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The assessment of cancer patient outcomes is important for any oncology departments. In head and neck cancer, not all patients are suitable for clinical studies. Unfortunately not all oncology centres are well resourced to undertake all available head and neck cancer trials. As a tertiary oncology unit with catchment radius of 50 miles and diverse patient demographics, it remains vital to assess outcomes of patients not included in formal studies. The aim of this study was to gather real world survival data of patients treated with definitive (chemo) radiotherapy. As standard of care, head and neck cancer patients are referred from 7 district general hospitals via 2 regional supra-multidisciplinary teams (sMDT). The data of patients demographics, and the clinical details of the head and neck cancer, are as routine collected prospectively for the institution electronic database. The date of disease recurrence on any patients is prospectively recorded at the sMDT. Non-HPV mucosal head and neck cancer patients who received definitive radiotherapy outside clinical trials between Jan 2018 and May 2022 were retrospectively reviewed. All advanced stage patients (Stages III & IVa/b) were considered concomitant chemotherapy. Radiotherapy volume quality assurance was standard prior to radiation [1]. HPV-mediated oropharynx patients, as well those treated with post-operative or adjuvant radiation, were excluded. The progression free survival (PFS) were calculated from the prospective database, and the overall survival (OS) retrospectively from the institution main death register. A total of 267 patients were identified: 122 (46%) Larynx, 68 (25%) p16- Oropharynx, 34 (13%) Hypopharynx, 33 (12%) Nasopharynx, and 10 (4%) Nasal Cavity/Paranasal sinus patients. In terms of UICC 8th edition staging, there were 33 Stage I (12%), 55 Stage II (21%), 71 Stage III (27%), and 108 Stage IVa/b (40%) cases across all tumour sites. The median age was 65 (range 58 - 72). The male to female ratio was 3.2 to 1. Ninety percent (n = 240) of the patients had performance status of 0 or 1. Majority of the patients (n = 209, 78%) had had exposure to tobacco: 122 (46%) ex-smokers and 87 (33%) current smokers. The median smoking pack years for the tobacco exposed patients was 30 (range 10 - 40). As for alcohol consumption, 130 (49%) patients consumed at least 14 units per week, with 30 (11%) being non-drinkers. All patients received 65Gy in 30 fractions (f) over 6 weeks, unless they were T1/2N0M0 glottic cancer for which they received 55Gy in 20f over 4 weeks. A total of 107 patients (40%) had at least 1 cycle of concomitant chemotherapy with their radiation. The median follow up was 3 years. Across all tumour sites, the 2 and 3 year PFS was 60% and 55% respectively, while the 2 and 3 year OS was 74% and 65% respectively. The OS probability according to the UICC staging across all disease sites is shown in Figure 1. For the Larynx subsite, there were 26 Stage I (21%), 30 Stage II (25%), 51 Stage III (42%), and 15 Stage IVa/b (12%) patients. The 2 and 3 year PFS for larynx patients were 70% and 65% respectively, with the 2 and 3 year OS being 82% and 75% respectively. For the p16- oropharynx cohort, there were 3 Stage I (4%), 12 Stage II (18%), 3 Stage III (4%), and 50 Stage IVa/b (74%) patients. In comparison to the larynx cohort, there were higher proportion of advanced stage patients in the Oropharynx cohort. As a result, the 2 and 3 year PFS for the p16-Oropharynx was 44% and 40% respectively, while the 2 and 3 year OS was 60% and 50% respectively. As for the hypopharynx group, there were no Stage I (0%) but 3 Stage II (9%), 8 Stage III (24%), and 23 Stage IVa/b (68%) cases. The 2 and 3 year PFS was 40% and 25% respectively, while the 2 and 3 year OS was 55% and 42% respectively. Separately, there were 2 Stage I (6%), 8 Stage II (24%), 8 Stage III (24%), and 15 Stage IVa (45%) Nasopharynx patients. The 2 and 3 year PFS for nasopharynx cohort was 75% and 60% respectively, with the 2 and 3 year OS being 78% and 70% respectively. [Display omitted] Despite varying tumour sites, the OS of patients overall corresponded to the UICC Stage of their disease, indicating the importance of accurate initial staging as part of prognostication. [ABSTRACT FROM AUTHOR]

