bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfer of miRNA in Macrophage-Derived Exosomes Induces Drug Resistance in Pancreatic Adenocarcinoma
Authors: Binenbaum Yoav , Fridman Eran , Yaari Zvi , Milman Neta , Schroeder Avi , Ben David Gil , Shlomi Tomer , Gil Ziv
Published: July 2018

Pancreatic ductal adenocarcinoma (PDAC) is known for its resistance to gemcitabine, which acts to inhibit cell growth by termination of DNA replication. Tumor-associated macrophages (TAM) were recently shown to contribute to gemcitabine resistance; however, the exact mechanism of this process is still unclear. Using a genetic mouse model of PDAC and electron microscopy analysis, we show that TAM communicate with the tumor microenvironment via secretion of approximately 90 nm vesicles, which are selectively internalized by cancer cells. Transfection of artificial dsDNA (barcode fragment) to murine peritoneal macrophages and injection to mice bearing PDAC tumors revealed a 4-log higher concentration of the barcode fragment in primary tumors and in liver metastasis than in normal tissue. These macrophage-derived exosomes (MDE) significantly decreased the sensitivity of PDAC cells to gemcitabine, in vitro and in vivo. This effect was mediated by the transfer of miR-365 in MDE. miR-365 impaired activation of gemcitabine by upregulation of the triphospho-nucleotide pool in cancer cells and the induction of the enzyme cytidine deaminase; the latter inactivates gemcitabine. Adoptive transfer of miR-365 in TAM induced gemcitabine resistance in PDAC-bearing mice, whereas immune transfer of the miR-365 antagonist recovered the sensitivity to gemcitabine. Mice deficient of Rab27 a/b genes, which lack exosomal secretion, responded significantly better to gemcitabine than did wildtype. These results identify MDE as key regulators of gemcitabine resistance in PDAC and demonstrate that blocking miR-365 can potentiate gemcitabine response.

Significance: Harnessing macrophage-derived exosomes as conveyers of antagomiRs augments the effect of chemotherapy against cancer, opening new therapeutic options against malignancies where resistance to nucleotide analogs remains an obstacle to overcome. Cancer Res; 78(18); 5287–99. ©2018 AACR.
Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration
Authors: Oweida Ayman , Hararah Mohammad K. , Phan Andy , Binder David , Bhatia Shilpa , Lennon Shelby , Bukkapatnam Sanjana , Van Court Benjamin , Uyanga Nomin , Darragh Laurel , Kim Hyun Min , Raben David , Tan Aik Choon , Heasley Lynn , Clambey Eric , Nemenoff Raphael , Karam Sana D.
Published: July 2018

Purpose: Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance.

Experimental Design: Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti–PD-L1 or anti–TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody.

Results: We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti–TIM-3 concurrently with anti–PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory.

Conclusions: These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. Clin Cancer Res; 24(21); 5368–80. ©2018 AACR.
Class Matters: Sensitivity of BRAF-Mutant Melanoma to MAPK Inhibition
Authors: Johnson Douglas B. , Dahlman Kimberly B.
Published: July 2018

Mutations in BRAF outside of the 600 codons (BRAF non- V600) occur across cancer types, including in 3% to 5% of melanomas. The optimal treatment strategies are not clear but based on preclinical studies could include MEK inhibitors. Combining BRAF and MEK inhibitors in this population may provide additional benefit.

See related article by Dankner et al., p. 6483
Exosomes from HNSCC Promote Angiogenesis through Reprogramming of Endothelial Cells
Authors: Ludwig Nils , Yerneni Saigopalakrishna S. , Razzo Beatrice M. , Whiteside Theresa L.
Published: July 2018

For solid tumors, such as head and neck squamous cell carcinoma (HNSCC), an adequate blood supply is of critical importance for tumor development and metastasis. Tumor-derived exosomes (TEX) accumulate in the tumor microenvironment (TME) and serve as a communication system between tumor and normal stromal cells. This study evaluates in vitro and in vivo effects mediated by TEX that result in promotion of angiogenesis. TEX produced by PCI-13 (HPV−) and UMSCC47 (HPV+) cell lines or from plasma of HNSCC patients were isolated by mini size exclusion chromatography (mini-SEC). TEX morphology, size, numbers, and molecular profile were characterized, and the angiogenesis-inducing potential was measured in arrays and real-time PCR with human endothelial cells (HUVEC). Uptake of labeled TEX by HUVECs was demonstrated by confocal microscopy. Tube formation, proliferation, migration, and adherence by HUVECs in response to TEX were investigated. The 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis mouse model was used to confirm that TEX induce the same results in vivo. TEX were found to be potent inducers of angiogenesis in vitro and in vivo through functional reprogramming and phenotypic modulation of endothelial cells. TEX carried angiogenic proteins and were internalized by HUVECs within 4 hours. TEX stimulated proliferation (P < 0.001), migration (P < 0.05), and tube formation (P < 0.001) by HUVECs and promoted formation of defined vascular structures in vivo. The data suggest that TEX promote angiogenesis and drive HNSCC progression. Future efforts should focus on eliminating or silencing TEX and thereby adding new options for improving existing antiangiogenic therapies.

