bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of Second-Line Pemetrexed-Carboplatin in EGFR-Activating Mutation-Positive NSCLC: Does Exon 19 Deletion Differ from Exon 21 Mutation?
Authors: Joshi Amit , Noronha Vanita , Patil Vijay M. , Chougule Anuradha , Bhattacharjee Atanu , Kumar Rajiv , Goud Supriya , More Sucheta , Ramaswamy Anant , Karpe Ashay , Pande Nikhil , Chandrasekharan Arun , Goel Alok , Talreja Vikas , Mahajan Abhishek , Janu Amit , Purandare Nilendu , Prabhash Kumar
Published: October 2017

Background. It is unknown whether the outcomes of second-line pemetrexed-carboplatin chemotherapy administered after progression on gefitinib are dependent on type of EGFR mutation present at baseline. Method. Adult non-small-cell lung cancer patients, with exon 19 deletion or exon 21 L858R mutation, who progressed on gefitinib and received pemetrexed-carboplatin chemotherapy were selected for this analysis. Result. 55 patients received pemetrexed-carboplatin as second-line treatment. Response rates in evaluable patients were 39.3% in exon 19 patients (n=28) and 33.3% in exon 21 patients (n=15) (p=0.752, Fisher’s exact 2-sided p value). The median PFS in exon 19 and 21 cohorts was 5.900 months (95% CI: 4.274–7.526) and 4.767 months (95% CI: 1.374–8.159), respectively. The median overall survival in exon 19 patients was (11.8 months, 95% CI: 9.916–13.684 months) significantly better than that seen in exon 21 mutation patients (6.2 months, 95% CI: 4.215–8.118 months, p = 0.024) on univariate analysis; however, on multivariate analysis, this association was not confirmed (HR = 0.361, 95% CI: 0.090–1.439, p = 0.149). Conclusion. Exon 19 deletion has no impact on PFS and OS in EGFR-mutated patients treated with second-line pemetrexed-carboplatin.
Analysis of Microbial Diversity in Soil under Ginger Cultivation
Authors: Liu Yiqing , Wu Lin , Wu Xingwen , Li Honghai , Liao Qinhong , Zhang Xiaojing , Sun Zhiqiang , Li Wenhua
Published: October 2017

Ginger is a perennial monocotyledonous herb, which can be used as both a vegetable and a medicinal plant. However, it is susceptible to various plant pathogens. Microbial diversity in soil is related closely to the health and productivity of plant crops including ginger. In the current study, we compared microbial diversity from soil samples under ginger cultivation (disease incidence of >50% [relatively unhealthy sample] versus disease incidence of <10% [relatively healthy sample]). The bacterial and fungal taxa were analyzed by Illumina-based sequencing, with 16S and ITS identification, respectively. Both bacterial and fungal OTUs were significantly more in the healthy soil sample than the unhealthy sample. Moreover, the dominant bacterial and fungal genera were detected to be different in each sample. Rhodanobacter and Kaistobacter were the dominant bacterial genera in the healthy sample, while Rhodoplanes and Bradyrhizobium were the dominant genera in the unhealthy sample. For fungal analysis, Cladosporium, Cryptococcus, and Tetracladium were the dominant genera in the healthy sample, while Lecanicillium, Pochonia, and Rhodotorula were the dominant genera in the unhealthy sample. Collectively, the basic information of microbial diversity in ginger soil is helpful for elucidating the ginger-microbe interactions and potentially selecting suitable plant growth-promoting rhizobacteria and biocontrol agents for ginger production.
Complex Brain Network Analysis and Its Applications to Brain Disorders: A Survey
Authors: Liu Jin , Li Min , Pan Yi , Lan Wei , Zheng Ruiqing , Wu Fang-Xiang , Wang Jianxin
Published: October 2017

It is well known that most brain disorders are complex diseases, such as Alzheimer’s disease (AD) and schizophrenia (SCZ). In general, brain regions and their interactions can be modeled as complex brain network, which describe highly efficient information transmission in a brain. Therefore, complex brain network analysis plays an important role in the study of complex brain diseases. With the development of noninvasive neuroimaging and electrophysiological techniques, experimental data can be produced for constructing complex brain networks. In recent years, researchers have found that brain networks constructed by using neuroimaging data and electrophysiological data have many important topological properties, such as small-world property, modularity, and rich club. More importantly, many brain disorders have been found to be associated with the abnormal topological structures of brain networks. These findings provide not only a new perspective to explore the pathological mechanisms of brain disorders, but also guidance for early diagnosis and treatment of brain disorders. The purpose of this survey is to provide a comprehensive overview for complex brain network analysis and its applications to brain disorders.
Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy
Authors: Taylor Alison , Rothstein David , Rudd Christopher E.
Published: October 2017

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small-molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti–PD-1 and PD-L1–blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3α/β reduced PD-1 expression on CD8+ T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T cells. Finally, the adoptive transfer of T cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti–PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1–blocking antibodies.