Radiologist input in peer review of head and neck radiotherapy has been introduced as a routine departmental approach. The aim was to evaluate this practice and to quantitatively analyse the changes made. Patients treated with radical-dose radiotherapy between August and November 2020 were reviewed. The incidence of major and minor changes, as defined by The Royal College of Radiologists guidance, was prospectively recorded. The amended radiotherapy volumes were compared with the original volumes using Jaccard Index (JI) to assess conformity; Geographical Miss Index (GMI) for undercontouring; and Hausdorff Distance (HD) between the volumes. In total, 73 out of 87 (84%) patients were discussed. Changes were recommended in 38 (52%) patients: 30 had ≥1 major change, eight had minor changes only. There were 99 amended volumes: The overall median JI, GMI and HD was 0.91 (interquartile range [IQR]=0.80–0.97), 0.06 (IQR = 0.02–0.18) and 0.42 cm (IQR = 0.20–1.17 cm), respectively. The nodal gross-tumour-volume (GTVn) and therapeutic high-dose nodal clinical-target-volume (CTVn) had the biggest magnitude of changes: The median JI, GMI and HD of GTVn was 0.89 (IQR = 0.44–0.95), 0.11 (IQR = 0.05–0.51), 3.71 cm (IQR = 0.31–6.93 cm); high-dose CTVn was 0.78 (IQR = 0.59–0.90), 0.20 (IQR = 0.07–0.31) and 3.28 cm (IQR = 1.22–6.18 cm), respectively. There was no observed difference in the quantitative indices of the 85 'major' and 14 'minor' volumes (p = 0.5). Routine head and neck radiologist input in radiotherapy peer review is feasible and can help avoid gross error in contouring. The major and minor classifications may benefit from differentiation with quantitative indices but requires correlation from clinical outcomes. [ABSTRACT FROM AUTHOR]

• Definitive RT/CRT for OSCC achieved acceptable rate of locoregional control. • Definitive RT is a reasonable alternative treatment strategy if surgery is not possible. • cN2-3 is associated with poor distant control, DFS, and OS. To determine the outcomes of oral cavity squamous cell cancer (OSCC) patients treated with non-surgical approach i.e. definitive intensity-modulated radiation therapy (IMRT). All OSCC patients treated radically with IMRT (without primary surgery) between 2005–2014 were reviewed in a prospectively collected database. OSCC patients treated with definitive RT received concurrent chemotherapy except for early stage patients or those who declined or were unfit for chemotherapy. The 5-year local, and regional, distant control rates, disease-free, overall, and cancer-specific survival, and late toxicity were analyzed. Among 1316 OSCC patients treated with curative-intent; 108 patients (8%) received non-operative management due to: medical inoperability (n = 14, 13%), surgical unresectability (n = 8, 7%), patient declined surgery (n = 15, 14%), attempted preservation of oral structure/function in view of required extensive surgery (n = 53, 49%) or extensive oropharyngeal involvement (n = 18, 17%). Sixty-eight (63%) were cT3-4, 38 (35%) were cN2-3, and 38 (35%) received concurrent chemotherapy. With a median follow-up of 52 months, the 5-year local, regional, distant control rate, disease-free, overall, and cancer-specific survival were 78%, 92%, 90%, 42%, 50%, and 76% respectively. Patients with cN2-3 had higher rate of 5-year distant metastasis (24% vs 3%, p = 0.001), with detrimental impact on DFS (p = 0.03) and OS (p < 0.02) on multivariable analysis. Grade ≥ 3 late toxicity was reported in 9% of patients (most common: grade 3 osteoradionecrosis in 6%). Non-operative management of OSCC resulted in a meaningful rate of locoregional control, and could be an alternative curative approach when primary surgery would be declined, unsuitable or unacceptably delayed. [ABSTRACT FROM AUTHOR]