Implications: TEX appear to play an important role in tumor angiogenesis and thus may contribute to tumor growth and metastasis of HNSCC in this context. Mol Cancer Res; 16(11); 1798–808. ©2018 AACR.
Multimodal Revoicing as an Interactional Mechanism for Connecting Scientific and Everyday Concepts
Authors: Flood Virginia J.
Published: July 2018

A perpetual problem learners face is identifying which aspects of embodied experiences are relevant for appreciating the world in culturally specific ways. Vygotsky argued that social interactions with more competent cultural members provide arenas for linking everyday and scientific concepts. However, the precise interactional mechanisms of how these linkages are forged remain underexamined. I argue that understanding these mechanisms requires examining how intersubjectivity is built and maintained. I propose that ethnomethodological conversation analysis and the co-operative action framework provide a uniquely suited analytic orientation for this project because they focus on the fine details of the actual practical methods people use to procedurally achieve intersubjectivity. To illustrate the utility of these approaches, I show how the fine details of multimodal revoicing interactions present semiotic challenges that allow learners to link everyday and scientific concepts. Specifically, I examine the role dialogic gesture plays in reformulating a multimodally expressed idea about what it means to “go faster.”
Combined Brain Mapping and Compact Intraoperative MRI for Brain Tumor Resection
Authors: White Timothy , Zavarella Salvatore , Jarchin Lauren , Nardi Dominic , Schaffer Sarah , Schulder Michael
Published: July 2018

Background: Surgery on patients with lesions in the dominant hemisphere for language is best done with awake language mapping. Intraoperative MRI (iMRI) has also been proposed as an ideal method for tumor resection control in patients with primary brain tumors. Objectives: This study examines the feasibility of low-field iMRI during awake craniotomy and tumor resection. Methods: 36 patients underwent awake resection with a compact iMRI for guidance. Outcomes were grouped using an A–D classification. Outcome A was defined as gross total resection (GTR) without iMRI, B as GTR achieved secondary to iMRI findings, C as resection stopped due to mapping but prior to iMRI, and, finally, D as resection stopped after iMRI had showed residual tumor but subsequent mapping limited further resection. Results: Diagnoses included primary brain tumors in all but 2 patients: 1 had mesial temporal sclerosis and 1 cysticercosis. Overall, outcomes A and D were the most common with 12 patients each, outcome C was the least common occurring in only 3 patients, and outcome B occurred in 9 patients. Hence, in 12 patients, iMRI led to increased tumor resection while in another 12 brain mapping limited the extent of resection. Conclusions: Combined awake language and motor mapping and iMRI guidance is feasible for resection of brain lesions. A compact iMRI has unique advantages for this approach.
Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Authors: Cheng Ying-Chih , Huang Yu-Chen , Liu Hsing-Cheng
Published: July 2018

Background: The apolipoprotein E ɛ4 (APOE ɛ4) genotype is the major genetic risk factor for Alzheimer’s disease (AD). However, its effect on an individual’s response to treatment is less well understood. Many studies have reported that the presence or absence of APOE ɛ4 may have influence on the therapeutic response for acetylcholinesterase inhibitors (AChEIs), but the results were inconsistent. This study performed a systematic review and meta-analysis to evaluate the association between response of treatment with AChEIs and the APOE ɛ4 carrier status. Methods: Clinical studies with AD patients reporting APOE ɛ4 genotype were included in the analysis. Cognitive outcome was measured by the change in Mini-Mental State Examination (MMSE), cognition subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog), or Cognitive Abilities Screening Instrument (CASI). A random effects model was employed to calculate the standardized mean difference (SMD) and odds ratio (OR). Results: Of the 284 screened abstracts, 38 studies were identified, 30 of which were included for meta-analysis. Continuous data for assessing the association between APOE ε4 and cognitive outcomes of AChEIs were available from 18 studies. The cognitive outcomes showed no significant difference between APOE ε4 carriers and APOE ε4 non-carriers (SMD = 0.022, 95% CI: –0.089∼0.133, p = 0.702, I2 = 55.3%). Twelve studies with binary data were included, also revealing insignificant difference between the two groups (OR = 1.164, 95% CI: 0.928∼1.459, p = 0.189, I2 = 16.4%). Subgroup analysis indicated that AChEIs were significantly more effective than placebo in both groups. Conclusions: APOE ɛ4 carrier status had no significant influence on the treatment response to AChEIs in patients with AD. AChEIs had a positive therapeutic effect compared with placebo regardless of APOE ε4 carrier status.
Pseudomonas aeruginosa in Chronic Obstructive Pulmonary Disease Patients with Frequent Hospitalized Exacerbations: A Prospective Multicentre Study
Authors: Rodrigo-Troyano Ana , Melo Valentina , Marcos Pedro J. , Laserna Elena , Peiro Meritxell , Suarez-Cuartin Guillermo , Perea Lidia , Feliu Anna , Plaza Vicente , Faverio Paola , Restrepo Marcos I. , Anzueto Antonio , Sibila Oriol
Published: July 2018

