bluuebunny/crossref_metadata_2025 huggingface dataset:
Disentangling the multiple links between renal dysfunction and cerebrovascular disease
Authors: Kelly Dearbhla , Rothwell Peter Malcolm
Published: September 2019

Chronic kidney disease (CKD) has a rapidly rising global prevalence, affecting as many as one-third of the population over the age of 75 years. CKD is a well-known risk factor for cardiovascular disease and, in particular, there is a strong association with stroke. Cohort studies and trials indicate that reduced glomerular filtration rate increases the risk of stroke by about 40% and that proteinuria increases the risk by about 70%. In addition, CKD is also strongly associated with subclinical cerebrovascular abnormalities, vascular cognitive impairment and dementia. The mechanisms responsible for these associations are currently unclear. CKD is associated with traditional risk factors such as hypertension, diabetes mellitus and atrial fibrillation, but non-traditional risk factors such as uraemia, oxidative stress, mineral and bone abnormalities, and dialysis-related factors, such as changes in cerebral blood flow or cardiac structure, are also postulated to play a role. Kidney disease can also impact and complicate the treatments used in acute stroke and in secondary prevention. In this review, we will outline our current understanding of the epidemiology and pathophysiology of cerebrovascular disease in CKD.
GrowChinook: an optimized multimodel and graphic user interface for predicting juvenile Chinook salmon growth in lentic ecosystems
Authors: Murphy Christina A. , Lee Chee Sing , Johnson Brent , Arismendi Ivan , Johnson Sherri L.
Published: September 2019

Linked foraging and bioenergetics models allow for increased understanding of fish growth potential and behavior by incorporating prey availability coupled to environmental conditions including temperature and prey visibility. To inform our understanding of growth and vertical migration patterns of Chinook salmon (Oncorhynchus tshawytscha) inhabiting lentic ecosystems, we linked foraging and bioenergetics models to create GrowChinook ( http://growchinook.fw.oregonstate.edu/ ). This multimodel design and optimization routine has broad applications in examining growth potential and predicting habitat use in stratified environments. We demonstrate the use of GrowChinook for the spring–summer rearing period in three Willamette River basin reservoirs, Oregon, USA. These reservoirs support juvenile spring Chinook salmon that exhibit a novel reservoir-reared life history that includes larger juvenile fish compared with nearby stream-reared subyearlings. Model outputs of predicted growth and depth use patterns based on observed prey distributions and environmental conditions were corroborated by observed empirical size and growth data from other years. Our simulations support diel vertical migration as a tactic that increases growth potential and contribute to understanding juvenile Chinook salmon growth in stratified systems.
A near horizon extreme binary black hole geometry
Authors: Ciafre Jacob , Rodriguez Maria J.
Published: September 2019

A new solution of four-dimensional vacuum General Relativity is presented. It describes the near horizon region of the extreme (maximally spinning) binary black hole system with two identical extreme Kerr black holes held in equilibrium by a massless strut. This is the first example of a non-supersymmetric, near horizon extreme binary black hole geometry of two uncharged black holes. The black holes are co-rotating, their relative distance is fixed, and the solution is uniquely specified by the mass. Asymptotically, the geometry corresponds to the near horizon extreme Kerr (NHEK) black hole. The binary extreme system has finite entropy.
Application of Chinese Medicine in Acute and Critical Medical Conditions
Authors: Luo Yun , Wang Chong-Zhi , Hesse-Fong Julia , Lin Jaung-Geng , Yuan Chun-Su
Published: September 2019

Western medicine is routinely used in developed nations as well as in Eastern countries, where traditional medicine is frequently used by a selection of patients or family member as a complement to mainstream Western medicine. Chinese medicine plays an important role in the treatment of chronic diseases, especially when Western medicine is not very effective. Many published reports have shown that Chinese medicine could also be successfully used in the management of acute and critical illnesses. Chinese medicine has a holistic view of the human body, and emphasizes individualization based on body balance and mind–body interaction and employs herbal medicines and acupuncture. This review paper gives a brief overview of Chinese medicine theory and therapeutic modality and then addresses the application of Chinese medicine in the treatment of acute and critical medical conditions, including epidemics. Using this ancient therapy as a complementary medicine, the management of serious medical conditions, such as SARS, acute heart diseases, and ischemic cerebral stroke, are presented. In order to promote more widespread application of Chinese medicine, well-designed controlled clinical trials are urgently needed to prove its safety and effectiveness.
Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations
Authors: Duncan Anna L. , Song Wanling , Sansom Mark S.P.
Published: September 2019