Global optimization of aerodynamic shapes usually requires a large number of expensive computational fluid dynamics simulations because of the high dimensionality of the design space. One approach to combat this problem is to reduce the design space dimension by obtaining a new representation. This requires a parametric function that compactly and sufficiently describes useful variation in shapes. This paper proposes a deep generative model, Bézier-GAN, to parameterize aerodynamic designs by learning from shape variations in an existing database. The resulted new parameterization can accelerate design optimization convergence by improving the representation compactness while maintaining sufficient representation capacity. The airfoil design is used as an example to demonstrate the idea and analyze Bézier-GAN's representation capacity and compactness. Results show that Bézier-GAN both 1) learns smooth and realistic shape representations for a wide range of airfoils and 2) empirically accelerates optimization convergence by at least two times compared with state-of-the-art parameterization methods. [ABSTRACT FROM AUTHOR]

The Wnt/β-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066). [ABSTRACT FROM AUTHOR]

Flaviviruses, including Zika and dengue (DENV), pose a serious global threat to human health. Of the 50+ million humans infected with DENV annually, approximately 1-3 % progress to severe disease manifestations, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Several factors are suspected to mediate the course of infection and pathogenesis of DENV infection. DHF and DSS are associated with vascular leakage and neurological sequelae. Our hypothesis was that altered astrocyte activation and morphology would alter the dynamics of the extracellular space and hence, neuronal and vascular function. We investigated the mechanisms of neuropathogenesis DENV infection in rhesus macaques. There were decreased numbers of GFAP immunopositive astrocytes per unit area, although those that remained had increased arbor length and complexity. This was combined with structural hypertrophy of white matter astrocytes in the absence of increased vascular leakage. Combined, these studies show how even low-grade infection with DENV induces measurable changes within the parenchyma of infected individuals. [ABSTRACT FROM AUTHOR]

The role of glia in the development and treatment of behavioral abnormalities is understudied. Recent reports have observed glial activation in several disorders, including depression, autism spectrum disorders and self-injurious behaviors (SIB). In the current study, we examined SIB in the physiologically and anatomically relevant nonhuman primate (NHP) model. At the Tulane National Primate Research Center (TNPRC), approximately 5% of singly housed macaques develop symptoms of SIB. We have previously demonstrated that naltrexone hydrochloride can be effective in reducing SIB. We have also demonstrated that the astrocytes of animals with SIB are distinctly atrophic and display heightened innate immune activation compared with control animals. We have added a third group of animals (five macaques identified with SIB and treated with oral naltrexone at a dose of 3.2 mg/kg) to the previous cohort (six macaques with a history of SIB but not treated, and nine animals with no history of SIB) for this study. Gray and white matter astrocytes from frontal cortical tissue were examined following necropsy. Innate immune activation of astrocytes, which was increased in SIB animals, was markedly decreased in animals receiving naltrexone, as was atrophy of both grey and white matter astrocytes. This was concomitant with improved behavioral correlates. Preventing astrocyte activation in select areas of the brain to reduce injurious behavior is an innovative concept with implications for mental health studies. Differences in multiple areas of primate brain would help determine how self-injurious behavior develops. These studies suggest a stronger role for astrocytes in the cellular events associated with self-injurious behaviors. [ABSTRACT FROM AUTHOR]

