bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vestibulo-sympathetic reflex in patients with bilateral vestibular loss
Authors: Kuldavletova O. , Denise P. , Quarck G. , Toupet M. , Normand H. 
Published: September 2019

This study assessed cardiovascular control during head-down neck flexion (HDNF) in a group of patients suffering from total bilateral idiopathic vestibular loss (BVL) for 7 ± 2 yr. Nine adult patients (age 54 ± 6 yr) with BVL were recruited. Calf blood flow (CBF), mean arterial pressure (MAP), and heart rate (HR) were measured with subjects’ eyes closed in two lying body positions: ventral prone (VP) and lateral (LP) on the left side. Vascular resistance (CVR) was calculated as MAP/CBF. The HDNF protocol consisted in passively changing the head position: head up (HU)–head down (HD)–HU. Measurements were taken twice at each head position. In VP CBF significantly decreased in HD (3.65 ± 0.65 mL·min−1·100 mL−1) vs. HU (4.64 ± 0.71 mL·min−1·100 mL−1) ( P < 0.002), whereas CVR in VP significantly rose in HD (31.87 ± 6.93 arbitrary units) vs. HU (25.61 ± 6.36 arbitrary units) ( P < 0.01). In LP no change in CBF or CVR was found between the two head positions. MAP and HR presented no difference between HU and HD in both body positions. Age of patients did not significantly affect the results. The decrease in CBF of the BVL patients was similar to the decrease observed with the same HDNF protocol in normal subjects. This suggests a sensory compensation for the lost vestibular inputs that could originate from the integration of inputs from trunk graviceptors and proprioceptive and cutaneous receptors. Another possibility is that the HDNF vascular effect is evoked mostly by nonlabyrinthine sensors.NEW & NOTEWORTHY The so-called vestibulo-sympathetic reflex, as demonstrated by the head-down neck flexion (HDNF) protocol, is present in patients with total bilateral vestibular idiopathic loss, equally in young and old subjects. The origin of the sympathetic effect of HDNF is questioned. Moreover, the physiological significance of the vestibulo-sympathetic reflex remains obscure, because it acts in opposition to the orthostatic baroreflex. It may serve to inhibit the excessively powerful baroreflex.
Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation
Authors: Wang Victoria E. , Xue Jenny Y. , Frederick Dennie T. , Cao Yi , Lin Eva , Wilson Catherine , Urisman Anatoly , Carbone David P. , Flaherty Keith T. , Bernards Rene , Lito Piro , Settleman Jeff , McCormick Frank 
Published: September 2019

Abstract

Purpose:
Combined MAPK pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAFV600E-driven tumors compared with either agent alone. However, resistance frequently arises.

Experimental Design:
We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacologic synthetic lethal approach to identify a novel, adaptive resistance mechanism mediated through the fibroblast growth factor receptor (FGFR) pathway.

Results:
In response to drug treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which potentiates extracellular signal-regulated kinases (ERK) activation. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in both cell lines and patient-derived xenograft (PDX) models. Abrogation of this bypass mechanism in the first-line setting enhances tumor killing and prevents the emergence of drug-resistant cells. Moreover, clinical data implicate serum FGF1 levels in disease prognosis.

Conclusions:
Taken together, these results describe a new, adaptive resistance mechanism that is more commonly observed in the context of dual BRAF/MEK blockade as opposed to single-agent treatment and reveal the potential clinical utility of FGFR-targeting agents in combination with BRAF and MEK inhibitors as a promising strategy to forestall resistance in a subset of BRAF-driven cancers.
Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy
Authors: Hamy Anne-Sophie , Bonsang-Kitzis Hélène , De Croze Diane , Laas Enora , Darrigues Lauren , Topciu Lucian , Menet Emmanuelle , Vincent-Salomon Anne , Lerebours Florence , Pierga Jean-Yves , Brain Etienne , Feron Jean-Guillaume , Benchimol Gabriel , Lam Giang-Thanh , Laé Marick , Reyal Fabien 
Published: September 2019

Abstract

Purpose:
High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC.

Experimental Design:
We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group.