Significance: These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. Cancer Res; 78(3); 706–17. ©2017 AACR.
A Synthetic CD8α:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens
Authors: Kaczanowska Sabina , Joseph Ann Mary , Guo Jitao , Tsai Alexander K , Lasola Jackline Joy , Younger Kenisha , Zhang Yuji , Gonzales Cruz Velasco , Davila Eduardo
Published: October 2017

T cell–based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T-cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88–engineered T cells exhibited increased proliferation and expression of effector and costimulatory molecules in a tumor antigen–dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor signaling-related proteins. CD8α:MyD88–expressing T cells improved antitumor responses in mice. Enhanced antitumor activity was associated with a unique tumor cytokine/chemokine signature, improved T-cell infiltration, reduced markers of T-cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T-cell responses to tumor antigens. Cancer Res; 77(24); 7049–58. ©2017 AACR.
[18F]fluorothymidine PET Informs the Synergistic Efficacy of Capecitabine and Trifluridine/Tipiracil in Colon Cancer
Authors: Kim Seog-Young , Jung Jin Hwa , Lee Haeng Jung , Soh Hyunsu , Lee Sang Ju , Oh Seung Jun , Chae Sun Young , Lee Jai Hyuen , Lee Seung Jin , Hong Yong Sang , Kim Tae Won , Moon Dae Hyuk
Published: October 2017

In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10–12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30–360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6–10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = −0.81, P = 0.02). The effects of these combinations were synergistic in vitro. A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. Cancer Res; 77(24); 7120–30. ©2017 AACR.
SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance
Authors: Orlacchio Arturo , Ranieri Michela , Brave Martina , Arciuch Valeria Antico , Forde Toni , De Martino Daniela , Anderson Karen E. , Hawkins Phillip , Di Cristofano Antonio
Published: October 2017

Activation of the PI3K–AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade. Cancer Res; 77(24); 6914–26. ©2017 AACR.
Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)
Authors: Sung Matthew , Tan Xingzhi , Lu Bingwen , Golas Jonathan , Hosselet Christine , Wang Fang , Tylaska Laurie , King Lindsay , Zhou Dahui , Dushin Russell , Myers Jeremy S. , Rosfjord Edward , Lucas Judy , Gerber Hans-Peter , Loganzo Frank
Published: October 2017

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2+ tumors, are not well understood. We used HER2+ cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an “on-off” routine until a T-DM1–resistant population was generated. T-DM1–resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non–cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells. Intriguingly, T-ADCs using auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors that remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1)–positive puncta and alter their trafficking to the lysosome compared with N87 cells. T-DM1 colocalization into intracellular CAV1-positive puncta correlated with reduced response to T-DM1 in a panel of HER2+ cell lines. Together, these data suggest that caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1. Mol Cancer Ther; 17(1); 243–53. ©2017 AACR.
CCL26 Participates in the PRL-3–Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor-Associated Macrophage Infiltration
Authors: Lan Qiusheng , Lai Wei , Zeng Yujie , Liu Lu , Li Shoufeng , Jin Shaowen , Zhang Yang , Luo Xingxi , Xu Heyang , Lin Xiangan , Chu Zhonghua
Published: October 2017

Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAM) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer invasion and metastasis by inducing TAM infiltration remains unclear. In the current study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and colorectal cancer invasion and the underlying mechanism in colorectal cancer cells by overexpressing or silencing PRL-3. We found that PRL-3 upregulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. In addition, IHC analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV colorectal cancer tissues and were associated with a worse prognosis in colorectal cancer patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were cocultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca2+of TAMs to increase the expression of IL6 and IL8. In addition, IHC results indicated that protein levels of CCR3 and TAMs counts were higher in stage III and IV colorectal cancer tissues and correlated with CCL26. Moreover, similar results were observed in vivo using mice injected with LoVo-P and HT29-C cells. These data indicate that PRL-3 may represent a potential prognostic marker that promotes colorectal cancer invasion and metastasis by upregulating CCL26 to induce TAM infiltration. Mol Cancer Ther; 17(1); 276–89. ©2017 AACR.
Antibakterielle In-vitro-Wirksamkeit ätherischer Öle gegen veterinärmedizinisch relevante Keime klinischer Isolate von Hunden, Katzen und Pferden
Authors: Bismarck Doris , Schneider Marianne , Müller Elisabeth
Published: October 2017

