tbuckley/cabot-search huggingface dataset:
Synthetic Smectic Clays: Bioprinting a Synthetic Smectic Clay for Orthopedic Applications (Adv. Healthcare Mater. 13/2019)
Authors: Samson Afewerki, Leila S. S. M. Magalhães, André D. R. Silva, Thiago D. Stocco, Edson C. Silva Filho, Fernanda R. Marciano, Anderson O. Lobo
Journal: Advanced Healthcare Materials (2019)

Bioprinting has advanced as a facile and vital technology with a wide range of application potential such as in tissue engineering and biomedical fields. In article number 1900158 by Samson Aferwerki, Anderson O. Lobo, and co-workers, bioprinting is reviewed and shown to be highly influenced from the material employed. In particular for orthopedic applications. Therefore a nanosized synthetic clay is shown to be a promising candidate due to its multifunctionalities and unique properties, e.g., osteoinductiveness and shear-thinning.
Pelvic node control in patients with locally advanced uterine cervical cancer treated with concurrent chemoradiotherapy
Authors: T. Toita, Y. Nagai, W. Tamaki, K. Ogawa, S. Gibo, Y. Kakinohana, K. Kamiyama, M. Inamine, Y. Aoki, S. Murayama
Journal: Journal of Clinical Oncology (2007)

16018 Background: To evaluate pelvic node control in cervical cancer patients treated with concurrent chemoradiotherapy (CCRT) without surgical resection. Methods: Ninety-six patients (stage IB2, 3; IIA, 2; IIB, 49; IIIA, 1; IIIB, 40; IVA, 1) with uterine cervical squamous cell carcinoma treated with CCRT were analyzed. Cervical tumor diameter and pelvic node status were assessed by MRI. The median maximum tumor diameter was 58 mm (range, 36–86 mm). Thirty-four patients had positive pelvic nodes (= 10 mm in shortest diameter). The largest diameter of the positive nodes ranged from 10–50 mm (median, 18 mm). All patients received CDDP (20 mg/m2 for 5 days every 21 days), pelvic external beam RT (PERT), and high-dose-rate intracavitary brachytherapy (HDR-ICBT). The planned RT schedule consisted of PERT with 40 Gy/20 fractions (frs) followed by HDR-ICBT with 18–24 Gy/3–4 frs and PERT with 10 Gy/5 frs using a midline block. Thirty of thirty-four node-positive patients received boost RT (6–10 Gy/3–5 frs) to involved nodes. The dose from HDR-ICBT to the pelvic nodes was estimated at a point 6 cm lateral to the midline at the level of the vaginal fornix. Doses of ERT and HDR-ICBT were simply summed and used for pelvic node dose-response analysis. The median total dose was 60 Gy (range, 52–64 Gy) for positive nodes and 54 Gy (range, 51–55 Gy) for negative nodes. Median follow-up of the surviving 79 patients was 41 months (range, 8–98 months). Results: Four-year overall survival (OAS), pelvic control (PC), and distant metastasis-free (DMF) rates for all 96 patients were 79%, 90%, and 79%, respectively. Four-year OAS, PC, and DMF rates for node-positive/node-negative patients were 60%/89% (P=0.002), 82%/95% (P=0.08), and 66%/86% (P=0.008), respectively. Pelvic nodal recurrence was observed in 4 patients. One patient developed isolated pelvic node recurrence while the other 3 had concurrent recurrences at other sites, including 1 with a cervical tumor and 2 with cervical tumor and distant metastases. Nodal recurrence rates by largest diameter were 1/62 for node-negative patients, 1/14 for nodes 10–14 mm, 0/13 for nodes 15–29 mm, and 2/7 for nodes = 30 mm. Conclusions: Pelvic nodal metastases &lt; 30 mm were well controlled by CCRT without surgical resections using RT dose delivered. No significant financial relationships to disclose.
The WASH Benefits and SHINE trials: interpretation of WASH intervention effects on linear growth and diarrhoea
Authors: Amy J Pickering, Clair Null, Peter J Winch, Goldberg Mangwadu, Benjamin F Arnold, Andrew J Prendergast, Sammy M Njenga, Mahbubur Rahman, Robert Ntozini, Jade Benjamin-Chung, Christine P Stewart, Tarique M N Huda, Lawrence H Moulton, John M Colford, Stephen P Luby, Jean H Humphrey
Journal: The Lancet Global Health (2019)