Ion channels and G protein–coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABAA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites.
Patient-specific modeling of aerosol delivery in healthy and asthmatic adults
Authors: Poorbahrami Kamran , Mummy David G. , Fain Sean B. , Oakes Jessica M.
Published: September 2019

The magnitude and regional heterogeneity of airway obstructions in severe asthmatics is likely linked to insufficient drug delivery, as evidenced by the inability to mitigate exacerbations with inhaled aerosol medications. To understand the correlation between morphometric features, airflow distribution, and inhaled dosimetry, we perform dynamic computational simulations in two healthy and four asthmatic subjects. Models incorporate computed tomography-based and patient-specific central airway geometries and hyperpolarized 3He MRI-measured segmental ventilation defect percentages (SVDPs), implemented as resistance boundary conditions. Particles [diameters ( dp) = 1, 3, and 5 μm] are simulated throughout inhalation, and we record their initial conditions, both spatially and temporally, with their fate in the lung. Predictions highlight that total central airway deposition is the same between the healthy subjects (26.6%, dp = 3 μm) but variable among the asthmatic subjects (ranging from 5.9% to 59.3%, dp = 3 μm). We found that by preferentially releasing the particles during times of fast or slow inhalation rates we enhance either central airway deposition percentages or peripheral particle delivery, respectively. These predictions highlight the potential to identify with simulations patients who may not receive adequate therapeutic dosages with inhaled aerosol medication and therefore identify patients who may benefit from alternative treatment strategies. Furthermore, by improving regional dose levels, we may be able to preferentially deliver drugs to the airways in need, reducing associated adverse side effects.

NEW & NOTEWORTHY Although it is evident that exacerbation mitigation is unsuccessful in some asthmatics, it remains unclear whether or not these patients receive adequate dosages of inhaled therapeutics. By coupling MRI and computed tomography data with patient-specific computational models, our predictions highlight the large intersubject variability, specifically in severe asthma.
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.
Primary Pericardial Mesothelioma, Which Was Veiled by a Pleural Empyema: A Case Report and Review
Authors: Tajjiou Morad , Wild Wolfgang , Sayed Nasir , Flauaus Alexander , Divo Markus , Schwarzbach Matthias
Published: September 2019

This case report shows that pleural empyema limits the diagnostic significance of imaging techniques. Hereafter, we present the case of an 82-year-old patient with primary pericardial mesothelioma, which was veiled by a pleural empyema. The patient met the typical triad of signs of heart failure (dyspnea, lower leg oedema), pericardial effusion, and pericarditis. Echocardiography in the identification of pericardial mesotheliomas is low. In this case, the cardiac function could be imaged well, but the tumor could not be imaged. The CT showed a pericardial effusion and a pleural effusion. Here, the tumor could not be diagnosed either. Only the operation led to diagnosis.
Dynamics of Breast Cancer under Different Rates of Chemoradiotherapy
Authors: Mkango Sara B. , Shaban Nyimvua , Mureithi Eunice , Ngoma Twalib
Published: September 2019

A type of cancer which originates from the breast tissue is referred to as breast cancer. Globally, it is the most common cause of death in women. Treatments such as radiotherapy, chemotherapy, hormone therapy, immunotherapy, and gene therapy are the main strategies in the fight against breast cancer. The present study aims at investigating the effects of the combined radiotherapy and chemotherapy as a way to treat breast cancer, and different treatment approaches are incorporated into the model. Also, the model is fitted to data on patients with breast cancer in Tanzania. We determine new treatment strategies, and finally, we show that when sufficient amount of chemotherapy and radiotherapy with a low decay rate is used, the drug will be significantly more effective in combating the disease while health cells remain above the threshold.
Gas Sensors Modified with Zeolite Y for Assessing Wine Aroma Compounds
Authors: Paredes-Doig A. L. , Cárcamo H. , Hurtado Cotillo M. , Sun-Kou R. , Doig-Camino E. , Picasso G. , Comina G. , La Rosa-Toro Gómez A.
Published: September 2019

