors: Fang Zhi-Yun , Zhang Hong-Tao , Lu Chao , Lu Qi-Ming , Yu Chao-Hui , Wang Hui-Ying
Published: August 2018

Background: The relationship between allergic disease and irritable bowel syndrome (IBS) is poorly understood. We aimed to investigate the potential association as well as the underlying immunological mechanisms. Methods: A retrospective case-control study of 108 atopic patients from among outpatients in an allergy clinic (allergic rhinitis [AR], n = 49; chronic urticaria [CU], n = 59) and 74 controls from among ward companions was conducted from November 2016 to March 2017. The detection rates and related gastrointestinal (GI) symptoms of IBS, as well as immunological indices, were calculated. Results: CU patients had a trend of increase in the detection of IBS compared to controls (OR = 4.846; 95% CI 0.967–24.279, p = 0.077). Loose stools (OR = 2.406; 95% CI 1.075–5.386, p < 0.05) and viscous stools (OR = 2.665; 95% CI 1.250–5.682, p < 0.05) were more common in CU patients. Atopic patients positive for serum total immunoglobulin E (IgE) (OR = 3.379; 95% CI 1.088–10.498, p < 0.05) or house dust mite (HDM)-specific IgE (OR = 3.640; 95% CI 1.228–10.790, p < 0.05) were more likely to have abdominal bloating. Besides, a positive association between levels of total IgE and severity of abdominal bloating was observed (p < 0.05). An HDM-specific IgE-positive reaction was independently associated with abdominal bloating in atopic patients (p < 0.05). Conclusions: Allergic disease has a clear clinical association with IBS with more frequent and severe symptoms of IBS. CU patients have a tendency to suffer from IBS, usually with diarrhea. Serum total IgE and HDM-specific IgE are positively correlated with GI symptoms in atopic patients.
Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency
Authors: Yokomichi Naosuke , Nishida Naoshi , Umeda Yuzo , Taniguchi Fumitaka , Yasui Kazuya , Toshima Toshiaki , Mori Yoshiko , Nyuya Akihiro , Tanaka Takehiro , Yamada Takeshi , Yagi Takahito , Fujiwara Toshiyoshi , Yamaguchi Yoshiyuki , Goel Ajay , Kudo Masatoshi , Nagasaka Takeshi
Published: August 2018

Objective: Keratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials. Patients and Methods: In vitro, KRT19 promoter methylation was analyzed and 5-aza-2’-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19 promoter/long interspersed nucleotide element-1 [LINE-1] methylation status). Results: KRT19 promoter methylation was clearly associated with K19 deficiency and 5-aza-2’-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p = 0.025) and extrahepatic recurrence-free survival (p = 0.017). Compared with K19-deficient HCCs, lower KRT19 promoter methylation level was observed in K19-proficient HCCs (p < 0.0001). Conversely, HCC with genome-wide LINE-1 hypermethylation was frequently observed in K19-proficient HCCs (p = 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p = 0.043), and reduced E-cadherin and HepPar-1 expression (p = 0.043 and p < 0.0001, respectively). Conclusions: K19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.
Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis
Authors: Martinez-Merino Leyre , Iridoy Marina , Galbete Arkaitz , Roldán Miren , Rivero Adriana , Acha Blanca , Irún Pilar , Canosa Cecilia , Pocoví Miguel , Mendioroz Maite , Jericó Ivonne
Published: August 2018

Background: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential. Objective: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers. Methods: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory ­biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects. Results: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme. Conclusions: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.
Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application
Authors: Dostert Melanie , Belanger Corrie R. , Hancock Robert E.W.
Published: August 2018

Highly antibiotic resistant, microbial communities, referred to as biofilms, cause various life-threatening infections in humans. At least two-thirds of all clinical infections are biofilm associated, and antibiotic therapy regularly fails to cure patients. Anti-biofilm peptides represent a promising approach to treat these infections by targeting biofilm-specific characteristics such as highly conserved regulatory mechanisms. They are being considered for clinical application and we discuss here key factors in discovery, design, and application, particularly the implementation of host-mimicking conditions, that are required to enable the successful advancement of potent anti-biofilm peptides from the bench to the clinic.
Endoscopic Diagnostic Support System for cT1b Colorectal Cancer Using Deep Learning
Authors: Ito Nao , Kawahira Hiroshi , Nakashima Hirotaka , Uesato Masaya , Miyauchi Hideaki , Matsubara Hisahiro
Published: August 2018