Child stunting is a global problem and is only modestly responsive to dietary interventions. Numerous observational studies have shown that water quality, sanitation, and handwashing (WASH) in a household are strongly associated with linear growth of children living in the same household. We have completed three randomised efficacy trials testing improved household-level WASH with and without improved infant and young child feeding (IYCF) on stunting and diarrhoea in Bangladesh, Kenya, and Zimbabwe. In all trials, improved IYCF had a statistically significant benefit, but WASH had no effect on linear growth. In observational analyses of data from the control groups of the three trials, baseline sanitation was a strong risk factor for stunting in the study populations, suggesting this frequently reported association might be confounded by unmeasured factors of household wellbeing. WASH interventions reduced diarrhoea in Bangladesh, but not in Kenya or Zimbabwe. Intervention promoters visited participants six times per month in Bangladesh compared with monthly in Kenya and Zimbabwe; a review of the literature shows that virtually all published studies that have reported an effect on diarrhoea through home-based water treatment and handwashing promotion achieved high adherence by visiting participants at daily to fortnightly intervals. Despite achieving substantial behavioural change and significant reduction in infection prevalence for some enteric pathogens, detection of enteropathogens among children in the WASH groups of the trials was typically at ten times higher prevalence compared with high-income countries. Considering these results, we recommend that future research in the WASH sector focus on developing and evaluating interventions that are radically more effective in reducing faecal contamination in the domestic environment than the interventions implemented in these trials.
Publication statuses of clinical trials supporting immune checkpoint inhibitors recently approved by the United States Food and Drug Administration: A meta-epidemiological investigation.
Authors: Kenji Omae, Yuki Kataoka, Yasushi Tsujimoto, Yusuke Tsutsumi, Shunichi Fukuhara, Toshi Furukawa
Journal: Journal of Clinical Oncology (2019)

89 Background: The low trial publication rate for drugs approved by the U.S. Food and Drug Administration (FDA) and the discrepancies between data submitted to the FDA and data found in published trials remain concerning. We investigated the publication statuses of trials of recently approved anticancer drugs documented by the FDA, especially immune checkpoint inhibitors (ICPis), to determine the discrepancies between data submitted to the FDA and those published. Methods: We identified all ICPis approved between 2011 (the year the first ICPi was approved by the FDA) and 2014 (selected to assure a follow-up of at least 3 years post-approval). We assessed the clinical trials for each drug indication and matched each trial with publications in the literature. The primary outcome was the publication status 2 years post-approval. We examined the association between time to publication and drug type using a multilevel Cox regression model, adjusted for clustering within drug indications and individual covariates. Results: Between 2011 and 2014, 36 anticancer drugs including 3 ICPis were newly approved by the FDA. Of 19 trials investigating the 3 ICPis, 11 (58%) were published within 2 years post-approval. We randomly selected 10 of the 33 remaining anticancer drugs; 68 of 101 trials investigating these drugs (67%) were published. Overall, the publication rate was 66% at 2 years post-approval with a median time to publication of 2.3 years. There was no significant difference in time to trial publication between ICPis and other anticancer drugs (adjusted hazard ratio [HR], 1.1; 95% confidence interval [CI], 0.8–1.7; P = 0.55); however, non-ICPIs investigated specifically in randomized phase 2 or 3 trials were significantly more likely to be published earlier than ICPis (adjusted HR, 7.4; 95% CI, 1.8–29.5; P = 0.005). Conclusions: One in three trials of the newest anticancer drugs remained unpublished 2 years after FDA approval. The ICPi publication rate was similar to that of other anticancer drugs. (Protocol registration: UMIN000030475).
iRGD in combination with IL-2 reprograms tumor immunosuppression.
Authors: Gregory P. Botta, Tatiana Hurtado De Mendoza, Harri Jarvelainen, Erkki Ruoslahti
Journal: Journal of Clinical Oncology (2019)