The present work develops a MOS-based e-nose with sensors modified with zeolite Y. For this purpose, the following SnO2 doped with Pd and/or Pt have been prepared: M1 ((0.25 Pd/0.75 Pt)/SnO2), M2 ((0.50 Pd/0.50 Pt)/SnO2), M3 ((0.75 Pd/0.25 Pt)/SnO2), Pd/SnO2, and Pt/SnO2, at the total concentrations of the noble metals of 0.1% and 0.2% for use in gas sensors and be part of the electronic nose. Then, the sensors were assembled with the oxides using the screen printing method. Different electronic noses of four sensors were prepared by combining tin oxides doped with palladium and/or platinum and zeolite Y. The physicochemical characterization of oxides using FRX, FTIR, sorption of N2, and RAMAN has been performed. Measurements for the detection of wine volatile compounds such as ethanol, methanol, 1-phenyl ethanol, propionic acid, and acetic acid were carried out with these sensors located in a gas chamber and using a program that includes the Labview software, which serves to automate the sensing process. It was found that the sensors modified with zeolite were the ones that in general had higher detections of volatile compounds and PCAs showed positive correlations only for ethanol and the mixture of ethanol at 12% and methanol at 3%. This is related to better detection of these sensors.
Train Wheelset Bearing Multifault Impulsive Component Separation Using Hierarchical Shift‐Invariant Dictionary Learning
Authors: Zhang Zhao-heng , Ding Jian-ming , Lin Jian-hui
Published: September 2019

A wheelset bearing is a crucial energy transmission element in high‐speed trains. Any parts of the wheelset bearing that have faults may endanger the safety of the railway service. Therefore, it is important to monitor the running condition of a wheelset bearing. The multifault on a wheelset bearing is very common, and these impulsive components generated by different types of faults may interact with each other, which increases the difficulty of entirely identifying those faults. To solve the multifault problem, this paper proposed a hierarchical shift‐invariant K‐means singular value decomposition (H‐SI‐K‐SVD) to hierarchically separate those multifault impulsive components based on their fault power levels. Each of the separated impulse signals contains only one fault impulse, and the fault information could be highlighted both in time domain and frequency domain. In addition, the sparsity of envelope spectrum (SES) is introduced as an indicator to adaptively tune a key parameter in this method. The effectiveness of the proposed method is verified by both simulation and experimental signals. Compared with ensemble empirical model decomposition (EEMD), the proposed method exhibits better performance in separating the multifault impulsive components and detecting the faults of a wheelset bearing.
Euphorbia bicolor(Euphorbiaceae) Latex Extract Reduces Inflammatory Cytokines and Oxidative Stress in a Rat Model of Orofacial Pain
Authors: Basu Paramita , Hornung Rebecca S. , Averitt Dayna L. , Maier Camelia
Published: September 2019

Recent studies have reported that the transient receptor potential V1 ion channel (TRPV1), a pain generator on sensory neurons, is activated and potentiated by NADPH oxidase-generated reactive oxygen species (ROS). ROS are increased by advanced oxidation protein products (AOPPs), which activate NADPH oxidase by upregulating Nox4 expression. Our previous studies reported thatEuphorbia bicolor(Euphorbiaceae) latex extract induced peripheral analgesia, partlyviaTRPV1, in hindpaw-inflamed male and female rats. The present study reports thatE.bicolorlatex extract also can evoke analgesiaviareduction of oxidative stress biomarkers and proinflammatory cytokines/chemokines in a rat model of orofacial pain. Male and female rats were injected with complete Freund’s adjuvant (CFA) into the left vibrissal pad to induce orofacial inflammation, and mechanical allodynia was measured by the von Frey method. Twenty-four hours later, rats received one injection ofE. bicolorlatex extract or vehicle into the inflamed vibrissal pad. Mechanical sensitivity was reassessed at 1, 6, 24, and/or 72 hours. Trigeminal ganglia and trunk blood were collected at each time point. In the trigeminal ganglia, ROS were quantified using 2′,7′-dichlorodihydrofluorescein diacetate dye, Nox4 protein was quantified by Western blots, and cytokines/chemokines were quantified using a cytokine array. AOPPs were quantified in trunk blood using a spectrophotometric assay.E. bicolorlatex extract significantly reduced orofacial mechanical allodynia in male and female rats at 24 and 72 hours, respectively. ROS, Nox4, and proinflammatory cytokines/chemokines were significantly reduced in the trigeminal ganglia, and plasma AOPP was significantly reduced in the trunk blood of extract-treated compared to vehicle-treated rats.In vitroassays indicate thatE.bicolorlatex extract possessed antioxidant activities by scavenging free radicals. Together our data indicate that the phytochemicals inE. bicolorlatex may serve as novel therapeutics for treating oxidative stress-induced pain conditions.
A Goal Programming Approach to Multichoice Multiobjective Stochastic Transportation Problems with Extreme Value Distribution
Authors: Al Qahtani Hadeel , El–Hefnawy Ali , El–Ashram Maha M. , Fayomi Aisha
Published: September 2019

