bluuebunny/crossref_metadata_2025 huggingface dataset:
Curricular Variables and Topics Studied in Veterinary Immunology Courses at Several Latin American Universities
Authors: Carrero Lilia Lisbeth
Published: May 2019

Competencies approach is a strategy advised by academicians, international organizations with competence in education (e.g., UNESCO), and those related to veterinary medicine practice (e.g., OIE [World Organisation for Animal Health, formerly International Office of Epizootics] and PANVET [Pan-American Association for Veterinary Sciences]) to answer society’s demands for professionals. In Latin American universities, important initiatives to adopt competencies approach were developed by Tuning América Latina and VINCULAENTORNO (project developed by several international institutions, including IESALC from UNESCO [International Institution for Higher Education in Latin America and the Caribbean] focused on the entailment of universities with their environment, to foster social and economic sustainable development) more than a decade ago. In Venezuela, renewed efforts concerning curricular revision were carried out by academicians, taking into account the recommendations made by peer reviewers, during the accreditation process with ARCU-SUR regarding veterinary programs. The present document explores curricular designs of immunology for veterinary students in different universities to determine common characteristics, in order to obtain valuable information for future curricular plans. Veterinary Immunology courses from 24 universities in six Latin-American countries were examined, searching for common content. Other curricular variables, e.g., instructional models, hours planned for theoretical and laboratory activities, educational credits, position in curricular trees, previous requirements, and implementation dates, were considered. The average ± standard deviation of immunology issues studied among the universities was 31±7.9 of the 63 listed topics, and the similarity was 79.2% (
n
= 19 courses), but other significant differences and curricular variations were recorded. This article describes novel aspects of curricular facts of this biomedical area in Latin America; these results may be valuable to design future curricular planning and a unified and precise curriculum on veterinary courses.
Acute hot foot: Charcot neuroarthropathy or osteomyelitis? Untangling a diagnostic web
Authors: Goldsmith Louise , Barlow Matthew , Evans Paul Jeffrey , Srinivas-Shankar Upendram
Published: May 2019

A 55-year-old man with poorly controlled type 1 diabetes with microvascular and macrovascular complications presented with a 1-week history of painful erythematous swelling on the dorsum of the left foot with two areas of foot ulceration. Inflammatory markers were raised. MRI of the left foot revealed a soft tissue swelling on the dorsum of the left foot, marrow oedema and destruction of several small joints of the foot, indicating osteomyelitis and Charcot neuroarthropathy (CN). The soft tissue swelling on the dorsum of the left foot was debrided; per-operatively bone destruction of base of the fifth metatarsal was found. The patient received intravenous antibiotics for 6 weeks. The clinical features of CN including erythema, oedema and elevated temperature of the left foot settled with off-loading the foot in an air cast walker after 6 months. Our case highlights the need to recognise CN in an acutely inflamed foot of diabetic patients with neuropathy, even when other conditions like soft tissue infection and osteomyelitis can explain the clinical features.
Hydroxychloroquine-induced podocytopathy mimicking Fabry disease
Authors: Serre Justine , Buob David , Boffa Jean-Jacques
Published: May 2019

Hydroxychloroquine (HCQ) is largely prescribed as an immunomodulator to prevent systemic diseases flares in patients with systemic lupus erythematous, rheumatoid arthritis, Sjogren’s disease. Among reported side effects, HCQ can accumulate in lysosomes and induced phospholipidosis. Here, we report an HCQ-induced podocytopathy mimicking Fabry disease (FD). They share the same histological lesions: cytoplasmic vacuolisation of the podocytes and zebra bodies on light and electronic microscopy. FD has been ruled out by measuring enzymatic activity and genetic test. The persistence of proteinuria after immunological remission of a systemic disease treated with HCQ could suggest this HCQ-induced podocytopathy.
The role of community health workers in cervical cancer screening in low-income and middle-income countries: a systematic scoping review of the literature
Authors: O’Donovan James , O’Donovan Charles , Nagraj Shobhana
Published: May 2019

Introduction

Community-based screening for cervical cancer and task sharing to community health workers (CHWs) have been suggested as a potential way to increase screening coverage in low- and middle-income countries (LMICs). The aims of the scoping review were to understand the following: (i) where and how CHWs are currently deployed in screening in LMIC settings; (ii) the methods used to train and support CHWs in screening, and (iii) The evidence on the cost-effectiveness of using CHWs to assist in screening.

Methods

A scoping literature search of 11 major databases and the grey literature was performed between 1978 and 2018. We included comprehensive search terms for ‘CHWs’ and ‘Cervical Cancer’, and used the World Bank criteria to define LMICs.