Einleitung: Ätherische Öle sind die Grundlage der Aromatherapie. Unter anderem wird ihnen eine antibakterielle Wirkung zugeschrieben. In dieser Studie sollte die In-vitro-Wirksamkeit ätherischer Öle gegen ein breites Spektrum veterinärmedizinisch relevanter Erreger getestet werden. Methoden: Die antibakterielle Aktivität von 16 ätherischen Ölen wurde mittels Agardiffusionstest bestimmt. Getestet wurden grampositive und gramnegative Erreger, die aus klinischen Isolaten von Hunden, Katzen und Pferden aus der veterinärmedizinischen Routinediagnostik stammten. Die Einteilung der Wirksamkeit in nicht, gering-, mittel- und hochgradig wirksam erfolgte anhand der Größe der Hemmhofradien des Bakterienwachstums. Ergebnisse: Generell zeigten sich sowohl grampositive als auch gramnegative Erreger empfindlich gegen einige der getesteten ätherischen Öle. Nicht nur gegen Staphylokokken, sondern auch gegen Methicillin-resistente Stämme der Staphylokokken wiesen die ätherischen Öle in vitro eine nicht zu vernachlässigende Wirkung auf. Pasteurella multocida stellte sich als eher sensibler Keim heraus, während Pseudomonas aeruginosa als vollkommen resistenter Keim eine Ausnahme bildete. Teebaum-, Oregano-, und Bergbohnenkrautöl waren die potentesten Öle. Zusätzlich zeigten sich bei den grampositiven Erregern Lemongrasöl und bei den gramnegativen Erregern Thymianöl als gut wirksam. Schlussfolgerung: Ätherische Öle verfügen in vitro über eine antibakterielle Aktivität gegen klinische Isolate von Hunden, Katzen und Pferden. Diese Studie bietet eine Grundlage für die Anwendung ätherischer Öle in der Veterinärmedizin. Es zeichneten sich Tendenzen im Wirkspektrum einzelner ätherischer Öle bzw. im Grad der Wirksamkeit ätherischer Öle hinsichtlich einzelner Erregerspezies ab, allerdings lässt sich keine sichere Vorhersage über ihre Wirksamkeit gegen einen spezifischen Keim eines individuellen Patienten treffen. Deswegen sollte vor einer Therapie mit ätherischen Ölen deren individuelle Wirksamkeit mittels Aromatogramm getestet werden.
Undiagnosed Esophageal Adenocarcinoma Presenting as Multiple Brain Metastases
Authors: Grzywacz Vincent , Balcueva Ernie
Published: October 2017

Brain metastases from gastrointestinal malignancies are exceedingly rare occurrences that carry a very poor prognosis. This holds especially true in cases where brain metastases from esophageal primaries are the initial presentation of a previously unidentified gastrointestinal malignancy. Our patient, a 60-year-old male with a past history of a right temporal teratoma, family history of breast cancer, and no smoking history, presented with a chief complaint of recurrent headaches. His history of present illness and physical examination included a two-month history of frontal headache, progressive fatigue, and unintentional weight loss. He underwent an extensive initial workup including CT-head, CT-abdomen/pelvis, CT-chest, bone scan, tumor marker analysis, and MRI-brain. The initial head CT revealed multiple intracranial lesions suspicious for malignancy. A PET scan later revealed his primary to be a malignancy of the distal esophagus. His treatment course thus far has been aggressive, consisting of surgical resection, systemic chemotherapy with capcetibine-oxaliplatin as well as paclitaxel-carboplatin, and radiation therapy. He has had several recurrences since starting treatment, but has continued to maintain a good performance status with only minor symptoms. Currently, the patient has survived for 17 months after his diagnosis of stage IV (T3, N2, M1) moderately differentiated adenocarcinoma and is undergoing treatment with trastuzumab and stereotactic radiosurgery. This report demonstrates that although cases of esophageal adenocarcinoma that present as brain metastases typically carry a poor prognosis, with early and aggressive treatment patients can survive well past one year after diagnosis.
Effect of Magnesium on Glomerular Filtration Rate and Recovery of Hypertension in Women with Severe Preeclampsia
Authors: Kreepala Chatchai , Luangphiphat Wongsakorn  , Villarroel Alfredo  , Kitporntheranunt Maethaphan  , Wattanavaekin Krittanont , Piyajarawong Teeraya 
Published: October 2017