This paper presents the study of a multichoice multiobjective transportation problem (MCMOTP) when at least one of the objectives has multiple aspiration levels to achieve, and the parameters of supply and demand are random variables which are not predetermined. The random variables shall be assumed to follow extreme value distribution, and the demand and supply constraints will be converted from a probabilistic case to a deterministic one using a stochastic approach. A transformation method using binary variables reduces the MCMOTP into a multiobjective transportation problem (MOTP), selecting one aspiration level for each objective from multiple levels. The reduced problem can then be solved with goal programming. The novel adapted approach is significant because it enables the decision maker to handle the many objectives and complexities of real-world transportation problem in one model and find an optimal solution. Ultimately, a mixed-integer mathematical model has been formulated by utilizing GAMS software, and the optimal solution of the proposed model is obtained. A numerical example is presented to demonstrate the solution in detail.
Gallbladder Polyps Are Associated with Proximal Colon Polyps
Authors: Lee Kuan-Chieh , Jeng Wen-Juei , Hsu Chen-Ming , Kuo Chia-Jung , Su Ming-Yao , Chiu Cheng-Tang
Published: September 2019

Background. The association between gallbladder (GB) disease and colorectal precancerous lesions remains elusive. This study sought to explore the association between GB disease and colorectal neoplasms at different locations. Methods. Patients who received general health checkup from January to December 2008 were included and subgrouped into three groups by polyp location: proximal, distal, and whole colon. GB disease and other known risk factors for colon cancer were compared and analyzed. Different types of polyps at different locations were further investigated. Results. Of a total of 3136 patients (1776 men and 1360 women; mean age, 49.3 years) who had colon polyps, 212 (6.8%) had GB stone and 512 (16.3%) had GB polyps. Patients in the proximal colon polyp group had higher rates of GB polyps and stones. GB polyps were independently associated with proximal colon polyps, including both hyperplastic polyps (odds ratio, 1.523; P=0.034) and adenomatous polyps (odds ratio, 1.351; P=0.048). No relationship between GB polyps and distal or any colon polyps was observed. Irrespective of the polyp location (i.e., proximal, distal, or any part of the colon), GB stone did not show any association with colon polyp. Conclusions. We suggested that GB polyps are associated with proximal colon polyps. Colonoscopy may be a more effective strategy for screening proximal precancerous lesions among patients with GB polyps. The association between GB disease and colon polyps demands further prospective investigation.
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

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

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 < 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 < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 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

Purpose:

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

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 < 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 < 0.001). Larger tumor size was associated with short DFS (HR, 2.384; 95% CI, 1.549–3.056; P < 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 <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 <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

Our 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

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

Locoregional 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 Bdellovibrio exovorous 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 cis-regulatory RNA element responding to flavin mononucleotide (an FMN riboswitch). Bdellovibrio exovorous JSS has a homolog belonging to this superfamily. It has 10 TMSs and shows 30% identity to the previously characterized ImpX transporter from Fusobacterium nucleatum. However, the ImpX homolog is not regulated by an FMN-riboswitch. In order to test the putative function of the ImpX homolog from B. exovorous (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 Escherichia coli strain, but the Khalf 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 F.  nucleatum, but also in the B2 auxotrophic species, B. exovorous.
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