Results:
Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (PInteraction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P &lt; 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = −0.80, P &lt; 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P &lt; 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02–1.06; P = 0.001), but not in luminal tumors or TNBCs (PInteraction = 0.04).

Conclusions:
The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.
Transcriptomic Analysis Reveals Prognostic Molecular Signatures of Stage I Melanoma
Authors: Thakur Rohit , Laye Jonathan P. , Lauss Martin , Diaz Joey Mark S. , O'Shea Sally Jane , Poźniak Joanna , Filia Anastasia , Harland Mark , Gascoyne Joanne , Randerson-Moor Juliette A. , Chan May , Mell Tracey , Jönsson Göran , Bishop D. Timothy , Newton-Bishop Julia , Barrett Jennifer H. , Nsengimana Jérémie 
Published: September 2019

AbstractPurpose:Previously identified transcriptomic signatures have been based on primary and metastatic melanomas with relatively few American Joint Committee on Cancer (AJCC) stage I tumors, given difficulties in sampling small tumors. The advent of adjuvant therapies has highlighted the need for better prognostic and predictive biomarkers, especially for AJCC stage I and stage II disease.Experimental Design:A total of 687 primary melanoma transcriptomes were generated from the Leeds Melanoma Cohort (LMC). The prognostic value of existing signatures across all the AJCC stages was tested. Unsupervised clustering was performed, and the prognostic value of the resultant signature was compared with that of sentinel node biopsy (SNB) and tested as a biomarker in three published immunotherapy datasets.Results:Previous Lund and The Cancer Genome Atlas signatures predicted outcome in the LMC dataset (P = 10−8 to 10−4) but showed a significant interaction with AJCC stage (P = 0.04) and did not predict outcome in stage I tumors (P = 0.3–0.7). Consensus-based classification of the LMC dataset identified six classes that predicted outcome, notably in stage I disease. LMC class was a similar indicator of prognosis when compared with SNB, and it added prognostic value to the genes reported by Gerami and colleagues. One particular LMC class consistently predicted poor outcome in patients receiving immunotherapy in two of three tested datasets. Biological characterization of this class revealed high JUN and AXL expression and evidence of epithelial-to-mesenchymal transition.Conclusions:A transcriptomic signature of primary melanoma was identified with prognostic value, including in stage I melanoma and in patients undergoing immunotherapy.
Long-Term Survival Analysis of Adjuvant Chemotherapy with or without Trastuzumab in Patients with T1, Node-Negative HER2-Positive Breast Cancer
Authors: He Xuexin , Ji Jiali , Tian Mei , Esteva Francisco J. , Hortobagyi Gabriel N. , Yeung Sai-Ching Jim 
Published: September 2019

Abstract

Purpose:
Adjuvant therapy for small, node-negative HER2-positive breast cancer (HER2+ BC) is controversial. We aimed to identify the subgroup that would benefit most from adjuvant chemotherapy and trastuzumab.

Experimental Design:
We reviewed records of patients with pT1N0M0 HER2+ BC treated at our institution from January 1, 1998, through October 31, 2009. We compared three groups: A, no adjuvant chemotherapy; B, adjuvant chemotherapy only; and C, adjuvant chemotherapy with trastuzumab. We evaluated disease-free survival (DFS), overall survival (OS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) in each group.

Results:
We reviewed 587 consecutive patients with a median follow-up of 123.0 months. The 10-year DFS rate was 81.0%, 65.4%, and 97.3% in groups A, B, and C, respectively (P &lt; 0.001). The restricted mean survival time ratio did not differ between groups A and B [ratio = 0.982; 95% confidence interval (CI), 0.930–1.036; P = 0.498). Cox regression showed that adjuvant chemotherapy with trastuzumab was associated with better DFS compared with no adjuvant chemotherapy [hazard ratio (HR), 0.071; 95% CI, 0.025–0.204; P &lt; 0.001). Larger tumor size was associated with short DFS (HR, 2.384; 95% CI, 1.549–3.056; P &lt; 0.001); improvements in DFS, OS, DRFS, and BCSS were observed with adjuvant chemotherapy plus trastuzumab in patients with tumors ≥0.8-cm diameter. Receiving adjuvant chemotherapy with trastuzumab was not associated with improved DFS, OS, or DRFS for tumors &lt;0.8 cm.