Introduction: Magnesium sulfate is used for preventing seizures in patients with severe preeclampsia. Previous studies have demonstrated that magnesium plays a significant role in the endothelial function and might have clinically beneficial vasodilating properties. Objectives: This study is aimed at evaluating the effect of magnesium sulfate on the glomerular filtration rate (GFR) during the first 24 h after delivery and during the duration of recovery from hypertension in preeclampsia. Methods: Severe preeclamptic patients who had normal serum creatinine levels (0.4–0.8 mg/dL) were included in the study. Twenty-three women with severe preeclampsia were divided into groups of 9, 8, and 6, and given 1.0, 1.5, and 2.0 g/h of magnesium sulfate, respectively. Magnesium sulfate infusion was used as seizure prophylaxis for 24 h after delivery. The cystatin C-based GFR was monitored for 24 h, and the blood pressure was recorded for 12 weeks postpartum. Results: Despite the minimal improvement of GFR 24-h after treatment initiation, survival analysis demonstrated a statistically significant relationship (log rank, p = 0.04) between magnesium dosage and recovery period from hypertension. The group receiving 2.0 g/h of magnesium experienced the shortest recovery period from hypertension (6.5 ± 1.8 days). Meanwhile, the other groups required 66.0 ± 26.9 and 48.3 ± 15.6 days to recover after 1.0 and 1.5 g/h of magnesium infusion, respectively. Conclusion: Magnesium sulfate has no impact on GFR improvement during the first 24 h after delivery. However, magnesium maintenance infusion at 2.0 g/h is capable of preventing seizure by optimizing the therapeutic magnesium level (4.8–8.4 mg/dL) and shortening the hypertensive episode in preeclampsia.
CD30+ Cutaneous Anaplastic Large-Cell Lymphoma of the Upper Eyelid: A Case Report
Authors: Olivier Stéphanie , Dachelet Claire , Theate Ivan , Tromme Isabelle , Baeck Marie
Published: October 2017

CD30+ cutaneous anaplastic large-cell lymphoma is part of the CD30+ T-cell lymphoproliferative disorders. This type of lymphoma is in most cases indolent, with a high survival rate. We report the case of a 59-year-old patient with a 1-month lasting crusty lesion of the upper eyelid. Eyelid involvement is very uncommon, as the most frequent locations are the trunk and the limbs.
Plac1 Expression Pattern at the Mouse Fetomaternal Interface and Involvement in Trophoblast Differentiation
Authors: Gu Yanli , Wan Junhui , Yao Lv , Peng Nan-Ni , Chang Wen-Lin
Published: October 2017

Background/Aims: It is well known that Plac1 is a placenta-specific gene; however, its spatiotemporal expression pattern and exact role at t h e mouse fetomaternal interface r e m a i n s unclear. Methods: In situ hybridization (ISH) was used to localize the Plac1 mRNA at the mouse fetomaternal interface. A trophoblast stem cell (TS) differentiation model with Plac1 shRNA-overexpressing lentivirus was employed to investigate the possible role of Plac1 in placentation. Real-time RT-PCR was used to detect changes in gene expression. Results: Plac1 was exclusively expressed in the ectoplacental cone (EPC) as well as in 8.5 and 9.5 days post-coitum (dpc) embryos. Subsequently, Plac1 expression was abundant in the spongiotrophoblast layer and moderately in the labyrinth layer until 13.5 dpc, and declined thereafter. Interestingly, Plac1 was also expressed by secondary trophoblast giant cells and glycogen trophoblast cells, but not in primary trophoblast giant cells. Plac1 transcription was increased during the TS differentiation (P < 0.01), and knockdown of Plac1 significantly impaired TS differentiation. Conclusion: Plac1 is abundantly expressed at the fetomaternal interface and in all trophoblast subtypes except in primary trophoblast giant cells. Plac1 knockdown retarded the progress of TS differentiation, indicating that Plac1 is necessary for normal trophoblast differentiation into various trophoblast subpopulations.
MiR-1246 Promotes LPS-Induced Inflammatory Injury in Chondrogenic Cells ATDC5 by Targeting HNF4γ
Authors: Wu Da-Peng , Zhang Jun-Lei , Wang Jing-Yu , Cui Ming-Xing , Jia Jin-Ling , Liu Xiang-Hua , Liang Qiu-Dong
Published: October 2017

Background/Aims: Osteoarthritis (OA) is a common inflammatory joint disease. miRNAs are associated with OA and functionally implicated in the pathogenesis of the disease. In the present study, we investigated the role of miR-1246 in the lipopolysaccharide (LPS)-induced inflammatory injury of ATDC5 cells. Methods: ATDC5 cells were cultured and treated with LPS in a series of concentration (0, 1, 5, and 10 µg/ml) for 5 h. The cells were transfected with miR-1246-mimic, inhibitor, si-HNF4γ or negative control, then were assessed for cell viability using CCK8 assay, apoptosis by flow-cytometry and expressions of miR-1246 and pro-inflammatory cytokines by qRT-PCR and western blot analysis. Results: Cell viability was significantly reduced and cell apoptosis was added in ATDC5 cells injured with LPS at the dosage of 5 and 10 µg/ml. Relative mRNA expressions of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) were significantly increased. miR-1246 was up-regulated in ATDC5 cells treated with LPS. Moreover, miR-1246 overexpression aggravated LPS-induced decrease in cell viability, increase in apoptosis and overproduction of pro-inflammatory factors. mRNA and protein expressions of HNF4γ were significantly suppressed in cells transfected with miR-124-mimic. Further, miR-1246 knockdown alleviated LPS-induced inflammatory injury by up-regulating the expression of HNF4γ and activation of PI3K/AKT and JAK/STAT pathways. Conclusions: Suppression of miR-1246 alleviated LPS-induced inflammatory injury in chondrogenic ADTC5 cells by up-regulation of HNF4γ and activation of PI3K/AKT and JAK/STAT pathways. The findings of this study will provide a novel viewpoint regarding miR-1246 target for clinical.
Technical issues and conservation conditions of medicines in the primary health care of the Brazilian Unified Health System
Authors: Costa Ediná Alves , Araújo Patrícia Sodré , Pereira Marcelo Tavares , Souto Ana Cristina , Souza Gisélia Santana , Guerra Junior Augusto Afonso , Acurcio Francisco de Assis , Guibu Ione Aquemi , Alvares Juliana , Costa Karen Sarmento , Karnikowski Margô Gomes de Oliveira , Soeiro Orlando Mario , Leite Silvana Nair
Published: October 2017