Background: Pseudomonas aeruginosa (PA) is a common microorganism related to severe exacerbations in Chronic Obstructive Pulmonary Disease (COPD). However, their role in COPD patients with frequent hospitalized exacerbations (FHE) is not well described. Objectives: We aimed to determine prevalence, risk factors, susceptibility patterns and impact on outcomes of PA in COPD patients with FHE. Methods: Prospective observational multicentre study that included COPD patients with FHE. The cohort was stratified in 2 groups according to the presence or absence of PA isolation in sputum. Patients were followed up for 12 months. Results: We enrolled 207 COPD patients with FHE. In 119 patients (57%), a valid sputum culture was collected. Of them, PA was isolated in 21 patients (18%). The risk factors associated with PA were prior use of systemic corticosteroids (OR 3.3, 95% CI 1.2–9.7, p = 0.01) and prior isolation of PA (OR 4.36, 95% CI 1.4–13.4, p < 0.01). Patients with PA had an increased risk of having ≥3 readmissions (OR 4.1, 95% CI 1.3–12.8, p = 0.01) and higher PA isolation rate (OR 7.7, 95% CI 2.4–24.6, p < 0.001) during the follow-up period. In 14 patients (67%), PA was resistant to at least one antibiotic tested. PA persisted in the sputum in 70% of patients. Conclusions: The presence of PA was related to 3 or more readmissions during the 1-year follow-up and PA persisted in the sputum despite an appropriate antibiotic treatment. This finding suggested an important role of PA in the course of the disease of COPD patients with FHE.
European Organization for Caries Research Workshop: Methodology for Determination of Potentially Available Fluoride in Toothpastes
Authors: Martinez-Mier E. Angeles , Tenuta Livia Maria Andaló , Carey Clifton M. , Cury Jaime A. , van Loveren Cor , Ekstrand Kim Rud , Ganss Carolina , Schulte Andreas , Baig Arif , Benzian Habib , Bottenberg Peter , Buijs Mark J. , Ceresa Alan , Carvalho Joana Christina , Ellwood Roger , González-Cabezas Carlos , Holmgren Christopher , Knapp Michael , Lippert Frank , Joiner Andrew , Manton David J. , Martignon Stefania , Mason Stephen , Jablonski-Momeni Anahita , Plett Walter , Rahiotis Chris , Sampaio Fábio , Zero Domenick T. ,   ORCA Fluoride in Toothpaste Analysis Work Group 
Published: July 2018

Toothpastes are the most universally accepted form of fluoride delivery for caries prevention. To provide anti-caries benefits, they must be able to release fluoride during the time of tooth brushing or post brushing into the oral cavity. However, there is no standard accepted procedure to measure how much fluoride in a toothpaste may be (bio) available for release. The European Organization for Caries Research proposed and supported a workshop with experts in fluoride analysis in toothpastes and representatives from industry. The objective of the workshop was to discuss issues surrounding fluoride analysis in toothpaste and reach consensus on terminology and best practices, wherever the available evidence allowed it. Participants received a background paper and heard presentations followed by structured discussion to define the problem. The group also reviewed evidence on the validity, reliability and feasibility of each technique (namely chromatography and fluoride electroanalysis) and discussed their strengths and limitations. Participants were able to reach a consensus on terminology and were also able to identify and summarize the advantages and disadvantages of each technique. However, they agreed that most currently available methods were developed for regulatory agencies several decades ago, utilizing the best available data from clinical trials then, but require to be updated. They also agreed that although significant advances to our understanding of the mechanism of action of fluoride in toothpaste have been achieved over the past 4 decades, this clearly is an extraordinarily complex subject and more work remains to be done.
Congenital Cholesteatoma: The Silent Pathology
Authors: Mostafa Badr Eldin , El Fiky Lobna
Published: July 2018

Background: Congenital cholesteatomas (CC) arise from epithelial remnants around the petrous bone. They enlarge gradually causing progressive destruction and functional damage to the ear and surrounding structures. Because of their insidious course, most patients are misdiagnosed and present late with complications. Methods: This is a retrospective study of 41 cases diagnosed as CC and followed up for 2 years. All patients underwent full audiological evaluation and a radiological study (CT, MRI). Results: The male:female ratio was 2.3: 1, and the mean age was 30.89 years. The mean delay before presentation was 13 months. The commonest presentations in order of frequency were: discharge (60.9%), hearing loss (51.2%), facial paralysis (31.7%) and intracranial complications (31.7%). Forty patients were treated surgically by a variety of approaches depending on the extensions and functional status. The facial nerve was decompressed in 9 cases and cable grafted in 4. Two cases underwent VII-XII anastomosis later on. Conclusion: CC present with a myriad of clinical manifestations and should be suspected in all patients with unexplained otological signs and symptoms. They must be completely excised and the functional status of the ear rehabilitated either immediately or later. Follow-up must be indefinite as they have a high recurrence rate.
Geospatial Visualization of Mobile Stroke Unit Dispatches: A Method to Optimize Service Performance
Authors: Rhudy Jr. James P. , Alexandrov Anne W. , Rike Joseph , Bryndziar Tomas , Hossein Zadeh Maleki Ana , Swatzell Victoria , Dusenbury Wendy , Metter E. Jeffrey , Alexandrov Andrei V.
Published: July 2018