Results

Of the 420 articles screened, 15 met the inclusion criteria for review. Studies were located in Africa (n=5), Asia (n=5), and South and Central America (n=5). CHWs played a role in community education and raising awareness (n=14), conducting or assisting in cervical screening (n=5), or follow-up (n=1). 11 studies described CHW training activities. Only one study provided a formal cost analysis.

Conclusion

The roles of CHWs in cervical cancer screening in LMICs have largely to date focused on education, outreach, and awareness programmes. Community-based approaches to cervical cancer screening are feasible, although the sociocultural context plays an important role in the acceptability of these interventions. Further in-depth contextually grounded studies exploring the acceptability of such interventions are required, as well as studies exploring the cost-effectiveness of involving CHWs in cervical cancer screening activities.
Impact of pretreatment with intravenous thrombolysis on reperfusion status in acute strokes treated with mechanical thrombectomy
Authors: Goyal Nitin , Tsivgoulis Georgios , Pandhi Abhi , Malhotra Konark , Krishnan Rashi , Ishfaq Muhammad F , Krishnaiah Balaji , Nickele Christopher , Inoa-Acosta Violiza , Katsanos Aristeidis H , Hoit Daniel , Elijovich Lucas , Alexandrov Andrei , Arthur Adam S
Published: May 2019

Introduction

We sought to evaluate the impact of pretreatment with intravenous thrombolysis (IVT) on the rate and speed of successful reperfusion (SR) in patients with emergent large vessel occlusion (ELVO) treated with mechanical thrombectomy (MT) in a high-volume tertiary care stroke center.

Methods

Consecutive patients with ELVO treated with MT were evaluated. Outcomes were compared between patients who underwent combined IVT and MT (IVT+MT) and those treated with direct MT (dMT). The elapsed time between groin puncture to beginning of reperfusion (GPTBRT) and the numbers of device passes required to achieve SR were also documented.

Results

A total of 287 and 132 patients were treated with IVT+MT and dMT, respectively. The IVT+MT group had higher SR (73.8% vs 62.9%; p=0.023) and 3-month functional independence (modified Rankin Scale score 0–2;51.6% vs 38.2%; p=0.008) rates. The median GPTBRT was shorter in the IVT+MT group (48 (IQR 33–70) vs 70 (IQR 44–98) min; p<0.001). Among patients who achieved SR (n=292), the median number of required device passes was lower in the IVT+MT subgroup (1 (IQR 1–1) vs 2 (IQR 1–2); p<0.001), while the rate of patients requiring ≤2 device passes was higher (98% vs 77%; p<0.001). IVT+MT was independently related to higher odds of SR (OR 1.64; 95% CI 1.03 to 2.61; p=0.036) and shorter GPTBRT (unstandardized linear regression coefficient −20.39; 95% CI −27.56 to –13.22; p<0.001) on multivariable analyses adjusting for potential confounders. Among patients with SR, IVT+MT was independently associated with a higher likelihood of ≤2 device passes (OR 14.63; 95% CI 4.46 to 48.00; p<0.001).

Conclusions

IVT pretreatment appears to increase the rates of SR and shortens the duration of the endovascular procedure by requiring fewer device passes in patients with ELVO treated with MT.
Classical and quantum correlations for a family of two-qutrit states
Authors: Parsian Hossein , Akhound Ahmad
Published: May 2019

The classical and quantum correlations for a family of two-qutrit states are investigated. For this purpose, a family of two-qutrit states, as well as a set of measurements are proposed. An analytical quantum discord treatment is presented for this family of two-qutrit states. Finally, we compute and illustrate the entanglement of formation, classical mutual information and quantum discord for this family of two-qutrit quantum states.
Effects of a Nano-Interleave on the Interlaminar Fracture Toughness for Autoclave and Out-of-Autoclave Processed Glass/Phenolic Composites
Authors: Barzoki P. Kheirkhah , Ipakchi H. , Rezadoust A. M. , Latifi M. , Esfandeh M.
Published: May 2019

In this research, Polyvinyl butyral (PVB) nanofiber as an interlaminar toughener was used in two autoclave and out-of-autoclave (OoA) curing processes in which the effect of curing method on the ability of nanofiber toughening and effectiveness of nanofiber to improve fracture properties of OoA-made structures were studied. For these investigations, PVB nanoweb was placed on mid plans of laminates and cured with the vacuum bag and the autoclave processing which were subsequently subjected to double cantilever beam (DCB) and end-notch flexure (ENF) tests. It was found that PVB nanoweb with the thickness of [Formula: see text] and nanofiber diameter of 158.6[Formula: see text]nm could increase mode-I fracture toughness ([Formula: see text]) 164% and 89% and mode-II fracture toughness ([Formula: see text] 58% and 62% for autoclave and out-of-autoclave-made specimens in comparison with their non-modified samples, respectively. This research also proved PVB nanofiber has the capacity to improve 16% and 10% [Formula: see text] and [Formula: see text] of OoA-made sample compared to the non-modified autoclave-made samples. So, we could conclude modified OoA-made laminated composite is a truly suitable replacement choice for autoclave-made glass–phenolic composites.
Integrals of polylogarithmic functions with alternating argument
Authors: Sofo Anthony
Published: May 2019