OBJECTIVE: To characterize the technical issues and conditions of medicines conservation in Primary Health Care of Brazilian regions, responsible for pharmacy/dispensing unit profile; environmental, storage, and dose fractioning conditions; inventory control and waste management; fire and electrical failure safety items; transportation problems; advertising regulation; and pharmacovigilance. METHODS: This article is part of the Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos – Serviços (National Survey on Access, Use and Promotion of Rational Use of Medicines – Services)–, a cross-sectional and exploratory study, of evaluative nature, consisting of an information survey within a representative sample of municipalities, stratified by Brazilian regions, which constitute the study domains, and a sample of Primary Health Care services. Pharmaceutical services (PS) were directly observed with photographic record and face-to-face interviews with those responsible for the dispensing of medicines and over the telephone with those responsible for pharmaceutical services. Data were processed with the SPSS® software version 21.RESULTS: The investigated dimensions showed relevant deficiencies and inequalities between the regions, generally more favorable in the Southeast and Midwest regions and weaker in the Northeast and North regions. We verified non-compliance with technical requirements and conditions essential to the conservation of medicines, which may interfere with the maintenance of stability and, thus, on their quality, efficacy, and safety. The regulation of advertising/promotion of medicines is still incipient and there is some progress in the structuring of mechanisms regarding pharmacovigilance. CONCLUSIONS: The sanitary situation of medicines in Brazilian Primary Health Care is alarming due to the violation of the specific sanitary legislation for dispensing establishments and due to a wide range of requirements essential to the conservation of medicines. We observed a disconnection between the efforts made in the Brazilian Unified Health System to promote access to medicines for all population and the organization and qualification of pharmaceutical services
Access to medicines by patients of the primary health care in the Brazilian Unified Health System
Authors: Álvares Juliana , Guerra Junior Augusto Afonso , Araújo Vânia Eloisa de , Almeida Alessandra Maciel , Dias Carolina Zampirolli , Ascef Bruna de Oliveira , Costa Ediná Alves , Guibu Ione Aquemi , Soeiro Orlando Mario , Leite Silvana Nair , Karnikowski Margô Gomes de Oliveira , Costa Karen Sarmento , Acurcio Francisco de Assis
Published: October 2017

OBJECTIVE: To evaluate the access to medicines in primary health care of the Brazilian Unified Health System (SUS), from the patients’ perspective. METHODS: This is a cross-sectional study that used data from the Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos – Services, 2015 (PNAUM – National Survey on Access, Use and Promotion of Rational Use of Medicines), conducted by interviews with 8,591 patients in cities of the five regions of Brazil. Evaluation of access to medicines used concepts proposed by Penshansky and Thomas (1981), according to the dimensions: availability, accessibility, accommodation, acceptability, and affordability. Each dimension was evaluated by its own indicators. RESULTS: For the “availability” dimension, 59.8% of patients reported having full access to medicines, without significant difference between regions. For “accessibility,” 60% of patients declared that the basic health unit (UBS) was not far from their house, 83% said it was very easy/easy to get to the UBS, and most patients reported that they go walking (64.5%). For “accommodation,” UBS was evaluated as very good/good for the items “comfort” (74.2%) and “cleanliness” (90.9%), and 70.8% of patients reported that they do not wait to receive their medicines, although the average waiting time was 32.9 minutes. For “acceptability,” 93.1% of patients reported to be served with respect and courtesy by the staff of the dispensing units and 90.5% declared that the units’ service was very good/good. For “affordability,” 13% of patients reported not being able to buy something important to cover expenses with health problems, and 41.8% of participants pointed out the expense with medicines. CONCLUSIONS: Results show 70%–90% compliance, which is compatible with developed countries. However, access to medicines remains a challenge, because it is still heavily compromised by the low availability of essential medicines in public health units, showing that it does not occur universally, equally, and decisively to the population
Use of medicines by patients of the primary health care of the Brazilian Unified Health System
Authors: Costa Clarisse Melo Franco Neves , Silveira Micheline Rosa , Acurcio Francisco de Assis , Guerra Junior Augusto Afonso , Guibu Ione Aquemi , Costa Karen Sarmento , Karnikowski Margô Gomes de Oliveira , Soeiro Orlando Mario , Leite Silvana Nair , Costa Ediná Alves , Nascimento Renata Cristina Rezende , Araújo Vânia Eloísa de , Álvares Juliana
Published: October 2017