Background: Timely treatment of acute ischemic stroke is crucial to optimize outcomes. Mobile stroke units (MSU) have demonstrated ultrafast treatment compared to standard emergency care. Geospatial analysis of the distribution of MSU cases to optimize service delivery has not been reported. Methods: We aggregated all first-year MSU dispatch occurrences and all cases classified by clinical teams as true stroke by zip code and calculated dispatch and true stroke incidence rates. We mapped dispatch and stroke cases and symbolized incidence rates by standard deviation. We confirmed visual impressions of clusters from map inspection by local Moran’s I, boxplot inspection, and t test. We calculated service areas using drive times to meet dispatch and true stroke need. Results: A significant cluster of high dispatch incident rate was confirmed around our MSU base in urban Memphis within a 5-min driving area supporting the initial placement of the MSU based on 911 activation. A significant cluster of high true stroke rate was confirmed to the east of our MSU base in suburban Memphis within a 10-min driving area. Mean incident longitude of cases of true stroke versus disregarded status was significantly eastward (p = 0.001785). Conclusion: Our findings will facilitate determination of socio-spatial antecedents of neighborhood overutilization of 911 and MSU services in our urban neighborhoods and service delivery optimization to reach neighborhoods with true stroke burden.
Cognitive Change at the End of Life in Nursing Home Residents: Differential Trajectories of Terminal Decline
Authors: Hülür Gizem , Wolf Henrike , Riese Florian , Theill Nathan
Published: July 2018

Background: Research on terminal decline has widely documented that cognitive performance steeply declines with nearing death. To date, it is unclear whether these changes are normative, based on pathologies associated with (preclinical) dementia, or both. Objectives: We analyzed heterogeneity in trajectories of terminal cognitive change in Swiss nursing home residents with the objective of examining whether terminal change is normative or whether one or multiple subgroup(s) with relative stability exist. Methods: We performed a longitudinal analysis based on routine assessments with the Resident Assessment Instrument – Minimal Data Set in 341 nursing homes between 1998 and 2014. In sum, we used 143,052 observations from 30,054 residents (69% women, average age at death 87 years) in the last 3 years of life. We analyzed trajectories of the Cognitive Performance Scale (CPS) score with latent class growth curve models and examined sociodemographic factors (age at death, sex, marital status, prior living situation) as well as functional and mental health (Activities of Daily Living Index and Depression Rating Scale) and dementia diagnosis as correlates of group membership. Results: We identified three distinct classes based on longitudinal trajectories of the CPS score. In the first group (transition from no to mild impairment, 27%), cognitive impairment increased with time to death (linear and quadratic), but remained at relatively mild levels at all times. The trajectories of the second group (transition from moderate to severe impairment, 43%) were characterized by linear and quadratic changes across time to death. The trajectories of the third group (severe impairment, 30%) were characterized by the lowest amount of linear increase across all groups and no quadratic increase indicating no accelerated change. Better functional health and absence of a dementia diagnosis predicted less impairment. Fewer depressive symptoms were associated with low as opposed to moderate or severe, but also severe versus moderate impairment. Conclusion: Our findings suggest that the majority of residents experience terminal change, with the exception of those at already high levels of impairment. Furthermore, late-life cognitive change is related to functional and mental health.
Intervention for Dysbiosis in Children Born by C-Section
Authors: Francavilla Ruggiero , Cristofori Fernanda , Tripaldi Maria Elena , Indrio Flavia
Published: July 2018

The symbiotic relationship between microbes and human is fundamental for a physiological development and health. The microbiome of the newborn undergoes to dramatic changes during the process of birth and in the first thousand days of life. Mother Nature provided us with the best possible start to achieve eubiosis: vaginal delivery to receive our mother’s microbiome and breast milk that favours the establishment of beneficial bacteria. Infants deprived of one or both of these evolutionary gifts undergo to important modification of the microbial communities leading to a state of dysbiosis enhancing the chance of the emergence of a variety of immune, inflammatory and metabolic disorders. Are we able to imitate nature? Is there any intervention for dysbiosis in children born by cesarean section? In this review we will try to answer to this intriguing question on the basis of the most recent scientific evidences.
Transferability and Sustainability of Motor-Cognitive Dual-Task Training in Patients with Dementia: A Randomized Controlled Trial
Authors: Lemke Nele Christin , Werner Christian , Wiloth Stefanie , Oster Peter , Bauer Jürgen M. , Hauer Klaus
Published: July 2018