Cortical function is disrupted in neuroinflammatory disorders, including HIV-associated neurocognitive disorders (HAND). Astrocyte dysfunction includes retraction of foot processes from the blood-brain barrier and decreased removal of neurotransmitters from synaptic clefts. Mechanisms of astrocyte activation, including innate immune function and the fine neuroanatomy of astrocytes, however, remain to be investigated. We quantified the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes per square millimeter and the proportion of astrocytes immunopositive for Toll-like receptor 2 (TLR2) to examine innate immune activation in astrocytes. We also performed detailed morphometric analyses of gray and white matter astrocytes in the frontal and parietal lobes of rhesus macaques infected with simian immunodeficiency virus (SIV), both with and without encephalitis, an established model of AIDS neuropathogenesis. Protoplasmic astrocytes (gray matter) and fibrous astrocytes (deep white matter) were imaged, and morphometric features were analyzed using Neurolucida. Gray matter and white matter astrocytes showed no change in cell body size in animals infected with SIV regardless of encephalitic status. In SIV-infected macaques, both gray and white matter astrocytes had shorter, less ramified processes, resulting in decreased cell arbor compared with controls. SIV-infected macaques with encephalitis showed decreases in arbor length in white matter astrocytes and reduced complexity in gray matter astrocytes compared to controls. These results provide the first evidence that innate immune activation of astrocytes is linked to altered cortical astrocyte morphology in SIV/HIV infection. Here, we demonstrate that astrocyte remodeling is correlated with infection. Perturbed neuron-glia signaling may be a driving factor in the development of HAND. [ABSTRACT FROM AUTHOR]

Background: Self-injurious behavior (SIB) is a complex condition that exhibits a spectrum of abnormal neuropsychological and locomotor behaviors. Mechanisms for neuropathogenesis could include irregular immune activation, host soluble factors, and astrocyte dysfunction. Methods: We examined the role of astrocytes as modulators of immune function in macaques with SIB. We measured changes in astrocyte morphology and function. Paraffin sections of frontal cortices from rhesus macaques identified with SIB were stained for glial fibrillary acidic protein (GFAP) and Toll-like receptor 2 (TLR2). Morphologic features of astrocytes were determined using computer-assisted camera lucida. Results: There was atrophy of white matter astrocyte cell bodies, decreased arbor length in both white and gray matter astrocytes, and decreased bifurcations and tips on astrocytes in animals with SIB. This was combined with a five-fold increase in the proportion of astrocytes immunopositive for TLR2. Conclusions: These results provide direct evidence that SIB induces immune activation of astrocytes concomitant with quantifiably different morphology. [ABSTRACT FROM AUTHOR]

Generally speaking, demographics explain two-thirds of everything. This study demonstrated how personal values may be associated with demographic characteristics to create a better market segmentation tool for investigating differences and similarities in both party identification and voting behavior. It supplied confirmation of the interrelationships among demographic characteristics, party identification, and voting behavior, as well as theoretical concept and empirical evidence of personal values in marketing research. Results indicated that personal values are far more likely than demographic characteristics to predict party identification and voting behavior. [ABSTRACT FROM AUTHOR]

Certificate of need (CON) regulations requires that health care providers obtain state approval before offering a new service or expanding existing facilities. The purported goal of CON regulations is to reduce health care costs by generating regional economies of scale and reducing redundant investments resulting from excessive competition. Critics of CON regulations note that the regulatory environment increases the costs of expansion and may incentivize health care providers to forgo capital investment, which can have a negative effect on health outcomes. To estimate the net effect of CON regulations, I use a border discontinuity design to measure within-regional heart attack mortality spanning 1968 to 1982. I estimate that CON regulations led to an increase in heart attack deaths, by 6%-10%, three years after the policy was enacted. [ABSTRACT FROM AUTHOR]

This study successfully provides the empirical practicability of a hybrid mechanism for helicopters. A turbine engine and a set of electricity power systems can operate simultaneously and/or independently as a symmetric structure. The latter power source works as an immediate supplementary device if the former one has malfunction. We look forward to promoting this experimental evidence in the helicopter industry. The ultimate purpose of this manuscript is to decrease the incidents of crashes and save people's lives. [ABSTRACT FROM AUTHOR]