Conclusions:
Adjuvant chemotherapy plus trastuzumab should be recommended for patients with pT1N0M0 HER2+ BC ≥0.8 cm in diameter; adjuvant therapy may not be necessary for tumors &lt;0.8 cm.
Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells
Authors: Fan Ping , Siwak Doris R. , Abderrahman Balkees , Agboke Fadeke A. , Yerrum Smitha , Jordan V. Craig 
Published: September 2019

AbstractOur clinically relevant finding is that glucocorticoids block estrogen (E2)-induced apoptosis in long-term E2-deprived (LTED) breast cancer cells. However, the mechanism remains unclear. Here, we demonstrated that E2 widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), IL6, and TNFα in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFα expression. Furthermore, dexamethasone was synergistic or additive with E2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFα expression induced by E2 in LTED breast cancer cells. Regarding regulation of endoplasmic reticulum stress, dexamethasone effectively blocked activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by E2, but it had no inhibitory effects on inositol-requiring protein 1 alpha (IRE1α) expression increased by E2. Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1α-mediated degradation of PI3K/Akt-associated signal pathways activated by E2. Unexpectedly, activated GR preferentially repressed nuclear factor-κB (NF-κB) DNA-binding activity and expression of NF-κB–dependent gene TNFα induced by E2, leading to the blockade of E2-induced apoptosis. Together, these data suggest that trans-suppression of NF-κB by GR in the nucleus is a fundamental mechanism thereby blocking E2-induced apoptosis in LTED breast cancer cells. This study provided an important rationale for restricting the clinical use of glucocorticoids, which will undermine the beneficial effects of E2-induced apoptosis in patients with aromatase inhibitor–resistant breast cancer.
Metabolic Flexibility in Cancer: Targeting the Pyruvate Dehydrogenase Kinase:Pyruvate Dehydrogenase Axis
Authors: Woolbright Benjamin L. , Rajendran Ganeshkumar , Harris Robert A. , Taylor John A. 
Published: September 2019

Abstract
Cancer cells use alterations of normal metabolic processes to sustain proliferation indefinitely. Transcriptional and posttranscriptional control of the pyruvate dehydrogenase kinase (PDK) family is one way in which cancer cells alter normal pyruvate metabolism to fuel proliferation. PDKs can phosphorylate and inactivate the pyruvate dehydrogenase complex (PDHC), which blocks oxidative metabolism of pyruvate by the mitochondria. This process is thought to enhance cancer cell growth by promoting anabolic pathways. Inhibition of PDKs induces cell death through increased PDH activity and subsequent increases in ROS production. The use of PDK inhibitors has seen widespread success as a potential therapeutic in laboratory models of multiple cancers; however, gaps still exist in our understanding of the biology of PDK regulation and function, especially in the context of individual PDKs. Efforts are currently underway to generate PDK-specific inhibitors and delineate the roles of individual PDK isozymes in specific cancers. The goal of this review is to understand the regulation of the PDK isozyme family, their role in cancer proliferation, and how to target this pathway therapeutically to specifically and effectively reduce cancer growth.
Fenretinide, Tocilizumab, and Reparixin Provide Multifaceted Disruption of Oral Squamous Cell Carcinoma Stem Cell Properties: Implications for Tertiary Chemoprevention
Authors: Mallery Susan R. , Wang Daren , Santiago Brian , Pei Ping , Bissonnette Caroline , Jayawardena Jayanetti Asiri , Schwendeman Steven P. , Spinney Richard , Lang James 
Published: September 2019