The connection between polylogarithmic functions and Euler sums is well-known. In this paper, we explore the representation and many connections between integrals of products of polylogarithmic functions with alternating signs in the argument and Euler sums. We shall consider mainly, polylogarithmic functions with negative and positive arguments, thereby producing new results and extending the work of Freitas. Many examples of integrals of products of polylogarithmic functions in terms of Riemann zeta values and Dirichlet values will be given.
Impaired insulin signaling in the B10.D2-Hc0H2dH2-T18c/oSnJ mouse model of complement factor 5 deficiency
Authors: Peterson Kristin R. , Gutierrez Dario A. , Kikuchi Takuya , Anderson-Baucum Emily K. , Winn Nathan C. , Shuey Megan M. , Bolus William R. , McGuinness Owen P. , Hasty Alyssa H.
Published: May 2019

Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2- Hc0H2dH2- T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5defmice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5defmice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5defmice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2- Hc0H2dH2- T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5contand C5defmice, indicating an insulin-sensitizing function of C5.
Phosphorylation status of fetuin-A is critical for inhibition of insulin action and is correlated with obesity and insulin resistance
Authors: Ren Guang , Kim Teayoun , Papizan James B. , Okerberg Carl K. , Kothari Vishal M. , Zaid Hilal , Bilan Phillip J. , Araya-Ramirez Felipe , Littlefield Laurel A. , Bowers Robert L. , Mahurin A. Jack , Nickles Mary M. , Ludvigsen Rebecca , He Xiaoming , Grandjean Peter W. , Mathews Suresh T.
Published: May 2019

Fetuin-A (Fet-A), a hepatokine associated with insulin resistance, obesity, and incident type 2 diabetes, is shown to exist in both phosphorylated and dephosphorylated forms in circulation. However, studies on fetuin-A phosphorylation status in insulin-resistant conditions and its functional significance are limited. We demonstrate that serum phosphofetuin-A (Ser312) levels were significantly elevated in high-fat diet-induced obese mice, insulin-resistant Zucker diabetic fatty rats, and in individuals with obesity who are insulin resistant. Unlike serum total fetuin-A, serum phosphofetuin-A was associated with body weight, insulin, and markers of insulin resistance. To characterize potential mechanisms, fetuin-A was purified from Hep3B human hepatoma cells. Hep3B Fet-A was phosphorylated (Ser312) and inhibited insulin-stimulated glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Furthermore, single (Ser312Ala) and double (Ser312Ala + Ser120Ala) phosphorylation-defective Fet-A mutants were without effect on glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Together, our studies demonstrate that phosphorylation status of Fet-A (Ser312) is associated with obesity and insulin resistance and raise the possibility that Fet-A phosphorylation may play a role in regulation of insulin action.
Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice
Authors: Prévost Gaëtan , Arabo Arnaud , Le Solliec Marie-Anne , Bons Justine , Picot Marie , Maucotel Julie , Berrahmoune Hind , El Mehdi Mouna , Cherifi Saloua , Benani Alexandre , Nédélec Emmanuelle , Coëffier Moïse , Leprince Jérôme , Nordqvist Anneli , Brunel Valéry , Déchelotte Pierre , Lefebvre Hervé , Anouar Youssef , Chartrel Nicolas
Published: May 2019

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.
Effects of Catheter Tip Location on the Spread of Sensory Block Caused by a Continuous Thoracic Paravertebral Block: A Prospective, Randomized, Controlled, Double-Blind Study
Authors: Yoshida Takayuki , Watanabe Yoshiko , Hashimoto Takeshi , Ohta Atsushi , Nakamoto Tatsuo
Published: May 2019