Highlights • This study validated a high DM risk-group in OSCC patients treated with postoperative IMRT with or without concurrent chemotherapy. • Patients with G2-3/pN2-3 were shown to be at high risk of DM and poor survival in the subsequent validation cohort. • Identifying this high risk group may allow alternate treatment strategies to be explored to improve the outcomes. Abstract Background This study aimed to derive distant metastases (DM) risk-groups in oral cavity squamous cell carcinoma (OSCC) patients treated with postoperative intensity-modulated radiation therapy (PO-IMRT). Methods OSCC patients treated with PO-IMRT were divided into discovery (2005–2012) and validation (2013–2014) cohorts. DM predictors were identified from multivariable analysis (MVA) to derive low- and high-risk groups in the discovery-cohort. The result was subsequently evaluated in validation-cohort. Results Overall 447 patients were included (discovery-cohort: n = 300, and validation-cohort: n = 147). Between the two cohorts, there were no significant differences in DM (p = 0.16) or OS (p = 0.26). MVA identified pN2-3 and histological grade 2–3 (G2-3) as DM predictors. High-risk group included patients who had both poor predictors (pN2-3 and G2-3), while low-risk group included patients with no or only one poor predictor. In discovery-cohort, 3-year distant control (DC) was 78% and 97% in high- and low-risk groups respectively (p < 0.001, concordance index = 0.72). In validation-cohort, risk-group classification performed similarly (concordance index = 0.73). The 3-year OS for high- versus low-risk group was 85% versus 95% in discovery-cohort (p < 0.001), and 74% versus 93% in validation-cohort (p < 0.001). Conclusion A model (G2-3/pN2-3) which identifies high DM risk was validated internally. This model might be used to design future prospective studies investigating treatment intensification and/or DM surveillance. [ABSTRACT FROM AUTHOR]

Purpose: To determine predictors and outcomes for oral squamous cell carcinoma (OSCC) patients who had early recurrence before commencement of postoperative radiation therapy (PORT).Methods: Retrospective review was performed for patients with OSCC treated with PORT between 2003 and 2015 after curative-intent surgery. Early recurrence was defined as tumor recurrence after surgical resection and before initiating planned PORT. Patients were classified into the following groups: (1) adjuvant PORT group (no early recurrence), (2) salvage PORT group (locoregional early recurrence), and (3) palliative PORT group (locoregional and distant early recurrence). For the whole cohort, multivariable analysis (MVA) was applied to identify predictors of early recurrence. In the salvage group, the post-PORT recurrence-free rate was estimated, and MVA was used to identify predictors of recurrence-free rate, disease-free survival, and overall survival (OS).Results: Six hundred and one patients were identified, of whom 513 (85%) were treated with adjuvant PORT. Eighty-eight patients (15%) had early recurrence (28 of 88; 32% were biopsy proven) before PORT (70 in the salvage group and 18 in the palliative group). On MVA, oral tongue subsite, microscopic positive resection margin, pT3-4, and pN2-3 were associated with the development of early recurrence (P < .05 for all). The 3-year OS rates for patients with OSCC treated with adjuvant and salvage PORT were 71% (95% confidence interval [CI], 67%-75%) and 41% (95% CI, 30%-56%), respectively (P < .001; median follow-up was 3.4 and 2.9 years, respectively). After salvage PORT, the 3-year recurrence-free rate was 36% (95% CI, 23%-47%). On MVA, extranodal extension and volume of early recurrent gross disease were associated with poor recurrence-free rate, disease-free survival, and OS (P < .05 for all).Conclusion: Early recurrences are not uncommon in patients with high-risk features, Further study is required to improve prediction and outcomes of this very high-risk group. [ABSTRACT FROM AUTHOR]