55 Background: Fibrotic solid tumors have lagged in immunotherapy efficacy. Although breast cancer (BC) shows modest single-agent activity, pancreatic ductal adenocarcinoma (PDAC) immunotherapy has repeatedly failed in clinical trials. A protective desmoplastic, inflammatory reaction encapsulates BC and PDAC where it can make up to 80% of the tumor microenvironment (TME). Reports in BC and PDAC patients and mouse models suggest that tumoricidal effector CD8+ T-cells are indeed present, yet suppressed by regulatory CD4+/CD25+/FoxP3+ T-cells (Tregs) and myeloid cells. Long-term PDAC and BC survivors harbor CD8+ T-cells by immunohistochemistry (IHC), and although inactivated (CD107a-), they are not terminally exhausted (PD-1 low ). Further, when CD8+ T-cells were found in large quantities within a treatment-naïve biopsy, that patient had an increased overall survival. We hypothesize that low doses of the T-cell proliferative cytokine IL-2 can class switch the TME T-cells if specifically concentrated within the tumor by the stroma-penetrating peptide iRGD. Methods: Subcutaneous BC tumors (4T1) and PDAC (KPC ) tumors were formed in immunocompetent mouse models. Mice were treated with either vehicle, iRGD, IL-2, or both in combination. Tumors were preserved for IHC or enzymatically digested for FACS. CD45+ live cells were fluorescently labeled for effector T-cells (CD4+/CD44+ or CD8+/CD44+), Tregs (CD4+/CD25+/FoxP3+), or cytotoxic T-cells (CD8+/CD44+/Granzyme B+/IL-2+). Results: Versus normal controls, tumors from BC and PDAC both showed a subsequent increase in bulk CD3+ T-cells within the tumor microenvironment (14.3% ± 5 vs. 27.6% ± 8). A significant increase in CD3+ T-cells within all tumors (10%) occured with iRGD only, IL-2 only, or iRGD + IL-2 treatment. Whereas sub-populations of T-cells in the iRGD only and IL-2 only treatment groups was overwhelming composed of Tregs (5%) at CD4/Treg and CD8/Treg ratios of 1.75 and 0.5 respectively, the combination of iRGD + IL-2 shifted the T-cell sub-populations away from Tregs (1.5%) and towards increased CD4/Treg and CD8/Treg ratios (4 and 12 respectively). Conclusions: The combination of iRGD + IL-2 is capable of reprogramming the immunosuppressive Treg tumor microenvironment, increasing effector CD4+ and CD8+ T-cells.
Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients previously treated with at least one prior systemic therapy.
Authors: Amod Sarnaik, Sajeve Samuel Thomas, Diwakar Davar, John M. Kirkwood, Harriet M. Kluger, Jose Lutzky, Melissa Wilson, Anna C. Pavlick, Brendan D. Curti, Eric D. Whitman, Giao Q. Phan, Marc S. Ernstoff, Kathryn Toshimi Takamura, Debora Barton, Sam Suzuki, Lavakumar Karyampudi, Nancy Louise Samberg, Maria Fardis, Jason Alan Chesney
Journal: Journal of Clinical Oncology (2019)

136 Background: While immunotherapies including checkpoint inhibitors and targeted therapies (BRAF/MEK inhibitors) are options for patients with metastatic melanoma, many patients still develop progressive disease. These patients have few treatment options available including high dose IL-2 and chemotherapy with reported second line response rates of 4-10%. Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma, able to elicit durable and complete responses in even heavily pretreated patients. We provide preliminary data for lifileucel TIL (LN-144) in heavily pre-treated metastatic melanoma patients who progressed on multiple checkpoint and BRAF/MEK inhibitors. Methods: C-144-01 is an ongoing global Phase 2, open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 47) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed at central GMP facilities in a 22-day manufacturing process. The final product was cryopreserved and shipped to sites. Patients received a one week cyclophosphamide/fludarabine preconditioning lymphodepletion regimen, a single lifileucel infusion, followed by up to 6 doses of iv IL-2 (600,000 IU/kg). Results: Patients with Stage IIIC/IV melanoma had 3.3 mean prior therapies (range: 1-9) and high baseline tumor burden, reflected by a mean sum of diameters of target lesions of 112 mm. Preliminary efficacy results: ORR = 38% (1 CR, 13 PR, 4 uPR), DCR = 77%, and median DOR 6.4 mo (range: 1.3 to 13.7) with median follow-up 6.0 mo. Longer follow-up led to improved responses in some patients including the CR. Frequency of AEs decreased over time, a potentially important benefit of one-time TIL treatment. Conclusions: Preliminary data support lifileucel TIL as an efficacious and well-tolerated therapeutic option for patients with metastatic melanoma who have failed multiple lines of prior therapies including checkpoint inhibitors and BRAF/MEK inhibitors. Clinical trial information: NCT02360579.
The Role of the EGF Receptor in Sex Differences in Kidney Injury
Authors: Ming-Zhi Zhang, Kensuke Sasaki, Yan Li, Zhilian Li, Yu Pan, Guan-nan Jin, Yinqiu Wang, Aolei Niu, Suwan Wang, Xiaofeng Fan, Jian Chun Chen, Corina Borza, Haichun Yang, Ambra Pozzi, Agnes B. Fogo, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Sex differences in the predisposition to CKD development or progression are well known. However, the underlying mechanisms involved remain unclear. The authors found markedly greater renal EGF receptor (EGFR) expression levels in adult wild-type male versus female mice, and a similar sex difference in EGFR expression in normal adult human kidneys. In Dsk5 mutant mice with constitutive EGFR activation, males developed significant spontaneous glomerular and tubulointerstitial injury, whereas females were relatively spared. In female mice, oophorectomy did not affect renal EGFR expression, but testosterone increased it; in male mice, castration decreased renal EGFR expression. These findings indicate that differential expression in renal EGFR expression plays a role in sex differences in susceptibility to progressive kidney injury, one that may be mediated in part by testosterone. Background Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. Methods To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. Results In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. Conclusions These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
Infographic. New Zealand Rugby’s concussion management pathway
Authors: Danielle Salmon, Janelle Romanchuk, Ian Murphy, John Sullivan, Simon Walters, Chris Whatman, Amanda Clacy, Sierra Keung, Klazina Van Der Vis
Journal: British Journal of Sports Medicine (2019)