Single injections in the anterior region of the thoracic paravertebral space (TPVS) have been reported to generate a multisegmental longitudinal spreading pattern more frequently than those in the posterior region of the TPVS. In this trial, we examined the hypothesis that a continuous thoracic paravertebral block (TPVB) administered through a catheter inserted into the anterior region of the TPVS allows a wider sensory block dispersion. Fifty consecutive patients undergoing video-assisted thoracic surgery were enrolled. Before the surgery, an infusion catheter was inserted into the TPVS through a needle placed adjacent to either the parietal pleura (group A) or internal intercostal membrane (group P) using an ultrasound-guided intercostal transverse approach according to a randomized allocation schedule. A chest radiograph was obtained postoperatively after injection of 10 mL of radiopaque dye through the catheter. Thereafter, 20 mL of 0.375% levobupivacaine was injected via the catheter, followed by commencement of continuous TPVB with 0.25% levobupivacaine at 8 mL/h. The primary outcome was the number of blocked dermatomes at 24 h after surgery. The secondary outcomes included radiopaque dye spreading patterns, the number of segments reached by the radiopaque dye, the number of blocked dermatomes at 2 h after surgery, and pain scores. The median (interquartile range [range]) number of blocked dermatomes 24 h after surgery was 3 (2.75–4 [1–6]) in group A (n = 22) and 2 (1.5–3 [0–7]) in group P (n = 25; p = 0.037). No significant differences in the other outcomes were found between the groups. In conclusion, a continuous TPVB administered using a catheter supposedly inserted into the anterior region of the TPVS allows a wider sensory block dispersion than a catheter inserted into the posterior region of the TPVS. This trial is registered with the UMIN Clinical Trials Registry (UMIN000018578).
Expression Concordance of 325 Novel RNA Biomarkers between Data Generated by NanoString nCounter and Affymetrix GeneChip
Authors: Delmonico Lucas , Attiya Said , Chen Joan W. , Obenauer John C. , Goodwin Edward C. , Fournier Marcia V.
Published: May 2019

Background. With the development of new drug combinations and targeted treatments for multiple types of cancer, the ability to stratify categories of patient populations and to develop companion diagnostics has become increasingly important. A panel of 325 RNA biomarkers was selected based on cancer-related biological processes of healthy cells and gene expression changes over time during nonmalignant epithelial cell organization. This “cancer in reverse” approach resulted in a panel of biomarkers relevant for at least 7 cancer types, providing gene expression profiles representing key cellular signaling pathways beyond mutations in “driver genes.” Objective. To further investigate this biomarker panel, the objective of the current study is to (1) validate the assay reproducibility for the 325 RNA biomarkers and (2) compare gene expression profiles side by side using two technology platforms. Methods and Results. We have mapped the 325 RNA transcripts and in a custom NanoString nCounter expression panel to be compared to all potential probe sets in the Affymetrix Human Genome U133 Plus 2.0. The experiments were conducted with 10 unique biological formalin-fixed paraffin-embedded (FFPE) breast tumor samples. Each site extracted RNA from four sections of 10-micron thick FFPE tissue over three different days by two different operators using an optimized standard operating procedure and quality control criteria. Samples were analyzed using mas5 in BioConductor and NanoStringNorm in R. Pearson correlation showed reproducibility between sites for all 60 samples with r=0.995 for Affymetrix and r=0.999 for NanoString. Correlation in multiple days and multiple users was for Affymetrix r=0.962−0.999 and for NanoString r=0.982−0.991. Conclusion. The 325 RNA biomarkers showed reproducibility in two technology platforms with moderate to high concordance. Future directions include performing clinical validation studies and generating rationale for patient selection in clinical trials using the technically validated assay.
Light Hydrocarbon Geochemistry: Insight into Mississippian Crude Oil Sources from the Anadarko Basin, Oklahoma, USA
Authors: Atwah Ibrahim , Sweet Stephen , Pantano John , Knap Anthony
Published: May 2019

The Mississippian limestone is a prolific hydrocarbon play in the northern region of Oklahoma and the southern part of Kansas. The Mississippian reservoirs feature variations in produced fluid chemistry usually explained by different possible source rocks. Such chemical variations are regularly obtained from bulk, molecular, and isotopic characteristics. In this study, we present a new geochemical investigation of gasoline range hydrocarbons, biomarkers, phenols, and diamondoids in crude oils produced from Mississippian carbonate and Woodford Shale formations. A set of oil samples was examined for composition using high-performance gas-chromatography and mass-spectrometry techniques. The result shows a distinct geochemical fingerprint reflected in biomarkers such as the abundance of extended tricyclic terpanes, together with heptane star diagrams, and diamantane isomeric distributions. Such compounds are indicative of the organic matter sources and stages of thermal maturity. Phenolic compounds varied dramatically based on geographic location, with some oil samples being depleted of phenols, while others are intact. Based on crude oil compositions, two possible source rocks were identified including the Woodford Shale and Mississippian mudrocks, with a variable degree of mixing reported. Variations in phenol concentrations reflect reservoir fluid dynamic and water interactions, in which oils with intact phenols are least affected by water-washing conversely and crude oils depleted in phenols attributed to reservoir water-washing. These geochemical parameters shed light into petroleum migration within Devonian-Mississippian petroleum systems and mitigate geological risk in exploring and developing petroleum reservoirs.
A Rare Case of Gastric Metastasis in Ewing’s Sarcoma of the Femur
Authors: Koti Krishna Amulya , Backianathan Selvamani , Sebastian Patricia , Matthew Leni G. , Raam Mithun , Masih Dipti
Published: May 2019