Accurate TNM classification and staging in head and neck cancer is an important part in prognostication, and in determining the extent of radiotherapy target volume delineation [1]. As standard of care locally, the TNM classification is performed in 2 regional supra-multidisciplinary team (MDT) meetings, prior to referral centrally for oncological treatment. Peer review quality assurance of radiotherapy volumes is a widely accepted and recommended practice. As a tertiary cancer centre, there is routine radiologist input in the departmental peer review of head and neck radiotherapy volumes [2]. The aim of this study was to evaluate the recommended treatment changes, and potential differences between the final peer review's TNM classification and of the MDTs'. All head and neck intensity modulated radiotherapy (IMRT) cases discussed in the weekly peer review meeting between May and mid-October 2023 were prospectively evaluated. A standard data collection proforma based on UK Royal College of Radiologists (RCR) recommendations was used [3]. Any radiological/clinical progression of disease (PD) since the diagnostic radiology, final TNM staging, in addition to the RCR defined 'major' or 'minor' changes to the clinical target volumes (CTVs), were prospectively recorded. A total of 109 patients were included, of which there were 77 (71%) definitive (chemo)IMRT, 30 (28%) post-operative radiation (PORT) and 2 complex palliative IMRT (2%). Across all three cohorts, there were 34 (32%) HPV-mediated oropharynx, 21 (19%) Larynx, 18 (17%) Oral cavity, 10 (9%) Hypopharynx, 7 (6%) Nasopharynx, 6 5.5%) Cutaneous carcinoma, 4 (4%) Major salivary gland, 3 (3%) p16-negative Oropharynx, 3 (3%) Nasal cavity/Paranasal sinuses, and 3 (3%) unknown primary cases. There was a median of 2 consultant oncologists (range 1–4), and one radiologist (range 0 – 3) at each meeting. In the definitive and palliative IMRT cohorts, excluding 7 patients who had received induction chemotherapy (6 Nasopharynx, 1 Nasal cavity), 16 out of 72 patients (22%) were found to have PD on their IMRT-CT simulation since their diagnostic radiology. With the final peer review TNM classification, a total of 15 (21%) patients were found to have been upstaged (Table 1). Of note, only 7 patients with PD (47%) were upstaged, while other 8 patients (11% of total) were upstaged from the original MDTs' classification despite lack of PD. The peer review upstaging led to 3 key changes in treatment plan, with 2 patients subsequently recommended for primary surgery instead, and 1 patient for additional concomitant chemotherapy. The median time from original diagnostic radiology to the MDT, and from diagnostics to IMRT-CT simulation, was 22 and 38 days respectively. For the PORT cohort, there were 3 (10%) discrepancies between the peer-review and the MDT recorded pathological (pTNM) classification: 2 patients were upstaged and 1 was down-staged. [Display omitted] For the IMRT volume quality assurance, the peer review recommended changes to 66 out of the 109 (61%) patients; 47 out of 77 (61%) definitive IMRT, 18 out of 30 (60%) PORT, and 1 out of 2 (50%) palliative patients. In the definitive IMRT cohort, 36 (77%) patients underwent IMRT volume changes deemed to be 'major', while 11 patients (23%) as 'minor'. A total of 44 changes were made to the individual CTVs: 22 (50%) to the primary CTV (CTVp), and 22 (50%) to the nodal CTV (CTVn). For the PORT cohort, 9 (50%) patients underwent 'major' changes and 9 (50%) had 'minor' changes. There were 10 changes made to the individual PORT CTVp, and 9 to the CTVn. Radiotherapy peer review with radiologist input is valuable in identifying gross error. Routine radiologist input may provide an additional layer of quality assurance to the MDT's TNM staging classification, and the subsequent recommended clinical management. [ABSTRACT FROM AUTHOR]

This paper attempts to utilize microarc oxidation (MAO) to fabricate the aluminum nitride/aluminum oxide composite ceramic coating on aluminum alloy surface. The effects of MAO voltages, different nitrogen sources, concentration on the surface morphology, and nitrogen content of the coatings are investigated. The results show that the highest nitrogen content (21.22 at%) is obtained on the surface of the coating by the energy dispersive spectrometer analysis under the condition of MAO voltage of 575 V, urea 22.50 g/L, and ammonium hydroxide 20 mL/L condition. [ABSTRACT FROM PUBLISHER]