Objective: This study aimed to use convolutional neural network (CNN), a deep learning software, to assist in cT1b diagnosis. Methods: This retrospective study used 190 colon lesion images from 41 cases of colon endoscopies performed between February 2015 and October 2016. Unenhanced colon endoscopy images (520 × 520 pixels) with white light were used. Images included 14 cTis cases with endoscopic resection and 14 cT1a and 13 cT1b cases with surgical resection. Protruding, flat, and recessed lesions were analyzed. AlexNet and Caffe were used for machine learning. Fine tuning of data to increase image numbers was performed. Oversampling for the training images was conducted to avoid impartiality in image numbers, and learning was carried out. The 3-fold cross-validation method was used. Sensitivity, specificity, accuracy, and area under the curve (AUC) values in the receiver operating characteristic curve were calculated for each group. Results: The results were the average of obtained values. With CNN learning, cT1b sensitivity, specificity, and accuracy were 67.5, 89.0, and 81.2%, respectively, and AUC was 0.871. Conclusion: Quantitative diagnosis is possible using an endoscopic diagnostic support system with machine learning, without relying on the skill and experience of endoscopists. Moreover, this system could be used to objectively evaluate endoscopic diagnoses.
Obstructive Sleep Apnoea and Aortic Aneurysm: A Nationwide Population-Based Retrospective Study
Authors: Shih Chang-Chih , Wang Jen-Chun , Tsai Shih-Hung , Chung Chi-Hsiang , Chen Sy-Jou , Liao Wen-I , Tsao Chang-Huei , Wu Yung-Fu  , Chien Wu-Chien
Published: August 2018

Objective: To determine whether patients with obstructive sleep apnoea (OSA) have an increased risk of aortic aneurysm (AA). Methods: The data for the nationwide population-based retrospective cohort study described here were obtained from the Taiwan National Health Insurance Research Database (NHIRD). We selected adult patients who had been newly diagnosed as having OSA and were followed up between 2000 and 2010. We excluded patients who had been diagnosed as having AA before the date of the new OSA diagnosis. The control cohort consisted of individuals who had no OSA history. The patients and the control cohort were selected by 1: 4 matching according to the following baseline variables: sex, age, index year, and comorbidities. The outcome measure was AA diagnosis. Results: In total, 31,274 patients diagnosed as having OSA were identified. Compared to patients without OSA, they had no significantly discrepant cumulative risk of developing AA in subsequent years (p from log-rank test = 0.442). We used the Cox proportional-hazards regression model, which found that only male sex, older age, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and coronary artery disease were independently associated with AA occurrence among subjects with an OSA diagnosis. OSA was not associated with AA development. On the other hand, in the subgroup of COPD, patients with OSA had a higher incidence of risk of AA than those without OSA. Conclusion: When compared to those without OSA, patients with OSA do not have an increased AA risk.
Association of T Helper 1 Cytokine Gene Single Nucleotide Polymorphisms with Ulcerative Colitis and Crohn’s Disease
Authors: Ebrahimi Daryani Nasser , Sadr Maryam , Soltani Samaneh , Saghazadeh Amene , Moossavi Shirin , Shahkarami Sepideh , Farhadi Elham , Rezaei Nima
Published: August 2018

Background: Inflammatory bowel disease (IBD) mostly comprised of Crohn’s disease (CD) and ulcerative colitis (UC) is a condition arising from the combined effects of genetic, environmental, and immunological factors. IBD is associated with inflammation and altered cytokine profile. Objective: This study was aimed at assessing the association between T helper type 1 (Th1) cytokine polymorphisms (interferon gamma [IFN-γ] +874 A/T, interleukin-12 [IL-12] –1188 A/C, IL-2 –330 G/T, IL-2 +166 G/T) and susceptibility to and clinical features of IBD. Methods: The study population was composed of 75 IBD patients (40 CD patients and 35 UC patients) and 140 healthy controls. Genotyping was performed using polymerase chain reaction with sequence-specific primers. Results: The A allele of IFN-γ +874 polymorphism was overrepresented in the whole population of patients with IBD (OR 1.63; 95% CI 1.08–2.47; p = 0.020) and as well in the subpopulation of patients with CD (OR 2.14; 95% CI 1.26–3.63; p = 0.004), but not in UC. Multiple pairwise comparisons indicated that genotypes of single nucleotide polymorphisms (SNPs) within the IL-2 and IFN-γ genes are correlated with IBD, CD, and UC, while neither allele nor genotype frequency of th1 IL-12 –1188 polymorphism was associated with IBD, CD, or UC. Haplotype analysis also revealed that the presence of IL-2 –330/+166 TG haplotype versus the remaining haplotypes (GG, TT, and GT) is a protective factor against IBD (OR 0.62; p = 0.046). Conclusions: The present study reports (for the first time) significant associations between SNPs within the IFN-γ and IL-2 genes and IBD.
A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase
Authors: Giardina Sarah F. , Werner Douglas S. , Pingle Maneesh , Bergstrom Donald E. , Arnold Lee D. , Barany Francis
Published: August 2018