Background: Specific dual-task (DT) training is effective to improve DT performance in trained tasks in patients with dementia (PwD). However, it remains an open research question whether successfully trained DTs show a transfer effect to untrained DT performances. Objective: To examine transfer effects and the sustainability of a specific DT training in PwD. Methods: One hundred and five patients with mild-to-moderate dementia (Mini-Mental State Examination: 21.9 ± 2.8 points) participated in a 10-week randomized, controlled trial. The intervention group (IG) underwent a specific DT training (“walking and counting”). The control group (CG) performed unspecific low-intensity exercise. DT performance was measured under three conditions: (1) “walking and counting” (trained); (2) “walking and verbal fluency” (semi-trained), and (3) “strength and verbal fluency” (untrained). Outcomes evaluated at baseline, after training, and 3 months after the intervention period included absolute values for the motor and cognitive performance under DT conditions, and relative DT costs (DTCs) in motor, cognitive and combined motor-cognitive performance. Results: The IG significantly improved DT performances in the trained condition for absolute motor and cognitive performance and for motor, cognitive, and combined motor-cognitive DTCs compared to the CG (p ≤ 0.001–0.047; ηp2 = 0.044–0.249). Significant transfer effects were found in the semi-trained condition for absolute motor and partly cognitive performance, and for motor but not for cognitive DTCs, and only partly for combined DTCs (p ≤ 0.001–0.041; ηp2 = 0.049–0.150). No significant transfer effects were found in the untrained condition. Three months after training cessation, DT performance in the trained condition was still elevated for most of the outcomes (p ≤ 0.001–0.038; ηp2 = 0.058–0.187). Training gains in the DT performance in the semi-trained condition were, however, not sustained, and no significant group differences were found in the DT performance in the untrained condition after the follow-up. Conclusion: This study confirmed that specific DT training is effective in improving specifically trained DT performances in PwD and demonstrated sustainability of training-induced effects for at least 3 months. Effects were partially transferable to semi-trained DTs but not to untrained DTs. With increasing distance between trained and untrained DTs, transferability of training effects decreased.
Surgical Management of Breast Cancer Treated with Neoadjuvant Therapy
Authors: Cordoba Octavi , Carrillo-Guivernau Lourdes , Reyero-Fernández Carmen
Published: July 2018

Neoadjuvant therapy (NAT) allows downstaging in some cases of breast cancer. By consequence, it may enable a more conservative surgical approach or make surgery possible in cases ineligible for surgery before NAT. In this article, we review the evidence and management recommendations for optimal surgical treatment in this setting.
SOST Gene Inhibits Osteogenesis from Adipose-Derived Mesenchymal Stem Cells by Inducing Th17 Cell Differentiation
Authors: You Li  , Chen Lin , Pan Ling , Peng Yongde , Chen Jinyu
Published: July 2018

Background/Aims: Postmenopausal osteoporosis is considered to be an autoimmune and inflammatory process, and IL-17 plays important roles in the loss of bone mass. Sclerostin (SOST) acts as a negative regulator of bone formation by inhibiting the Wnt signaling pathway. It also is a mediator of the crosstalk between the skeletal and immune systems. However, few studies have examined the role of SOST gene in the differentiation of T helper 17 (Th17) cells. Methods: Adipose-derived stem cells (ADSCs) were isolated and transfected with pcDNA3-SOST or shSOST, and then co-cultured with CD4+ T cells isolated from peripheral blood mononuclear cells. The differentiation, adipogenesis, and osteogenesis of Th17 and regulatory T (Treg) cells were examined by western blot, intracellular and intranuclear staining, ELISA, and real-time quantitative PCR in this co-culture model. Results: The SOST gene promoted the secretion of IL-6 and TGF-β in ADSCs. After co-culture of ADSCs with CD4+ T cells, the SOST gene increased the number of CD4+IL-17+ cells and the levels of IL-17 and RORγ. However, the number of CD4+CD25+Foxp3+ cells was decreased, which was accompanied with a reduction of IL-10 and Foxp3 expression. In the meantime, the SOST gene inhibited the expression of COL1, OCN, and OPN, reduced the activity of alkaline phosphatase, and increased the expression of LPL and PPARγ. Furthermore, IL-17 promoted SOST gene-induced adipogenesis and increased the inhibition of osteogenesis. Conclusions: SOST promoted the differentiation of Th17 cells and reduced the differentiation of Treg cells, which exacerbated the SOST gene-induced inhibition of osteogenesis from ADSCs.
An Engineered DC-Targeting Lentivector Induces Robust T Cell Responses and Inhibits HBV Replication in HBV Transgenic Mice via Upregulating T Cell Autophagy
Authors: Ma Siyuan , Chen Xiaohua , Tan Quanhui , Dai Shenglan , Li Dan , Wu Shanshan , Yu Yongsheng , Zang Guoqing , Tang Zhenghao
Published: July 2018