OBJECTIVE: To characterize the use of medicines by patients of the primary health care of the Brazilian Unified Health System (SUS). METHODS: This is a cross-sectional, exploratory, and descriptive study, part of the Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos – Serviços, 2015 (PNAUM – National Survey on Access, Use and Promotion of Rational Use of Medicines – Services, 2015). Interviews were carried out with patients present in the services by semi-structured questionnaires. Sociodemographic, clinical, and use of medicines variables were assessed and the use of medicines in the 30 days prior to the interview was also verified. The population was stratified into three age groups: 18 to 44, 45 to 64, and 65 years or more. The differences between the age groups were verified using the Student’s t-test for continuous variables and chi-square test for the categorical ones. The complex samples analysis plan was employed. The medicines were classified according to the Anatomical Therapeutic Chemical Classification System. RESULTS: Of the 8,803 patients interviewed, 6,511 (76.2%) reported to have used medicines in the 30 days prior to the interview. On average, each patient used 2.32 medicines, without difference between the sexes. Among medicine users, 18.2% were aged 65 years or more. Compared to the other age groups, older adults presented more comorbidities, used more medicines, and self-reported worse health conditions. They were also less educated, reported worse economic situation, and lived alone. The medicines that were mostly used were “other analgesics and antipyretics” (3rd ATC level) and Losartan (5th ATC level). CONCLUSIONS: Most medicine users had lower education level and presented comorbidities. The most used medicines were the antihypertensive ones. Self-medication was higher among young people. Most patients reported to use generic medicines. The average number of medicines and the prevalence of use increased with age. Due to the characteristics observed and the difficulties in the use of medicines, older adults are in a situation of greater vulnerability
The Impact of De‐escalation of Antianginal Medications on Health Status After Percutaneous Coronary Intervention
Authors: Qintar Mohammed , Towheed Arooge , Tang Fengming , Salisbury Adam C. , Ho P. Michael , Grantham J. Aaron , Spertus John A. , Arnold Suzanne V.
Published: October 2017

Background

Antianginal medications (
AAMs
) can be perceived to be less important after percutaneous coronary intervention (
PCI
) and may be de‐escalated after revascularization. We examined the frequency of
AAM
de‐escalation at discharge post‐
PCI
and its association with follow‐up health status.

Methods and Results

In a 10‐center
PCI
registry, the Seattle Angina Questionnaire was assessed before and 6 months post‐
PCI
.
AAM
de‐escalation was defined as fewer
AAMs
at discharge versus admission or >25% absolute dose decrease. Of 2743
PCI
patients (70% male),
AAM
were de‐escalated, escalated, and unchanged in 299 (11%), 714 (26%), and 1730 (63%) patients, respectively. Patients whose
AAM
were de‐escalated were more likely to report angina at 6 months, compared with unchanged or escalated
AAM
(34% versus 24% versus 21%;
P
<0.001). The association of
AAM
de‐escalation with health status was examined using multivariable models adjusting for the predicted risk of post‐
PCI
angina, completeness of revascularization, and the interaction of
AAM
de‐escalation×completeness of revascularization. There was a significant interaction between
AAM
de‐escalation and completeness of revascularization (
P
<0.001), suggesting that
AAM
de‐escalation was associated with greater impairment of health status among patients with incomplete revascularization. In patients with incomplete revascularization, de‐escalation of
AAM
at discharge was associated with 43% increased angina risk (relative risk, 1.43; 95% confidence interval, 1.26–1.63) and worse angina‐related health status at 6 months post‐
PCI
.

Conclusions

De‐escalation of
AAM
occurs in 1 in 10 patients post‐
PCI
, and it is associated with an increased risk of angina and worse health status, particularly among those with incomplete revascularization.
Development and Validation of a Predictive Model for Functional Outcome After Stroke Rehabilitation
Authors: Scrutinio Domenico , Lanzillo Bernardo , Guida Pietro , Mastropasqua Filippo , Monitillo Vincenzo , Pusineri Monica , Formica Roberto , Russo Giovanna , Guarnaschelli Caterina , Ferretti Chiara , Calabrese Gianluigi
Published: October 2017

Background and Purpose—

Prediction of outcome after stroke rehabilitation may help clinicians in decision-making and planning rehabilitation care. We developed and validated a predictive tool to estimate the probability of achieving improvement in physical functioning (model 1) and a level of independence requiring no more than supervision (model 2) after stroke rehabilitation.