Background: Progressive chronic kidney disease (CKD) inevitably leads to salt and water retention and disturbances in the macro-and microcirculation. Objectives: We hypothesize that salt and water dysregulation in advanced CKD may be linked to inflammation and microvascular injury pathways. Methods: We studied 23 CKD stage 5 patients and 11 healthy controls (HC). Tissue sodium concentration was assessed using 23Sodium magnetic resonance (MR) imaging. Hydration status was evaluated using bioimpedance spectroscopy. A panel of inflammatory and endothelial biomarkers was also measured. Results: 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; p = 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]; p = 0.03), but not the muscle (CKD = 24.9 ± 5.5 mmol/L vs. HC = 22.8 ± 2.5 mmol/L; p = 0.26). Tissue sodium in both compartments correlated to FO (muscle: r = 0.63, p < 0.01; SC: rs = 0.63, p < 0.01). CKD subjects had elevated levels of vascular cell adhesion molecule (p < 0.05), tumor necrosis factor-alpha (p < 0.01), and interleukin (IL)-6 (p = 0.01) and lower levels of vascular endothelial growth factor-C (p = 0.04). FO in CKD was linked to higher IL-8 (r = 0.51, p < 0.05) and inversely associated to E-selectin (r = –0.52, p = 0.01). Higher SC sodium was linked to higher intracellular adhesion molecule (ICAM; rs = 0.54, p = 0.02). Conclusion: 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.
Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective
Authors: Collett-Solberg Paulo F. , Ambler Geoffrey , Backeljauw Philippe F. , Bidlingmaier Martin , Biller Beverly M.K. , Boguszewski Margaret C.S. , Cheung Pik To , Choong Catherine Seut Yhoke , Cohen Laurie E. , Cohen Pinchas , Dauber Andrew , Deal Cheri L. , Gong Chunxiu , Hasegawa Yukihiro , Hoffman Andrew R. , Hofman Paul L. , Horikawa Reiko , Jorge Alexander A.L. , Juul Anders , Kamenický Peter , Khadilkar Vaman , Kopchick John J. , Kriström Berit , Lopes Maria de Lurdes A. , Luo Xiaoping , Miller Bradley S. , Misra Madhusmita , Netchine Irene , Radovick Sally , Ranke Michael B. , Rogol Alan D. , Rosenfeld Ron G. , Saenger Paul , Wit Jan M. , Woelfle Joachim
Published: September 2019

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
Post-Traumatic Endophthalmitis Caused by Oerskovia turbata
Authors: Rohowetz Landon J. , Patel Nimesh A. , Yannuzzi Nicolas A. , Fan Kenneth C. , Miller Darlene , Flynn Jr. Harry W.
Published: September 2019

Purpose: To present a previously unreported cause of bacterial endophthalmitis manifesting as delayed post-traumatic endophthalmitis ultimately responsive to total capsulectomy. Case Report: A patient presented with chronic endophthalmitis that occurred after ocular trauma with organic material and Oerskovia turbata was eventually isolated. After a prolonged treatment course, including two pars plana vitrectomies and total capsulectomy, the patient achieved 20/80 visual acuity at 1-year follow-up. Conclusion: This is the first reported patient with endophthalmitis due to O. turbata, a Gram-positive bacillus found in soil that rarely causes human infection. The infection had a delayed presentation despite early prophylactic antibiotics and was ultimately eliminated with total capsulectomy. Removal of lens and lens capsule may be necessary in the management of post-traumatic endophthalmitis unresponsive to more conservative therapy, particularly in cases involving atypical organisms and lens capsule violation.
Current State of Sarcoma Care in Germany: Results of an Online Survey of Physicians
Authors: Eichler Martin , Richter Stephan , Hohenberger Peter , Kasper Bernd , Andreou Dimosthenis , Heidt Vitali , Bornhäuser Martin , Schmitt Jochen , Schuler Markus K.
Published: September 2019

Background: Sarcoma treatment is a complex and multidisciplinary process. Little is known about the actual status of sarcoma care in Germany. Objectives: We evaluated: (1) on an institutional level, which physician diagnosed and treated sarcomas; (2) whether guidelines and tumor board recommendations were routinely implemented; and (c) access to which diagnosis and treatment options was regarded as problematic. We also examined factors that were associated with access problems. Methods: A cross-sectional online survey was employed among German sarcoma physicians between June 2017 and February 2018 with convenience sampling. Results: Two hundred fourteen physicians participated; 46% were oncologists and 27% surgeons, 38% worked in hospitals of maximum care, 34% were office based and 27% worked in other hospitals, 68% of all of the physicians consulted established guidelines, and 93% presented their patients in multidisciplinary tumor boards. The most common access problems were: isolated limb perfusion (39%), deep-wave hyperthermia (33%), and FDG-PET (27%), and 42% reported no access problems at all. Those physicians who treat more than 100 patients per year reported “no access problems” more frequently compared to centers with lower patient numbers (vs. 0–10 patients, OR 0.14; 95% CI 0.03–0.61; vs. 11–100 patients, OR 0.21; 95% CI 0.06–0.73). Conclusions: Access to multidisciplinary tumor boards seems to be largely guaranteed in the participants of our survey. The use of guidelines could be further implemented and expanded. The number of treated patients appears to be a significant factor to avoid access problems to treatment options.
Renal Pathological Findings in Action Myoclonus-Renal Failure Syndrome
Authors: Desbuissons Geoffroy , Brocheriou Isabelle , Touchard Guy , Goujon Jean-Michel , Méneret Aurélie , Isnard-Bagnis Corinne
Published: September 2019