Background/Aims: Developing engineered dendritic cell (DC)-targeting lentivectors (LVs) have been the target of intense research for their potential to create antigen-directed immunotherapeutics which can be safely administered to patients. In this study, we constructed a DC-directed LV (LVDC-UbHBcAg-LIGHT) as a potential vaccine to induce anti-HBV immune responses. Methods: Specificity of LVDC-UbHBcAg-LIGHT for DCs in vivo was confirmed through live animal imaging studies. The levels of cytokine production in T cells were assessed by flow cytometry. The HBcAg-specific cytotoxic T lymphocyte (CTL) responses and antibody responses induced by direct administration of the LVs were detected by LDH release assay and ELISA respectively. The levels of serum HBsAg and HBV DNA were evaluated by Abbott kits and quantitative PCR respectively. The expression levels of HBsAg and HBcAg in liver tissues of HBV transgenic mice were examined by immunohistochemistry. In addition, molecular mechanism underlying the activation of CD8+ T cells was explored. Results: Live animal imaging studies showed that following subcutaneous administration of LVDC-UbHBcAg-LIGHT, no obvious luminescence signal was detected at the injection site. Immunization with LVDC-UbHBcAg-LIGHT elicited potent T cell responses in HBV transgenic mice evidenced by increased percentages of IFN-γ, TNF-α and GzmB producing CD8+ T cells as well as IFN-γ producing CD4+ T cells, improved HBcAg-specific CTL activities and antibody responses. Additionally, vaccination with LVDC-UbHBcAg-LIGHT efficiently reduced serum HBsAg, HBV DNA levels and the expression of HBsAg and HBcAg in liver tissues of HBV transgenic mice. More importantly, autophagy was induced in the activated CD8+ T cells, and the induced autophagy noticeably promoted the proliferation of T cells and decreased the frequencies of apoptotic CD8+ T cells by selectively degrading ubiquitinated apoptosis and cell cycle-associated protein aggregates. Futhermore, we confirmed the interaction between autophagosomes and ubiquitinated aggregates by confocal microscopy and immunoprecipitation analysis. Conclusions: These results demonstrated that LVDC-UbHBcAg-LIGHT provided a simple method of eliciting effective antiviral immune responses in HBV transgenic mice and might potentially be used as a therapeutic strategy to eradicate HBV with more safety and efficiency. Moreover, our results revealed a direct role of autophagy in promoting the survival and proliferation of activated CD8+ T cells.
Anatomy of a Scandal: Physicians Facing the Inquisition in Late Seventeenth-Century Rome
Authors: Donato Maria Pia
Published: July 2018

In the 1690s the Roman Inquisition targeted medical circles, as they allegedly disseminated atheism under the veil of new explanations of the body. This article revisits these affairs, focussing on Rome. It argues that increased inquisitorial pressure must be set against the backdrop of struggles for hegemony in the papal curia, in which physicians were entangled. Notwithstanding such political vicissitudes, ecclesiastical control played a relevant role in shaping Italian medicine at the turn of the seventeenth and eighteenth centuries. The article suggests that the result may have been, paradoxically, a form of un-assumed materialism, though framed within the disciplinary borders of practical medicine, which enabled physicians to re-assert their autonomy.
Medicine and the Inquisition in Portugal (Sixteenth and Seventeenth Centuries): People and Books
Authors: Baudry Hervé
Published: July 2018

The Tribunal of the Inquisition was established in Portugal in 1536. This paper deals with three aspects concerning medicine in sixteenth- and seventeenth-century Portugal: the institution and its members, the medical practitioners, and the books. On the one hand, doctors were necessary to carry out specific duties in the life of the Inquisition. On the other hand, a significant percentage of the victims of the Inquisition were medical professionals, the overwhelming majority being New Christians accused of Judaism. Finally, as did the Roman and Spanish Inquisitions, the Portuguese Holy Office looked after the censorship of books, many of which dealt with medical matters.
Notes on Indian species of Calvatia and Langermannia including Calvatia natarajanii sp. nov.
Authors: GUNASEKARAN SENTHILARASU , CHINNARAJAN RAVINDRAN , PARASNIS ANJALI
Published: July 2018

A new species, Calvatia natarajanii, is presented as well as brief notes on the distribution of Calvatia sensu stricto and Langermannia in India. Calvatia natarajanii is distinguished by basidiomes having yellowish white to orange-white exoperidium, brownish orange to grayish red, persistent endoperidium, grayish orange to brownish orange cottony gleba, persistent cellular subgleba and globose to subglobose, echinulate basidiospores. It is described, illustrated and compared with the closely related taxa C. cyathiformis, C. fragilis, C. rugosa, C. aff. rugosa, C. pyriformis, C. vinosa and C. rosacea. Maximum Parsimony analysis based on ITS sequences confirmed that C. natarajanii is closely related to C. fragilis and distinct from other morphologically similar species. In addition, a key to the species of Calvatia and Langermannia recorded in India is presented. Four species recognized under Calvatia are excluded from the key since their transfer to Lycoperdon.
Introducing Dictyochaeta aquatica sp. nov. and two new species of Chloridium (Chaetosphaeriaceae, Sordariomycetes) from aquatic habitats
Authors: WEI MING-JIE , ZHANG HUANG , DONG WEI , BOONMEE SARANYAPHAT , ZHANG DI
Published: July 2018

During our ongoing investigations of freshwater fungi in Thailand, three new chaetosphaeriaceous species, Chloridium aquaticum, Chloridium aseptatum and Dictyochaeta aquatica, were found on submerged wood in freshwater habitats. To determine their placement, a phylogenetic analysis of combined LSU and ITS sequence data was performed. Chloridium aquaticum is the only species having proliferating conidiophores and holoblastic conidiogenous cell in Chloridium. A detailed description and illustrations of the taxa is provided and phylogenetic relationship between the new taxa and their relatives are compared and discussed.
New species and records of Uncispionidae and Pygospiopsis (Polychaeta, Spionida) from deep water off the east and west coasts of North America, the Gulf of Mexico, the Antarctic Peninsula, and Southeast Asia
Authors: BLAKE JAMES A. , MACIOLEK NANCY J.
Published: July 2018