The stomach is a very unusual site of metastasis. Published reports on metastatic lesion in the stomach is generally limited to single case reports and case series. Gastric metastasis in an Ewing’s sarcoma is extremely rare and has been reported in English literature but once to our knowledge. We present a case report of Ewing’s sarcoma of the right proximal femur metastasizing to the stomach. A young female treated for Ewing’s sarcoma of the femur in 2012 presented with gastric metastasis after four years of disease-free interval. She was treated with irinotecan-based chemotherapy followed by total gastrectomy with esophagojejunal anastomosis and radiation therapy. At one-year follow-up, she was disease free.
Oxidative Stability of Acylated and Hydrogenated Ricinoleates Using Synthetic and Natural Antioxidants
Authors: Luna F. Murilo T. , Salmin Davi Costa , Santiago Vanessa S. , Maia Francisco J. N. , Silva Francisco O. N. , Mazzetto Selma E. , Cavalcante Célio L.
Published: May 2019

As increasing environmental policies constrains are imposed, the demand for biodegradable products also increases. Although vegetable oils present some properties that favor its use for formulation of a bio-based lubricant, its poor resistance to oxidation hinders its application as such. In this study, the thermo-oxidative stability of bio-based products was compared to petroleum-based lubricants and vegetable oils through the PetroOXY method. Chemical modifications in the ricinoleic acids were carried out using long-chain alcohols in esterification reactions. Acetates were obtained from ricinoleates with and without hydrogenation steps. Additionally, commercial antioxidants and phenolic compounds (saturated and unsaturated cardanol) obtained from cashew nut shell liquid were added to the synthesized samples with higher induction times. The results show that the chemically modified bio-based products exhibited improved oxidative stability (up to 6 times) and depressed pour point (−42°C) when compared to pure castor oil. Overall, the addition of antioxidants increased from 6 to 20 times the oxidative stability of the bio-based products. Propyl gallate and saturated cardanol showed higher efficiency for retarding the oxidative process of bio-based samples than the commercial antioxidants.
Copper (II) Ions Activate Ligand-Independent Receptor Tyrosine Kinase (RTK) Signaling Pathway
Authors: He Fang , Chang Cong , Liu Bowen , Li Zhu , Li Hao , Cai Na , Wang Hong-Hui
Published: May 2019

Receptor tyrosine kinase (RTK) is activated by its natural ligand, mediating multiple essential biological processes. Copper (II) ions are bioactive ions and are crucial in the regulation of cell signaling pathway. However, the crosstalk between copper (II) ions and RTK-mediated cellular signaling remains unclear. Herein, we reported the effect of copper (II) ions on the ligand-independent RTK cellular signaling pathway. Our results indicate that both EGFR and MET signaling were activated by copper (II) in the absence of the corresponding ligands, EGF and HGF, respectively. Consequently, copper (II) ions initiate two RTK-mediated downstream signal transductions, including AKT and ERK. Moreover, copper (II) significantly increased proliferation and cellular migration. Our study proposes a novel role of copper in RTK-mediated signaling for growth factor-independent cancer cell proliferation and migration, implying that targeting both the copper (II) and growth factor in tumor microenvironments may be necessary for cancer treatment.
Clinical Features, Etiology, and 6-Month Prognosis of Isolated Corpus Callosum Infarction
Authors: Zhang Zhiyong , Meng Xiufeng , Liu Wei , Liu Zunjing
Published: May 2019

As the largest subcortical commissural fiber, the corpus callosum plays an important role in cerebral functions and has abundant blood supply from bilateral circulation. Isolated corpus callosum infarction (ICCI) may have specific characteristics. The aim of the study is to evaluate the clinical features, etiology, and 6-month prognosis of ICCI. Consecutive patients with acute ICCI treated at the China-Japan Friendship Hospital between June 2012 and June 2016 were retrospectively assessed for clinical and imaging findings. These cases were compared with patients suffering from other isolated supratentorial subcortical infarctions, matched for age, sex, and infarction size (n=60; control group). ICCI etiology and 6-month prognosis were further analyzed. ICCI cases accounted for 2.9% (33/1125) of all acute ischemic strokes and 30 patients were included. Most patients (n=28, 93.3%) presented nonspecific clinical symptoms, and only two (6.7%) with diffuse infarction developed callosal disconnection syndrome (CDS). The splenium was the most frequent site (37.5%). Large artery atherosclerosis (LAA) (n=16, 53.3%) was the most common etiology. Only four (13.3%) patients developed transient ischemic attacks (n=1, 3.3%) or cerebral infarction (n=3, 10%) during the 6-month follow-up. The frequency of good prognosis (modified Rankin score of 1-2 and without cardiovascular events) was higher in patients with ICCI compared with controls (P=0.024). Poor prognosis was associated with multiple cerebrovascular stenosis, diffuse/large infarction, and diabetes (all P<0.05). ICCI is a rare stroke type, frequently involving the splenium; its common etiology is likely LAA. Most patients show nonspecific symptoms, with only a few developing CDS. ICCI generally shows favorable short-term outcome.
Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors
Authors: Bahleda Rastislav , Italiano Antoine , Hierro Cinta , Mita Alain , Cervantes Andres , Chan Nancy , Awad Mark , Calvo Emiliano , Moreno Victor , Govindan Ramaswamy , Spira Alexander , Gonzalez Martha , Zhong Bob , Santiago-Walker Ademi , Poggesi Italo , Parekh Trilok , Xie Hong , Infante Jeffrey , Tabernero Josep
Published: May 2019