AbstractLocoregional recurrence of oral squamous cell carcinoma (OSCC) dramatically reduces patient survival. Further, as many OSCC recurrences are inoperable, radiotherapy and chemotherapy with or without biological adjuncts are the remaining treatment options. Although the tumors may initially respond, radiotherapy- and chemotherapy-resistant cancer stem cells (CSC) can readily repopulate OSCC tumors. Currently, following the initial OSCC treatment, patients are closely monitored until a recurrence or a second primary is detected. Identification of agents with complementary mechanisms to suppress CSC tumorigenic functions could change this passive approach. The goals of this study were twofold: (1) develop and validate CSC-enriched (CSCE) OSCC cell lines and (2) identify chemopreventive agents that obstruct multiple CSCE protumorigenic pathways. CSCE cultures, which were created by paclitaxel treatment followed by three tumorsphere passes, demonstrated CSC characteristics, including increased expression of stem cell and inflammatory genes, increased aldehyde dehydrogenase (ALDH) activity, and enhanced in vitro/in vivo proliferation and invasion. Three chemopreventives, fenretinide, tocilizumab, and reparixin, were selected due to their distinct and complementary CSC-disruptive mechanisms. The CSCE selection process modulated the cells' intermediate filaments resulting in an epithelial-predominant (enhanced cytokeratin, proliferation, IL6 release) line and a mesenchymal-predominant (upregulated vimentin, invasive, IL8 release) line. Our results confirm that 4HPR binds with appreciably higher affinity than Wnt at the Frizzled binding site and significantly inhibits CSC-enabling Wnt–β-catenin downstream signaling. Notably, combination fenretinide–tocilizumab–reparixin treatment significantly suppressed IL6 and IL8 release, stem cell gene expression, and invasion in these diverse CSCE populations. These promising multiagent in vitro data provide the basis for our upcoming in vivo CSCE tertiary chemoprevention studies.
A Riboflavin Transporter in <b><i>Bdellovibrio exovorous</i></b> JSS
Authors: Rodionova Irina A. , Heidari Tajabadi Fereshteh , Zhang Zhongge , Rodionov Dmitry A. , Saier Jr. Milton H. 
Published: September 2019

The ImpX transporters of the drug/metabolite transporter superfamily were first proposed to transport riboflavin (RF; vitamin B2) based on findings of a <i>cis</i>-regulatory RNA element responding to flavin mononucleotide (an FMN riboswitch). <i>Bdellovibrio exovorous</i> JSS has a homolog belonging to this superfamily. It has 10 TMSs and shows 30% identity to the previously characterized ImpX transporter from <i>Fusobacterium nucleatum</i>. However, the ImpX homolog is not regulated by an FMN-riboswitch. In order to test the putative function of the ImpX homolog from <i>B. exovorous</i> (BexImpX), we cloned and heterologously expressed its gene. We used functional complementation, growth inhibition experiments, direct uptake experiments and inhibition studies, suggesting a high degree of specificity for RF uptake. The EC50 for growth with RF was estimated to be in the range 0.5–1 µM, estimated from the half-maximal RF concentration supporting the growth of a RF auxotrophic <i>Escherichia coli</i> strain, but the K<sub>half</sub> for RF uptake was 20 µM. Transport experiments suggested that the energy source is the proton motive force but that NaCl stimulates uptake. Thus, members of the ImpX family members are capable of RF uptake, not only in RF prototrophic species such as <i>F. nucleatum</i>, but also in the B2 auxotrophic species, <i>B. exovorous</i>.
Salt and Water Retention Is Associated with Microinflammation and Endothelial Injury in Chronic Kidney Disease
Authors: Mitsides Nicos , Alsehli Fahad Mohammaed S. , Mc Hough Damien , Shalamanova Liliana , Wilkinson Fiona , Alderdice Jane , Mitra Roshni , Swiecicka Agnieszka , Brenchley Paul , Parker Geoffrey J.M. , Alexander M. Yvonne , Mitra Sandip 
Published: September 2019