Methods—

The models were derived from 717 patients admitted for stroke rehabilitation. We used multivariable logistic regression analysis to build each model. Then, each model was prospectively validated in 875 patients.

Results—

Model 1 included age, time from stroke occurrence to rehabilitation admission, admission motor and cognitive Functional Independence Measure scores, and neglect. Model 2 included age, male gender, time since stroke onset, and admission motor and cognitive Functional Independence Measure score. Both models demonstrated excellent discrimination. In the derivation cohort, the area under the curve was 0.883 (95% confidence intervals, 0.858–0.910) for model 1 and 0.913 (95% confidence intervals, 0.884–0.942) for model 2. The Hosmer–Lemeshow χ
2
was 4.12 (
P
=0.249) and 1.20 (
P
=0.754), respectively. In the validation cohort, the area under the curve was 0.866 (95% confidence intervals, 0.840–0.892) for model 1 and 0.850 (95% confidence intervals, 0.815–0.885) for model 2. The Hosmer–Lemeshow χ
2
was 8.86 (
P
=0.115) and 34.50 (
P
=0.001), respectively. Both improvement in physical functioning (hazard ratios, 0.43; 0.25–0.71;
P
=0.001) and a level of independence requiring no more than supervision (hazard ratios, 0.32; 0.14–0.68;
P
=0.004) were independently associated with improved 4-year survival. A calculator is freely available for download at
https://goo.gl/fEAp81
.

Conclusions—

This study provides researchers and clinicians with an easy-to-use, accurate, and validated predictive tool for potential application in rehabilitation research and stroke management.
Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack
Authors: Pan Yuesong , Cai Xueli , Jing Jing , Meng Xia , Li Hao , Wang Yongjun , Zhao Xingquan , Liu Liping , Wang David , Johnston S. Claiborne , Wei Tiemin , Wang Yilong
Published: October 2017

Background and Purpose—

We aimed to determine the association between stress hyperglycemia and risk of new stroke in patients with a minor ischemic stroke or transient ischemic attack.

Methods—

A subgroup of 3026 consecutive patients from 73 prespecified sites of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) were analyzed. Stress hyperglycemia was measured by glucose/glycated albumin (GA) ratio. Glucose/GA ratio was calculated by fasting plasma glucose divided by GA and categorized into 4 even groups according to the quartiles. The primary outcome was a new stroke (ischemic or hemorrhagic) at 90 days. We assessed the association between glucose/GA ratio and risk of stroke by multivariable Cox regression models adjusted for potential covariates.

Results—

Among 3026 patients included, a total of 299 (9.9%) new stroke occurred at 3 months. Compared with patients with the lowest quartile, patients with the highest quartile of glucose/GA ratio was associated with an increased risk of stroke at 3 months after adjusted for potential covariates (12.0% versus 9.2%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.06–2.01). Similar results were observed after further adjusted for fasting plasma glucose. We also observed that higher level of glucose/GA ratio was associated with an increased risk of stroke with a threshold of 0.29 using a Cox regression model with restricted cubic spline.

Conclusions—

Stress hyperglycemia, measured by glucose/GA ratio, was associated with an increased risk of stroke in patients with a minor ischemic stroke or transient ischemic attack.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00979589.
Duty Without Obligation
Authors: Lloyd S.A.
Published: October 2017

There is ongoing scholarly debate over the role that Hobbes’s laws of nature play in grounding the moral requirement that subjects obey the government under which they live. This essay demonstrates how the laws of nature, when understood as natural duties, may directly ground a moral duty to obey one’s sovereign without positing that subjects have undertaken any covenant of subjection. Such a grounding avoids the problems that attend accounts that depend on tacit covenant and coerced covenant. The essay describes the advantages of a natural duty account of the laws of nature over accounts that regard those laws as contractual obligations entered through voluntary acts, or as legal obligations to treat the natural laws as literal laws legislated by a sovereign God.
Climatological Variability of Fire Weather in Australia
Authors: Dowdy Andrew J.
Published: October 2017