Purpose:

Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.

Patients and Methods:

Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.

Results:

The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were <10%.

Conclusions:

Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.
HIF Inactivation of p53 in Ovarian Cancer Can Be Reversed by Topotecan, Restoring Cisplatin and Paclitaxel Sensitivity
Authors: Parmakhtiar Basmina , Burger Robert A. , Kim Jai-Hyun , Fruehauf John P.
Published: May 2019

Ovarian cancer growth under hypoxic conditions results in hypoxia-inducible factor-1α (HIF1α) stabilization. HIF1α is an adverse prognostic factor that may contribute to worse outcomes via its capacity to bind to p53, potentially blocking p53-mediated apoptosis. We determined whether HIF1α-p53 binding occurred in hypoxic ovarian cancer cell lines, and if this blocked p53 transcriptional activity. Topotecan (TPT), used in the treatment of ovarian cancer, inhibits HIF1α translation via a topoisomerase-1 (TOPO1)–dependent mechanism. We examined if TPT knockdown of HIF1α restored p53 transcriptional function. TPT effects on HIF1α and p53-related transcriptional targets were assessed by PCR. Associations between TPT effects and TOPO1 expression levels were examined by Western blots and knockdown by siRNA. RNA-binding protein immunoprecipitation was used to assess if TOPO1 was resident on HIF1α mRNA. We determined if sublethal doses of TPT, used to knockdown HIF1α, reversed hypoxia-related cisplatin and paclitaxel resistance (XTT assay). Flow cytometry was used to assess HIF1α-mediated upregulation of ABCB1 and ABCB5 efflux pump expression. We found that HIF1α binding to, and inhibition of, p53 transcriptional activity in hypoxic ovarian cancer cells was associated with drug resistance. TPT-mediated downregulation of HIF1α in hypoxic cells required TOPO1 resident on HIF1α mRNA, restored p53 transcriptional activity, downregulated ABCB1/ABCB5 cell surface expression, and reversed hypoxia-related cisplatin and paclitaxel resistance.

Implications:

TPT-mediated reduction of HIF1α accumulation in hypoxic ovarian cancer cell lines restores p53 tumor-suppressor function, offering a novel approach to reverse chemoresistance. Further clinical investigation is warranted.
The Codon 72 TP53 Polymorphism Contributes to TSC Tumorigenesis through the Notch–Nodal Axis
Authors: Cho Jun-Hung , Patel Bhaumik , Bonala Santosh , Mansouri Hossein , Manne Sasikanth , Vadrevu Surya Kumari , Ghouse Shanawaz , Kung Che-Pei , Murphy Maureen E. , Astrinidis Aristotelis , Henske Elizabeth P. , Kwiatkowski David J. , Markiewski Maciej M. , Karbowniczek Magdalena
Published: May 2019

We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of TP53 and that R72 increases the risk for angiomyolipoma. R72 transactivates NOTCH1 and NODAL better than the proline variant of codon 72 (P72); therefore, the expression of NOTCH1 and NODAL is increased in angiomyolipoma cells that carry R72. The loss of Tp53 and Tsc1 within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high Notch1 and Nodal expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine Tp53 or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways.