How aging impacts the central nervous system (CNS) is an area of intense interest. Glial morphology is known to affect neuronal and immune function as well as metabolic and homeostatic balance. Activation of glia, both astrocytes and microglia, occurs at several stages during development and aging. The present study analyzed changes in glial morphology and density through the entire lifespan of rhesus macaques, which are physiologically and anatomically similar to humans. We observed apparent increases in gray matter astrocytic process length and process complexity as rhesus macaques matured from juveniles through adulthood. These changes were not attributed to cell enlargement because they were not accompanied by proportional changes in soma or process volume. There was a decrease in white matter microglial process length as rhesus macaques aged. Aging was shown to have a significant effect on gray matter microglial density, with a significant increase in aged macaques compared with adults. Overall, we observed significant changes in glial morphology as macaques age indicative of astrocytic activation with subsequent increase in microglial density in aged macaques. [ABSTRACT FROM AUTHOR]

Chikungunya, 'that which bends up' in the Makonde dialect, is an emerging global health threat, with increasing incidence of neurological complications. Until 2013, Chikungunya infection had been largely restricted to East Africa and the Indian Ocean, with cases within the USA reported to be from foreign travel. However, in 2014, over 1 million suspected cases were reported in the Americas, and a recently infected human could serve as an unwitting reservoir for the virus resulting in an epidemic in the continental USA. Chikungunya infection is increasingly being associated with neurological sequelae. In this study, we sought to understand the role of astrocytes in the neuropathogenesis of Chikungunya infection. Even after virus has been cleared form the circulation, astrocytes were activated with regard to TLR2 expression. In addition, white matter astrocytes were hypertrophic, with increased arbor volume in gray matter astrocytes. Combined, these would alter the number and distribution of synapses that each astrocyte would be capable of forming. These results provide the first evidence that Chikungunya infection induces morphometric and innate immune activation of astrocytes in vivo. Perturbed glia-neuron signaling could be a major driving factor in the development of Chikungunya-associated neuropathology. [ABSTRACT FROM AUTHOR]

Abstract: HER2-positive breast cancer initially responds to trastuzumab treatment, but over time, resistance develops and rapid cancer progression occurs, for which various explanations have been proposed. Here we tested the hypothesis that induction of the unfolded protein response (UPR) could override HER2 inhibition by trastuzumab, leading to the re-activation of growth signaling and the activation of the downstream target Lipocalin 2 (LCN2). Trastuzumab significantly inhibited the basal expression of LCN2 in HER2 + SKBr3 human breast cancer cells. The induction of the UPR completely abrogated trastuzumab-mediated LCN2 downregulation, and, in fact caused an increase in transcription and secretion of LCN2 over baseline. Reduction of the UPR using 4-phenyl butyric acid (PBA) a chemical chaperone that ameliorates ER stress, restored trastuzumab-mediated inhibition. Inhibition of the PI3K/AKT signaling pathway in trastuzumab-treated/UPR-induced SKBr3 cells partially reduced the upregulation of LCN2. These results suggest that the UPR is a possible way to override the effect of trastuzumab in HER2+ cancer cells. [Copyright &y& Elsevier]

Abstract: Educators need to know how to motivate business students (i.e., future business practitioners) to learn and use statistical software, which can provide the practical skills necessary for business professionals to analyze data and make informed decisions. Using a sample of 207 online MBA students from an AACSB accredited university in the Midwest, a modified TAM model was examined using LISREL 8.80. The empirical results show that both computer attitude and statistical software self-efficacy have significant, positive effects on perceived usefulness. In addition, it was found that both perceived usefulness and perceived ease of use positively influence learners’ intentions to use statistical software, whereas their anxiety with statistics has a significant, negative impact on perceived usefulness, perceived ease of use and behavioral intentions. Both theoretical and practical implications are discussed in this paper. [Copyright &y& Elsevier]

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small‐molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro‐inflammatory cytokines in human mesenchymal stem cells, rat tendon‐derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC‐like kinase 2 (CLK2) and dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight‐bearing function in rat collagenase‐induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy. [ABSTRACT FROM AUTHOR]