Long-term variations in fire weather conditions are examined throughout Australia from gridded daily data from 1950 to 2016. The McArthur forest fire danger index is used to represent fire weather conditions throughout this 67-yr period, calculated on the basis of a gridded analysis of observations over this time period. This is a complementary approach to previous studies (e.g., those based primarily on model output, reanalysis, or individual station locations), providing a spatially continuous and long-term observations-based dataset to expand on previous research and produce climatological guidance information for planning agencies. Long-term changes in fire weather conditions are apparent in many regions. In particular, there is a clear trend toward more dangerous conditions during spring and summer in southern Australia, including increased frequency and magnitude of extremes, as well as indicating an earlier start to the fire season. Changes in fire weather conditions are attributable at least in part to anthropogenic climate change, including in relation to increasing temperatures. The influence of El Niño–Southern Oscillation (ENSO) on fire weather conditions is found to be broadly consistent with previous studies (indicating more severe fire weather in general for El Niño conditions than for La Niña conditions), but it is demonstrated that this relationship is highly variable (depending on season and region) and that there is considerable potential in almost all regions of Australia for long-range prediction of fire weather (e.g., multiweek and seasonal forecasting). It is intended that improved understanding of the climatological variability of fire weather conditions will help lead to better preparedness for risks associated with dangerous wildfires in Australia.
The Emergence of Shallow Easterly Jets within QBO Westerlies
Authors: Hitchcock Peter , Haynes Peter H. , Randel William J. , Birner Thomas
Published: October 2017

A configuration of an idealized general circulation model has been obtained in which a deep, stratospheric, equatorial, westerly jet is established that is spontaneously and quasi-periodically disrupted by shallow easterly jets. Similar to the disruption of the quasi-biennial oscillation (QBO) observed in early 2016, meridional fluxes of wave activity are found to play a central role. The possible relevance of two feedback mechanisms to these disruptions is considered. The first involves the secondary circulation produced in the shear zones on the upper and lower flanks of the easterly jet. This is found to play a role in maintaining the aspect ratio of the emerging easterly jet. The second involves the organization of the eddy fluxes by the mean flow: the presence of a weak easterly anomaly within a tall, tropical, westerly jet is demonstrated to produce enhanced and highly focused wave activity fluxes that reinforce and strengthen the easterly anomalies. The eddies appear to be organized by the formation of strong potential vorticity gradients on the subtropical flanks of the easterly anomaly. Similar wave activity and potential vorticity structures are found in the ERA-Interim for the observed QBO disruption, indicating this second feedback was active then.
Role of Equatorial Pacific SST Forecast Error in the Late Winter California Precipitation Forecast for the 2015/16 El Niño
Authors: Jong Bor-Ting , Ting Mingfang , Seager Richard , Henderson Naomi , Lee Dong Eun
Published: October 2017

During the strong 2015/16 El Niño, only normal to below-average precipitation fell across California in the late winter. This disagrees with both predictions by the ensemble mean of forecast models and expectations for strong El Niños. The authors examine one of the possible reasons why this event did not bring expected precipitation to California in the late winter. The maximum equatorial Pacific sea surface temperature anomalies (SSTAs) were located, compared to the 1982/83 and 1997/98 strong El Niños, farther to the west in the 2015/16 winter, which possibly caused less convection in the eastern tropical Pacific and shifted the teleconnection patterns westward in the North Pacific, thus weakening the influences on California. The SSTA and precipitation forecast for February–April 2016, based on the North American Multimodel Ensemble, showed large discrepancies from observations, with the ensemble mean of most of the models overestimating SSTAs in the eastern tropical Pacific and California precipitation. Atmospheric general circulation model (AGCM) experiments were conducted to test the hypothesis that the warmer eastern tropical Pacific SSTA forecast may have caused the wetter forecast in California in 2015/16 compared to observations. The AGCM experiments suggest it is difficult to assert that the eastern tropical Pacific SSTAs caused the too-wet California precipitation forecast, especially in Southern California, given that the models disagree. Results indicate forecast error can be influenced by atmosphere-model sensitivity to forecast SSTs, but they also indicate atmospheric internal variability may have been responsible for the combination of a strong El Niño and near-normal California precipitation.
Greater Temperature and Precipitation Extremes Intensify Western U.S. Droughts, Wildfire Severity, and Sierra Nevada Tree Mortality
Authors: Crockett Joseph L. , Westerling A. Leroy
Published: October 2017

Extensive drought in the western United States (WUS) during the twenty-first century and associated wildfire and tree mortality incidence has highlighted the potential for greater area of severity within widespread droughts. To place recent WUS droughts into a historical context, the authors analyzed gridded daily climate (temperature, precipitation, and climatic water deficit) data to identify and characterize the spatiotemporal evolution of the largest WUS droughts of the last 100 years, with an emphasis on severe cores within drought extents. Cores of droughts during the last 15 years (2000–02 and 2012–14) covered a greater area than in earlier droughts, driven by greater temperature and precipitation extremes. Comparing fire extent and severity before, during, and after drought events using the monitoring trends in burn severity dataset (1984–2014), the authors found fire size and high-severity burn extent were greater during droughts than before or after. Similarly, recent Sierra Nevada forest mortality was greatest in cores immediately after the drought. Climate simulations anticipate greater extremes in temperature and precipitation in a warming world; droughts and related impacts of the last 15 years may presage the effects of these extremes.