Action myoclonus – renal failure is a rare syndrome associated with a progressive myoclonic epilepsy and renal impairment that may lead to end-stage renal failure. It is an autosomal recessive genetic disease related to a loss-of-function mutation in SCARB2, which encodes for lysosomal integral membrane protein type 2. Renal involvement is poorly described, and we report here the first electron microscopy renal analysis after having performed a kidney biopsy in a 31-year-old Gambian patient.
Discursos ecologistas e um processo de licenciamento ambiental na região da Baía de Guanabara
Authors: Soares David Gonçalves , Irving Marta Azevedo
Published: September 2019

Neste artigo propomos refletir sobre algumas das principais expressões de defesa ambiental manifestadas por atores sociais participantes de um conflito ambiental. Para tal, analisamos os conflitos ocorridos em função do conturbado processo de licenciamento ambiental do Complexo Petroquímico do Rio de Janeiro (Comperj), no ano de 2007, sob a ótica de seus diferentes atores e discursos em disputa. Analiticamente, esses atores e discursos são associados às três principais matrizes de ecologismo, segundo classificação elaborada por Martinez Alier (2007), as quais são: o culto à vida silvestre, o evangelho da ecoeficiência e o ecologismo dos pobres. Metodologicamente, o trabalho é resultado do acompanhamento etnográfico do processo de licenciamento ambiental, e os desdobramentos no campo ambiental da região. Como principal resultado do trabalho, está a compreensão dos jogos de aliança, aproximação e afastamento entre os argumentos e discursos ecologistas, demonstrando que tais discursos não devem ser observados como essências fixas e imutáveis.
GRILLOTTI DI GIACOMO M. G. Nutrir o homem, vestir o planeta: alimentação - agricultura - ambiente entre imperialismo e cosmopolitismo. Milão: Franco Angeli, 2012.
Authors: Mastroberardino Loredana
Published: September 2019

Nutrir bem o homem é vestir o planeta com formas respeitosas de exploração do ambiente natural e próximas às culturas alimentares das comunidades locais. Essa é a tese central desenvolvida no presente volume por Maria Gemma Grillotti Di Giacomo, responsável pelos temas ligados à alimentação no mundo da Università Campus Bio-Medico di Roma, Itália, autora da obra, que destaca a centralidade do homem na relação Alimentação-Agricultura-Ambiente para dar valor à diversidade e redescobrir a mensagem cosmopolita que o mundo agrícola continua a enviar. O livro aborda o tema da ligação indissociável e complexa que une Alimentação-Agricultura-Ambiente, tratados por uma ótica integrada, cujo equilíbrio depende das políticas agroalimentares dos governos locais e das organizações internacionais. A autora destaca os paradoxos da atual situação agroalimentar, concentra-se sobre a análise histórica da demografia do globo, sobre a capacidade de povoamento da Terra e reconstrói as etapas históricas da evolução da relação Alimentação-Agricultura-Ambiente. Debruça-se também sobre as políticas agrícolas dos países socialistas e dos países capitalistas sensíveis às problemáticas ambientais e territoriais, lança um olhar para a nova PAC (2014-2018), aborda com especial atenção os problemas da agricultura food e no food para a produção de biomassas vegetais destinadas aos agrocombustíveis e para as consequências dessas escolhas relacionadas à má nutrição e à fome, à segurança e à soberania alimentar. Por fim, é também apresentada a metodologia de pesquisa do Grupo de Pesquisa Interuniversitário GECOAGRI-LANDITALY, que interpreta a relação Alimentação-Agricultura-Ambiente do qual a paisagem rural é a expressão mais viva.