Five new species and one new genus of the obscure spioniform family Uncispionidae are described together with three new species of the rare and unusual spionid genus Pygospiopsis Blake, 1983. All species are from offshore habitats with most from deep-sea continental slope depths. Among the Uncispionidae are the second and third species of the genus Uncopherusa Fauchald & Hancock, 1981, collected from off Brunei in the South China Sea and off Louisiana in the Gulf of Mexico; two new species of Uncispio Green, 1982, the third and fourth to be described, from deep water off the U.S. Atlantic coast and the Gulf of Mexico; and a new species of a new genus, Rhamphispio n. gen., from off the U.S. Atlantic coast. All species of Uncispionidae are compared and a key to the known species is presented. The genus Pygospiopsis Blake, 1983, is currently known for only two species: P. dubia (Monro, 1930) from Antarctic and sub-Antarctic waters and P. occipitalis Blake, 1996, from shelf depths off southern California. In the present study, new collections of the type-species P. dubia from the Antarctic Peninsula include post-larvae and juveniles as well as adults, thus permitting documentation of the development of some key adult morphology. Three new species of Pygospiopsis are described from deep water off the U.S. Atlantic and Pacific coasts and from the Antarctic Peninsula. A review of all species of Pygospiopsis suggests that, based on branchial distribution patterns, the closely related Pseudatherospio fauchaldi Lovell, 1994, should be referred to Pygospiopsis, bringing the total known species to six. All of these are compared and contrasted and the generic definition of Pygospiopsis updated. The status of Pygospiopsis within the Spionidae relative to the closely related genus Atherospio Mackie & Duff, 1986, is discussed.
Simulation of an Evolving Convective Boundary Layer Using a Scale-Dependent Dynamic Smagorinsky Model at Near-Gray-Zone Resolutions
Authors: Efstathiou G. A. , Plant R. S. , Bopape M.-J. M.
Published: July 2018

A scale-dependent Lagrangian-averaged dynamic Smagorinsky subgrid scheme with stratification effects is used to simulate the evolving convective boundary layer of the Wangara (Australia) case study in the gray-zone regime (specifically, for grid lengths from 25 to 400 m). The dynamic Smagorinsky and standard Smagorinsky approaches are assessed for first- and second-order quantities in comparison with results derived from coarse-grained large-eddy simulation (LES) fields. In the LES regime, the subgrid schemes produce very similar results, albeit with some modest differences near the surface. At coarser resolutions, the use of the standard Smagorinsky approach significantly delays the onset of resolved turbulence, with the delay increasing with coarsening resolution. In contrast, the dynamic Smagorinsky scheme much improves the spinup and so is also able to maintain consistency with the LES temperature profiles at the coarser resolutions. Moreover, the resolved part of the turbulence reproduces well the turbulence profiles obtained from the coarse-grained fields, especially in the near gray zone. The dynamic scheme does become somewhat overenergetic with further coarsening of the resolution, especially near the surface. The dynamic scheme reaches its limit in the current configuration when the test filter starts to sample at the unresolved scales, returning very small Smagorinsky coefficients. Sensitivity tests reveal that the dynamic model can adapt to changes in the imposed numerical or subgrid diffusion by adjusting the Smagorinsky constant to the changing flow field and minimizing the dissipation effects on the resolved turbulence structures.
Effect of Planetary Rotation on Oceanic Surface Boundary Layer Turbulence
Authors: Liu Jinliang , Liang Jun-Hong , McWilliams James C. , Sullivan Peter P. , Fan Yalin , Chen Qin
Published: July 2018

A large-eddy simulation (LES) model is configured to investigate the effect of the horizontal (northward) component of Earth’s rotation on upper-ocean turbulence. The focus is on the variability of the effect with latitude/hemisphere in the presence of surface gravity waves and when capped by a stable stratification beneath the surface layer. When is included, the mean flow, turbulence, and vertical mixing depend on the wind direction. The value and effect of are the largest in the tropics and decrease with increasing latitudes. The variability in turbulent flows to wind direction is different at different latitudes and in opposite hemispheres. When limited by stable stratification, the variability in turbulence intensity to wind direction reduces, but the entrainment rate changes with wind direction. In wave-driven Langmuir turbulence, the variability in mean current to wind direction is reduced, but the variability of turbulence to wind direction is evident. When there is wind-following swell, the variability in the mean current to wind direction is further reduced. When there is strong wind-opposing swell so that the total wave forcing is opposite to the wind, the variability in the mean current to wind direction is reduced, but the variability of turbulence to wind direction is enhanced, compared to in Ekman turbulence. The profiles of eddy viscosity, including its shape and its value, show a strong wind direction dependence for both stratified wind-driven and wave-driven Langmuir turbulence. Our study demonstrates that wind direction is an important parameter to upper-ocean mixing, though it is overlooked in existing ocean models.
Examining the Career Pathways of Educators With Superintendent Certification
Authors: Davis Bradley W. , Bowers Alex J.
Published: July 2018

