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11.
Phonphimon Wongthida Matthew R Schuelke Christopher B Driscoll Timothy Kottke Jill M Thompson Jason Tonne Cathy Stone Amanda L Huff Cynthia Wetmore James A Davies Alan L Parker Laura Evgin Richard G Vile 《Neuro-oncology》2020,22(12):1757
BackgroundDiffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.MethodsSyngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models.ResultsExpression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity.ConclusionsVirus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity. 相似文献
12.
Harinakshi Sanikini David C. Muller Marisa Sophiea Sabina Rinaldi Antonio Agudo Eric J. Duell Elisabete Weiderpass Kim Overvad Anne Tjønneland Jytte Halkjær Marie-Christine Boutron-Ruault Franck Carbonnel Iris Cervenka Heiner Boeing Rudolf Kaaks Tilman Kühn Antonia Trichopoulou Georgia Martimianaki Anna Karakatsani Valeria Pala Domenico Palli Amalia Mattiello Rosario Tumino Carlotta Sacerdote Guri Skeie Charlotta Rylander María-Dolores Chirlaque López Maria-Jose Sánchez Eva Ardanaz Sara Regnér Tanja Stocks Bas Bueno-de-Mesquita Roel C.H. Vermeulen Dagfinn Aune Tammy Y.N. Tong Nathalie Kliemann Neil Murphy Marc Chadeau-Hyam Marc J. Gunter Amanda J. Cross 《International journal of cancer. Journal international du cancer》2020,146(4):929-942
Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow-up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m2: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist-to-hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers. 相似文献
13.
14.
Rebecca Carman Lesley Andrew Amanda Devine Jacques Oosthuizen 《Australian and New Zealand journal of public health》2019,43(6):563-569
Objective: To identify behavioural barriers of service provision within general practice that may be impacting the vaccination coverage rates of Aboriginal children in Perth, Western Australia (WA). Methods: A purposive developed survey was distributed to 316 general practices across Perth and three key informant interviews were conducted using a mixed‐methods approach. Results: Of the surveyed participants (n=101), 67.4% were unaware of the low vaccination coverage in Aboriginal children; 64.8% had not received cultural sensitivity training in their workplace and 46.8% reported having inadequate time to follow up overdue child vaccinations. Opportunistic vaccination was not routinely performed by 30.8% of participants. Key themes identified in the interviews were awareness, inclusion and cultural safety. Conclusion: Inadequate awareness of the current rates, in association with a lack of cultural safety training, follow‐up and opportunistic practice, may be preventing greater vaccination uptake in Aboriginal children in Perth. Cultural safety is a critical component of the acceptability and accessibility of services; lack of awareness may restrict the development of strategies designed to equitably address low coverage. Implications: The findings of this study provide an opportunity to raise awareness among clinicians in general practice and inform future strategies to equitably deliver targeted vaccination services to Aboriginal children. 相似文献
15.
John Lennon Silva Cunha Amanda Almeida Leite Thamiris de Castro Abrantes Lorena Passoni Vervloet Thayn Melo de Lima Morais Gerson de Oliveira Paiva Neto Tatiana Nayara Librio Kimura Snia Maria Soares Ferreira Ricardo Luiz Cavalcanti de Albuquerque‐Júnior Aline Corrêa Abraho Mario Jos Romaach Bruno Augusto Benevenuto de Andrade Oslei Paes de Almeida Ciro Dantas Soares 《Journal of cutaneous pathology》2021,48(1):24-33
16.
Prahlad V. Raninga Andy C. Lee Debottam Sinha Yu-Yin Shih Deepak Mittal Ashwini Makhale Amanda L. Bain Devathri Nanayakarra Kathryn F. Tonissen Murugan Kalimutho Kum Kum Khanna 《International journal of cancer. Journal international du cancer》2020,146(1):123-136
Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients. 相似文献
17.