β-Tryptase is released from mast cells upon degranulation in response to allergic and inflammatory stimuli. Human tryptase is a homotetrameric serine protease with 4 identical active sites directed toward a central pore. These active sites present an optimized scenario for the rational design of bivalent inhibitors, which bridge 2 adjacent active sites. Using (3-[1-acylpiperidin-4-yl]phenyl)methanamine as the pharmacophoric core and a disiloxane linker to span 2 active sites we have successfully produced a novel bivalent tryptase inhibitor, compound 1a, with a comparable profile to previously described inhibitors. Pharmacological properties of compound 1a were studied in a range of in vitro enzymic and cellular screening assays, and in vivo xenograft models. This non-peptide inhibitor of tryptase demonstrated superior activity (IC50 at 100 pmol/L tryptase = 1.82 nmol/L) compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and 1a demonstrated good oral bioavailability and efficacy in HMC-1 xenograft models. Furthermore, compound 1a demonstrated extremely slow off rates and high selectivity against-related proteases. This highly potent, orally bioavailable and selective inhibitor of human tryptase will be an invaluable tool in future studies to explore the therapeutic potential of attenuating the activity of this elusive target.
An Unusual Case of DMEK Graft Loss into the Vitreous and Its Successful Retrieval and Survival
Authors: Helaiwa Khaled , Januschowski Kai , Boden Karl T. , Rickmann Annekatrin
Published: August 2018

Purpose: The aim of this article is to report an unusual case of postoperative graft loss into the vitreous cavity after Descemet membrane endothelial keratoplasty (DMEK) in a patient with an unstable iris-lens diaphragm (scleral-fixated intraocular lens [sf-IOL]) and its successful retrieval with a favourable outcome. Methods: This is a retrospective case report. Results: DMEK procedure was performed in a vitrectomized eye of an 80-year-old woman with pre-existing sf-IOL due to pseudophakic bullous keratopathy. In the setting of an inadvertently created oversized Ando iridectomy and unstable iris-lens diaphragm due to sf-IOL, repeated loss of an anterior chamber gas tamponade occurred. At the 3rd postoperative day, the patient noticed a change in visual perception, and we could detect a loss of the graft into the vitreous via B-scan ultrasound. A 23-G vitrectomy was performed promptly to recover the graft using a bimanual hand-over-hand technique. Six months after DMEK, the patient had a clear cornea without dehiscences with a central corneal thickness of 533 µm and endothelial cell count of 1,219 cells/mm2. Conclusions: This case demonstrates the possibility of graft recovery from the vitreous after DMEK and subsequent corneal clearing despite unstable iris-lens diaphragm and vitrectomized eye.
Frequent Mutations in Natural Killer/T Cell Lymphoma
Authors: Zhang Yanjie , Li Chaoping , Xue Weili , Zhang Mingzhi , Li Zhaoming
Published: August 2018

Extranodal natural killer (NK)/T cell lymphoma (ENKTL-NT or NKTCL), with its aggressive nature and poor prognosis, has been widely studied to discover more effective treatment options. Various somatic gene alterations have been identified by traditional Sanger sequencing. However, recently, novel gene mutations in NKTCL have been revealed by next-generation sequencing (NGS) technology, suggesting the potential for novel targeted therapies. This review discusses recurrent aberrations in NKTCL detected by NGS, which can be categorized into three main groups, specifically, tumor suppressors (TP53, DDX3X, and MGA), the JAK/STAT cascade, and epigenetic modifiers (KMT2D, BCOR, ARID1A, and EP300). Some epigenetic dysregulation and DDX3X mutation, which have been rarely identified by traditional sequencing technology, were recently uncovered with high frequencies by NGS. In this review, we summarize the mutational frequencies of various genes in NKTCL. In general, based on our analysis, BCOR is the most frequently mutated gene (16.9%), followed by TP53 (14.7%), and DDX3X (13.6%). The characterization of such genes provides new insight into the pathogenesis of this disease and indicates new biomarkers or therapeutic targets.