Monocyte and dendritic cell (DC) development was evaluated using in vivo BrdU pulse-chase analyses in rhesus macaques, and phenotype analyses of these cells in blood also were assessed by immunostaining and flow cytometry for comparisons among rhesus, cynomolgus, and pigtail macaques, as well as African green monkeys and humans. The nonhuman primate species and humans have three subsets of monocytes, CD14+CD16-, CD14+CD16+, and CD14-CD16+ cells, which correspond to classical, intermediate, and nonclassical monocytes, respectively. In addition, there exist presently two subsets of DC, BDCA-1+ myeloid DC and CD123+ plasmacytoid DC, that were first confirmed in rhesus macaque blood. Following BrdU inoculation, labeled cells first appeared in CD14+CD16- monocytes, then in CD14+CD16+ cells, and finally in CD14-CD16+ cells, thus defining different stages of monocyte maturation. A fraction of the classical CD14+CD16- monocytes gradually expressed CD16+ to become CD16+CD14+ cells and subsequently matured into the nonclassical CD14-CD16+ cell subset. The differentiation kinetics of BDCA-1+ myeloid DC and CD123+ plasmacytoid DC were distinct from the monocyte subsets, indicating differences in their myeloid cell origins. Results from studies utilizing nonhuman primates provide valuable information about the turnover, kinetics, and maturation of the different subsets of monocytes and DC using approaches that cannot readily be performed in humans and support further analyses to continue examining the unique myeloid cell origins that may be applied to address disease pathogenesis mechanisms and intervention strategies in humans. [ABSTRACT FROM AUTHOR]

Evolutionarily conserved short (20-30 nucleotides) noncoding RNAs (microRNAs) are powerful regulators of gene expression in a variety of physiological and pathological processes. As such, means to efficiently modulate microRNA function constitute an important therapeutic opportunity. Here we demonstrate that primary B lymphocytes can be genetically programmed with nonviral plasmid DNA for the biogenesis and delivery of antisense sequences (anti-microRNA) against microRNA-150 (miR-150). Within 18 h of transfection with an anti-miR-150 construct, primary B lymphocytes secrete ∼3,000 copies of anti-miR-150 molecules per cell. Anti-miR-150 molecules released by B lymphocytes were internalized by CD8 T lymphocytes during cross-priming in vitro and in vivo, resulting in marked down-regulation of endogenous miR- 150. However, such internalization was not observed in the absence of cross-priming. These results suggest that shuttling anti-miR-150 molecules from B lymphocytes to T cells requires the activation of receiver T cells via the antigen receptor. Finally, anti-miR-150 synthesized in B cells were secreted both as free and extracellular vesicleassociated fractions, but only extracellular vesicle-associated antimiR- 150 were apparently taken up by CD8 T cells. Collectively, these data indicate that primary B lymphocytes represent an efficient platform for the synthesis and delivery of short, noncoding RNA, paving the way for an approach to immunogenomic therapies. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating myeloid cells, such as dendritic cells (BMDC), are key regulators of tumor growth. However, the tumorderived signals polarizing BMDC to a phenotype that subverts cell-mediated anti-tumor immunity have yet to be fully elucidated. Addressing this unresolved problem we show that the tumor unfolded protein response (UPR) can function in a cell-extrinsic manner via the transmission of ER stress (TERS) to BMDC. TERS-imprinted BMDC upregulate the production of pro-inflammatory, tumorigenic cytokines but also the immunosuppressive enzyme arginase. Importantly, they downregulate cross-presentation of high-affinity antigen and fail to effectively cross-prime CD8+ T cells, causing T cell activation without proliferation and similarly dominantly suppress cross-priming by bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth in vivo with fewer tumor-infiltrating CD8+ T cells. In sum, we demonstrate that tumor-borne ER stress imprints ab initio BMDC to a phenotype that recapitulates several of the inflammatory/suppressive characteristics ascribed to tumor-infiltrating myeloid cells, highlighting the tumor UPR as a critical controller of anti-tumor immunity and a new target for immune modulation in cancer. [ABSTRACT FROM AUTHOR]