Esther M. John Amanda I. Phipps Lisa M. Hines Jocelyn Koo Sue A. Ingles Kathy B. Baumgartner Martha L. Slattery Anna H. Wu 《International journal of cancer. Journal international du cancer》2020,147(7):1808-1822
We pooled multiethnic data from four population-based studies and examined associations of menstrual and reproductive characteristics with breast cancer (BC) risk by tumor hormone receptor (HR) status [defined by estrogen receptor (ER) and progesterone receptor (PR)]. We estimated odds ratios and 95% confidence intervals using multivariable logistic regression, stratified by age (<50, ≥50 years) and ethnicity, for 5,186 HR+ (ER+ or PR+) cases, 1,365 HR− (ER− and PR−) cases and 7,480 controls. For HR+ BC, later menarche and earlier menopause were associated with lower risk in non-Hispanic whites (NHWs) and Hispanics, and higher parity and longer breast-feeding were associated with lower risk in Hispanics and Asian Americans, and suggestively in NHWs. Positive associations with later first full-term pregnancy (FTP), longer interval between menarche and first FTP and shorter time since last FTP were limited to younger Hispanics and Asian Americans. Except for nulliparity, reproductive characteristics were not associated with risk in African Americans. For HR− BC, lower risk was associated with later menarche, except in African Americans and older Asian Americans and with longer breast-feeding in Hispanics and Asian Americans only. In younger African Americans, HR− BC risk associated with higher parity (≥3 vs. 1 FTP) was increased fourfold in women who never breast-fed, but not in those with a breast-feeding history, suggesting that breast-feeding may mitigate the adverse effect of higher parity in younger African American women. Further work needs to evaluate why menstrual and reproductive risk factors vary in importance according to age and ethnicity. 相似文献
18.
Amanda Leal Rocha Alessandra Figueiredo De Souza Laiz Fernandes Mendes Nunes Nayara Dias de Souza Cunha Clia Regina Moreira Lanza Denise Vieira Travassos Tarcília Aparecida da Silva 《Pediatric dermatology》2019,36(1):e27-e30
Drug‐induced reactions are complications associated with high mortality and significant morbidity. Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are examples of these conditions, which are characterized by skin and mucous lesions. Here, we report a case of a 9‐year‐old girl who presented with blisters associated with an extensive vesicular rash and multiple ulcerations on the lips and oral cavity. A drug‐induced hypersensitivity reaction to antibiotics was suspected, and a diagnosis of TEN was made. The patient was managed with withdrawal of the suspected causative agent, and the oral lesions were treated with low‐level laser therapy (LLLT) and oral hygiene. This case highlights that TEN requires interdisciplinary intervention with dental assistance and follow‐up to improve symptoms, nutrition, systemic condition, and quality of life. 相似文献
19.
Dane Scantling Robert Kucejko John Williamson Alvaro Galvez Amanda Teichman Ryan Gruner Nicholas Serniak Brendan McCracken 《Injury》2019,50(1):54-60
Background
Most elderly trauma patients suffer blunt head injury and many utilize antithrombotic (AT) medications. The utility of delayed CT-head (D-CTH) in neurologically intact elderly patients using AT who have an intracranial hemorrhage (ICH) on presentation is unknown. We hypothesized that D-CTH would not alter clinical management and aimed to evaluate the role of D-CTH in this population.Methods
A retrospective cohort study was performed. Patients ≥65 years sustaining blunt head injuries from January 2010 to July 2017 were identified using our level 1 trauma center database. AT-patients presenting with ICH who underwent D-CTH were included. Patients with worsened ICH were compared to those with stable to improved ICH on D-CTH. AT-patients were compared to a cohort of non-AT patients. Fisher’s Exact and Mann-Whitney U tests were utilized and a power analysis conducted.Results
137?A?T and 34 non-AT patients were identified. There was no difference in hemorrhage progression or appearance of new ICH. No patient had a change in management from D-CTH in either cohort. AT-patients were slightly older (p?<?0.001), but cohorts were otherwise similar.50 AT-patients with worsened ICH were compared to 87 with stable ICH. There was no difference in cohort demographics. Hemorrhage progression did not vary with type of AT used but did increase if multiple types of synchronous ICH were present (p?<?0.001).Conclusions
Our data supports abstaining from routine D-CTH of elderly ICH patients with an intact neurologic examination who are utilizing aspirin, clopidogrel or warfarin. Conclusions cannot be drawn regarding new oral anticoagulants (NOACs) given low enrollment. Further multicenter study is required to provide adequate power and detect small levels of management change. 相似文献20.