Implications:

This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling.
Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma
Authors: Nejo Takahide , Matsushita Hirokazu , Karasaki Takahiro , Nomura Masashi , Saito Kuniaki , Tanaka Shota , Takayanagi Shunsaku , Hana Taijun , Takahashi Satoshi , Kitagawa Yosuke , Koike Tsukasa , Kobayashi Yukari , Nagae Genta , Yamamoto Shogo , Ueda Hiroki , Tatsuno Kenji , Narita Yoshitaka , Nagane Motoo , Ueki Keisuke , Nishikawa Ryo , Aburatani Hiroyuki , Mukasa Akitake , Saito Nobuhito , Kakimi Kazuhiro
Published: May 2019

Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II–IV glioma patients (glioblastoma, IDH-wild-type, n = 8; grade II–III astrocytoma, IDH-mutant, n = 9; and grade II–III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, n = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the “neoantigen expression ratio,” decreased significantly at recurrence (P = 0.003). This phenomenon was particularly pronounced for “high-affinity,” “clonal,” and “passenger gene–derived” neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.
A Tool for Grammatical Development Assessment in a Second Language
Authors: Salameh Eva-Kristina
Published: May 2019

Objective: This paper describes an alternative assessment tool for second language learning, based on Processing Theory (PT). The basis of this theory is that language learners cannot acquire what they cannot process. This paper presents a tool, based on this theory that avoids the over- or under-diagnosis of language impairment in second language learners. Method: This tool has five levels, with the prerequisites for the following step at each level. Each level is designed to determine children’s ability to process language factors required at each stage. The five levels begin with identification and acquisition of words in a target language and end with the acquisition of grammar based on word order rules. Results: Findings were that bilingual children, with typical language development, were successful at level 4 (the phrase and morphology level) after 2 years of exposure to Swedish. Bilingual children with language impairment were much slower in their language development in both their first and second languages.
Collaborative Approaches to the Support of People with Disabilities: The Underserved and Unserved
Authors: Cheng Li-Rong Lilly , Levey Sandra
Published: May 2019

Background: Underserved and unserved people are individuals who lack necessary health services. They can be found in both high- and low-income countries with disabilities in areas such as speech, language, hearing, swallowing, physical, and neurological, as well as other health problems. In addition, academic programs that prepare students to serve underserved or unserved communities do not exist in some countries. Collaborative projects allow those with expertise to share their knowledge, strategies, methods, and technologies with health practitioners, administrators, educators, students, and families. The goal is to assist populations who require special services. Collaborative projects can be interdisciplinary, international, or involve academic institutions or organizations. It is also essential that collaboration projects consider the strengths and assets that are present in the environment and in the population. This asset-based approach supports sustainability as long-term solutions can take advantage of existing strengths. Sustainability is essential so that the goals of projects can continue to contribute to a population. Objectives: The primary objective of this article is to present collaborative projects that positively impact underserved and unserved populations. The strengths of these projects are also presented as a model for further work. Summary: This article presents several collaborative projects, along with the impact of these efforts.
Emergent Literacy Support for Children from Marginalised Populations
Authors: Moonsamy Sharon , Carolus Stephanie
Published: May 2019

Background: The purpose of this paper is to describe the content and process of a literacy and language support model that was implemented with young children from marginalised communities, where no access to speech and language pathologist (SLP) services exists. The importance of language for literacy development is emphasised with explicit strategies for classroom application. Method: The SLP introduced an intervention programme to Early Childhood Development (ECD) kindergarten teachers, as part of a pre- and post-test literacy study. The strategies included oral reading, one-on-one reading and paired-reading. The participants provided informed consent. The intervention was presented to the experimental (Exp) group during the study process and to the comparison group after the study was completed. Results: Post-intervention findings revealed a significant improvement in the Exp group scores on concepts about print. The ECD teachers reported a difference in the children’s awareness of printed materials, confirming that the approaches introduced by the SLP are central in teachers’ instruction. This finding supports the contribution that emergent literacy and language support models would have for children, especially those from marginalised communities, where access to resources are limited. Furthermore, the collaboration between SLP and the ECD staff will strengthen these support structures. Thus, explicit early intervention develops skills for school-readiness and academic success; this forms part of the solution in providing early access to language and literacy programmes in developing countries.
Indoxyl Sulfate-Induced Extracellular Vesicles Released from Endothelial Cells Stimulate Vascular Smooth Muscle Cell Proliferation by Inducing Transforming Growth Factor-Beta Production
Authors: Ryu Jung-Hwa , Jeon Eun-Young , Kim Seung-Jung
Published: May 2019