Purpose: We used gatekeeping theory to frame our examination of whether and when educators with superintendent certification become superintendents, and how their likelihood of making that transition is influenced by race, sex, and other characteristics. Furthermore, we sought to identify variation in career pathways to the superintendency. Data and Method: We analyzed 26,071 observations of 4,813 unique individuals, representing the entire population of Texas public school educators who obtained their first superintendent certificate between the 2000-2001 and 2014-2015 school years. We constructed alluvial diagrams to visualize these educators’ career pathways. In addition to compiling a life table and visual displays of hazard, we used a discrete-time hazard model to control for individual and contextual characteristics associated with transitions into the superintendency. Findings: Educators are most likely to enter the superintendency in the academic year immediately following that in which they obtained the requisite certification. Furthermore, pathways to the superintendency differ greatly based on educator sex and race, as well as the level and locale employment setting. Finally, we determined that age, experience, education, level of employment, and sex all have statistically significant impacts on the likelihood of becoming a superintendent. Implications for Research and Practice: We discuss the role that researchers must play in coordinating with practitioners to ensure more equitable opportunity for aspiring superintendents. We also emphasize the important role that preparation programs play in preparing candidates for the job market. Finally, we ponder further expansions of similar presuperintendency research, as well as more robust applications of alluvial diagrams.
Assessment of the NSQIP Surgical Risk Calculator in Predicting Microvascular Head and Neck Reconstruction Outcomes
Authors: Ma Yue , Laitman Benjamin M. , Patel Vir , Teng Marita , Genden Eric , DeMaria Samuel , Miles Brett A.
Published: July 2018

Objective

This study evaluated the accuracy of the Surgical Risk Calculator (SRC) of the ACS NSQIP (American College of Surgeons National Surgical Quality Improvement Program) in predicting head and neck microvascular reconstruction outcomes.

Study Design

Retrospective analysis.

Setting

Tertiary medical center.

Subjects and Methods

A total of 561 free flaps were included in the analysis. The SRC‐predicted 30‐day rates of postoperative complications, hospital length of stay (LOS), and rehabilitation discharge were compared with the actual rates and events. The SRC's predictive value was examined with Brier scores and receiver operating characteristic area under the curve.

Results

A total of 425 myocutaneous, 134 osseous (84 fibula, 47 scapula, and 3 iliac crest), and 2 omental free flaps were included in this study. All perioperative complications evaluated had area under the curve values ≤0.75, ranging from 0.480 to 0.728. All but 2 postoperative complications had Brier scores >0.01. SRC‐predicted LOS was 9.4 ± 2.38 days (mean ± SD), which did not strongly correlate with the actual LOS of 11.98 ± 9.30 days (r = 0.174, P <. 0001).

Conclusion

The SRC is a poor predictor for surgical outcome among patients undergoing microvascular head and neck reconstruction.
Platelet‐Rich Plasma Fat Graft versus Cartilage Perichondrium for Repair of Medium‐Size Tympanic Membrane Perforations
Authors: Mandour Mahmoud Fawzy , Elsheikh Mohamed Nasser , Khalil Mohamed Fathy
Published: July 2018

Objectives

To compare clinical and audiologic outcomes among patients who underwent myringoplasty with fat graft enriched with platelet‐rich plasma and cartilage perichondrium graft.

Study Design

Prospective randomized controlled study.

Setting

Department of Otolaryngology–Head and Neck Surgery, Tanta University, Egypt.

Subjects and Methods

The study comprised 50 patients who had tympanic membrane perforation of medium size (25%‐50% of its surface area) without evidence of active otitis media or ossicular abnormalities and who had surgery between December 2016 and December 2017. Patients randomly underwent myringoplasty with fat graft enriched with platelet‐rich plasma (group 1) or cartilage perichondrium graft (group 2).

Results

Twenty‐five patients were included in each group. Rates of successful closure at 3‐month follow‐up were 88% (group 1) and 92% (group 2). The mean overall improvement in pure tone average was 18.08 dB (95% CI, 16.9‐19.25) for group 1 and 18.24 dB (95% CI, 16.94‐19.53) for group 2.

Conclusion

Fat graft enriched with platelet‐rich plasma can be recommended as an alternative choice for first‐line treatment of medium‐size central perforations of the tympanic membrane, with healing and hearing results comparable to those of conventional cartilage perichondrium myringoplasty.
Giving in the bedroom: The costs and benefits of responding to a partner’s sexual needs in daily life
Authors: Impett Emily A. , Muise Amy , Harasymchuk Cheryl
Published: July 2018

A common reason why people in ongoing romantic relationships report engaging in sex with their partner—in addition to pursuing their own pleasure—is to meet their partner’s sexual needs. While meeting a partner’s needs with responsiveness and care is crucial in romantic relationships, it is important, especially in the domain of sexuality, that people do not neglect their own needs when meeting the needs of their partner. In a 21-day daily experience study of both members of 122 romantic couples recruited from the community, we tested whether being responsive to a partner’s sexual needs (i.e., high sexual communal strength) and focusing on a partner’s needs while neglecting one’s own needs (i.e., high unmitigated sexual communion) were associated with both partners’ daily sexual and relationship satisfaction. We also tested attention to positive partner-focused and negative self-focused cues during the sexual experience as novel mechanisms of these effects. The results generally showed that on days when people (or their romantic partner) reported higher sexual communal strength, they reported greater attention to positive partner-focused sexual cues and, in turn, both partners experienced greater daily sexual and relationship satisfaction. In contrast, on days when people reported higher unmitigated sexual communion, they reported greater attention to negative self-focused sexual cues and, in turn, experienced lower relationship and sexual satisfaction, although these effects did not extend to their romantic partner. Implications of the results for promoting higher quality sexual experiences and relationships are discussed.