<b><i>Background:</i></b> Progressive chronic kidney disease (CKD) inevitably leads to salt and water retention and disturbances in the macro-and microcirculation. <b><i>Objectives:</i></b> We hypothesize that salt and water dysregulation in advanced CKD may be linked to inflammation and microvascular injury pathways. <b><i>Methods:</i></b> We studied 23 CKD stage 5 patients and 11 healthy controls (HC). Tissue sodium concentration was assessed using <sup>23</sup>Sodium magnetic resonance (MR) imaging. Hydration status was evaluated using bioimpedance spectroscopy. A panel of inflammatory and endothelial biomarkers was also measured. <b><i>Results:</i></b> CKD patients had fluid overload (FO) when compared to HC (overhydration index: CKD = 0.5 ± 1.9 L vs. HC = –0.5 ± 1.0 L; <i>p</i> = 0.03). MR-derived tissue sodium concentrations were predominantly higher in the subcutaneous (SC) compartment (median [interquartile range] CKD = 22.4 mmol/L [19.4–31.3] vs. HC = 18.4 mmol/L [16.6–21.3]; <i>p</i> = 0.03), but not the muscle (CKD = 24.9 ± 5.5 mmol/L vs. HC = 22.8 ± 2.5 mmol/L; <i>p</i> = 0.26). Tissue sodium in both compartments correlated to FO (muscle: <i>r</i> = 0.63, <i>p</i> &#x3c; 0.01; SC: <i>r</i><sub>s</sub> = 0.63, <i>p</i> &#x3c; 0.01). CKD subjects had elevated levels of vascular cell adhesion molecule (<i>p</i> &#x3c; 0.05), tumor necrosis factor-alpha (<i>p</i> &#x3c; 0.01), and interleukin (IL)-6 (<i>p</i> = 0.01) and lower levels of vascular endothelial growth factor-C (<i>p</i> = 0.04). FO in CKD was linked to higher IL-8 (<i>r</i> = 0.51, <i>p</i> &#x3c; 0.05) and inversely associated to E-selectin (<i>r</i> = –0.52, <i>p</i> = 0.01). Higher SC sodium was linked to higher intracellular adhesion molecule (ICAM; <i>r</i><sub>s</sub> = 0.54, <i>p</i> = 0.02). <b><i>Conclusion:</i></b> Salt and water accumulation in CKD appears to be linked with inflammation and endothelial activation pathways. Specifically IL-8, E-Selectin (in FO), and ICAM (in salt accumulation) may be implicated in the pathophysiology of FO and merit further investigation.
A americanização das cidades brasileiras: novas formas urbanas e a ideia de unidade de vizinhança
Authors: Rego Renato Leão 
Published: September 2019

Este artigo explora a repercussão da americanização da sociedade brasileira em meados do século XX no campo urbanístico, mais especificamente na conformação de novas cidades nas frentes pioneiras de colonização agrícola, e examina quais ideias norteamericanas contribuíram para a construção de novas formas urbanas no Brasil. Ao analisar os traçados de Goiânia-GO (1936), Angélica-MS (1954), e Medicilândia e Rurópolis-PA (1972), e compreender seu contexto sociocultural, o artigo mostra que a unidade de vizinhança norte-americana ajudou a materializar o anseio local por modernização e desenvolvimento, então referenciados no American way of life. A conformação da unidade de vizinhança no traçado destas novas cidades revela que a ideia norte-americana foi apropriada e adaptada e que o fenômeno da americanização coincidiu com a consolidação da hegemonia do urbanismo racionalista/funcionalista no país, e confundiu-se com ele.
Introduction to a four-year biodiversity survey of Tengchong Section of Gaoligongshan National Nature Reserve, in the footsteps of pioneering naturalists in western Yunnan, China
Authors: Chan Bosco Pui Lok , Bi Zeng , Duan Shao-Zhong 
Published: September 2019

The Gaoligongshan Mountains in Yunnan Province, southwestern China, is one of the biologically richest areas on Earth. In 2014, we launched a four-year biodiversity survey in the Tengchong Section of Gaoligongshan National Nature Reserve and its immediate vicinity, aiming to update the current diversity, distribution, and status of the mammals, birds, herpetofauna, freshwater fishes, and butterflies on which we have expertise. Despite the intensity of earlier scientific explorations, our survey resulted in the discoveries of a new genus, a number of new species, genera and species new to China, Gaoligongshan, or Tengchong County, and updated the altitude limits for some species. Species richness of mammalian and avian fauna, the two groups most susceptible to habitat loss and hunting, remains remarkably high, but past impacts of hunting and habitat degradation were in evidence. Our results clearly illustrate the immense conservation value of this mountain range and the necessity for more in-depth, focused biodiversity field surveys. This monograph summarizes our findings, and this chapter gives an overview of the geography, climate, vegetation, and ecology of Tengchong, a history of earlier and present biodiversity explorations, and conservation recommendations based on our findings.