Vascular access stenosis predominantly occurs as a result of neointimal hyperplasia (NH) formation at the anastomosis. Moreover, in the presence of NH, transforming growth factor-beta (TGF-β) promotes vascular smooth muscle cell (VSMC) proliferation. Extracellular vesicles (EVs) released by endothelial cells are closely associated with vascular dysfunction. Here, we investigated the effects of EVs on TGF-β signaling and VSMC proliferation. Specifically, EVs were collected from the culture medium of indoxyl sulfate (IS)-treated human umbilical vein endothelial cells and used (2 × 106) to stimulate human aortic smooth muscle cells (SMCs) (1 × 106). Western blotting was performed to assess the levels of Akt, ERK1/2, p38 MAPK, and Smad3. BrdU proliferation assays, quantitative PCR, and ELISA assays were performed to evaluate SMC proliferation and TGF-β production. The IS-induced EVs stimulated the proliferation of aortic SMCs in a concentration-dependent manner. The EVs both contained TGF-β and promoted TGF-β production by SMCs by phosphorylating Akt, ERK1/2, p38 MAPK, and Smad3, which was significantly inhibited by an anti-TGF-β antibody. SMC proliferation was suppressed by both an anti-TGF-β antibody and inhibitors of the downstream factors. These results suggest that EVs are involved in the pathogenesis of vascular access stenosis by modulating TGF-β signaling in VSMCs under uremic conditions.
Activation and Impaired Tumor Necrosis Factor-α Production of Circulating Mucosal-Associated Invariant T Cells in Patients with Trauma
Authors: Jo Young-Goun , Jin Hye-Mi , Cho Young-Nan , Kim Jung-Chul , Kee Seung-Jung , Park Yong-Wook
Published: May 2019

Mucosal-associated invariant T (MAIT) cells rapidly produce proinflammatory cytokines in an innate-like manner and play an important role in controlling the host immune response. This study examined the function of MAIT cells in trauma patients. The expression of cytokines in peripheral blood MAIT cells was measured by flow cytometry. MAIT cells in trauma patients displayed impaired tumor necrosis factor (TNF)-α production, together with elevated CD69 expression. The expression of CD69 was negatively correlated with MAIT cell frequency. These patients had higher plasma levels of interleukin (IL)-12 and IL-18. In particular, CD69 expression of MAIT cells was increased by stimulation with IL-18 in synergy with other proinflammatory cytokines or plasma of trauma patients. The production of TNF-α by MAIT cells was characterized by an initial burst and rapid decline, in contrast to delayed and sustained production of interferon (IFN)-γ. Activated MAIT cells showed a functional defect in the production of TNF-α upon restimulation. This study demonstrates that circulating MAIT cells are activated and functionally impaired in TNF-α production in patients with trauma. The activation and dysfunction of MAIT cells was mediated by proinflammatory cytokines. These findings provide important information underlying the innate immune response of patients with trauma.
Evaluation of Quantum Dot Skin Penetration in Porcine Skin: Effect of Age and Anatomical Site of Topical Application
Authors: Nastiti Christofori M.R.R. , Mohammed Yousuf , Telaprolu Krishna C. , Liang Xiaowen , Grice Jeffrey E. , Roberts Michael S. , Benson Heather A.E.
Published: May 2019

Background: Pig skin is a widely acknowledged surrogate for human skin for in vitro/ex vivo skin penetration studies with application for small molecules and nanosystems. We have investigated the influence of biological factors such as age and anatomical site on the penetration and distribution of nanoparticles (2.1 nm hydrophilic CdTe/CdS quantum dots: QDs) in adult pig skin (APS), weanling pig skin (WPS) and newborn pig skin (NBPS) at two different anatomical sites (ear and abdomen). Methods: QDs in saline were applied to 1 × 1 cm2 skin (62.5 pmol/cm2) with 2-min finger rubbing using a standardized protocol. After 6- or 24-h incubation on Franz diffusion cells, tape stripping (×10) followed by manual follicular casting was conducted. Cadmium in QDs was quantified using inductively coupled plasma mass spectrometry for all samples. The presence of QDs in similarly treated skin samples was also captured using multiphoton tomography. Results: QDs were mainly localized in hair follicles after 6 and 24 h of exposure with no cadmium detected in the Franz cell receptor compartment regardless of pig age or anatomical site. The amount of QDs deposited in the follicles was similar at 6 h but higher on APS and WPS ears compared to NBPS ears at 24 h. This is associated with the high follicle density and small follicle diameter of the NBPS compared to the smaller density of much larger follicles on the APS. NBPS showed consistent QD distribution for ear and abdomen up to 24 h. Conclusions: There is minimal penetration of QDs through pig skin. Density and diameter of follicles in association with age of pigs and application site influenced the amount of QDs deposited in follicles. The structure of the stratum corneum, follicle density and diameter of NBPS are similar to human skin suggesting that NBPS is an appropriate model for human skin in the evaluation of topical applications of a range of chemicals including nanosystems.
“I Have Become a Brother of Jackals”: Evolutionary Psychology and Suicide in the Book of Job
Authors: Cho Paul K.-K.
Published: May 2019

Job compares himself time and again to defeated and trapped animals in the poetic core of the Book of Job. God, in responding to Job, describes in loving detail, as would a proud parent her children, the animals that populate creation. This paper argues that the Joban Poet uses animal imagery to allow Job to express an evolving sense of his traumatized self and the world and God to affirm the beauty and vitality of creation and, indirectly, also of Job who has come to think of himself as a trapped and hunted animal.