Concussions in rugby union (rugby) impact not only player welfare but parental and players’ decisions around participation, a concern for rugby administrators around the world.1 2 To ensure player welfare, World Rugby has developed concussion management recommendations (http://playerwelfare.worldrugby.org/concussion)3; however, the practical application and enforcement of these recommendations presents a challenge.4 5 To address this challenge, New Zealand Rugby (NZR) as part of a National Concussion Initiative (infographic 1) developed a concussion management pathway (CMP) that considers the various stakeholders involved in the management of concussion as well as ways to support improved concussion management at the …
Resuscitation Strategies Using Peripheral Perfusion vs Serum Lactate Levels—Reply
Authors: Jan Bakker, Glenn Hernández
Journal: JAMA (2019)

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Oncolytic adenovirus drives specific immune response generated by a poly-epitope pDNA vaccine encoding melanoma neoantigens into the tumor site
Authors: Alessandra Lopes, Sara Feola, Sophie Ligot, Manlio Fusciello, Gaëlle Vandermeulen, Véronique Préat, Vincenzo Cerullo
Journal: Journal for ImmunoTherapy of Cancer (2019)

DNA vaccines against cancer held great promises due to the generation of a specific and long-lasting immune response. However, when used as a single therapy, they are not able to drive the generated immune response into the tumor, because of the immunosuppressive microenvironment, thus limiting their use in humans. To enhance DNA vaccine efficacy, we combined a new poly-epitope DNA vaccine encoding melanoma tumor associated antigens and B16F1-specific neoantigens with an oncolytic virus administered intratumorally.Genomic analysis were performed to find specific mutations in B16F1 melanoma cells. The antigen gene sequences were designed according to these mutations prior to the insertion in the plasmid vector. Mice were injected with B16F1 tumor cells (n = 7-9) and therapeutically vaccinated 2, 9 and 16 days after the tumor injection. The virus was administered intratumorally at day 10, 12 and 14. Immune cell infiltration analysis and cytokine production were performed by flow cytometry, PCR and ELISPOT in the tumor site and in the spleen of animals, 17 days after the tumor injection.The combination of DNA vaccine and oncolytic virus significantly increased the immune activity into the tumor. In particular, the local intratumoral viral therapy increased the NK infiltration, thus increasing the production of different cytokines, chemokines and enzymes involved in the adaptive immune system recruitment and cytotoxic activity. On the other side, the DNA vaccine generated antigen-specific T cells in the spleen, which migrated into the tumor when recalled by the local viral therapy. The complementarity between these strategies explains the dramatic tumor regression observed only in the combination group compared to all the other control groups.This study explores the immunological mechanism of the combination between an oncolytic adenovirus and a DNA vaccine against melanoma. It demonstrates that the use of a rational combination therapy involving DNA vaccination could overcome its poor immunogenicity. In this way, it will be possible to exploit the great potential of DNA vaccination, thus allowing a larger use in the clinic.
Impaired dendritic cell functions in lung cancer: a review of recent advances and future perspectives
Authors: Jing‐Bo Wang, Xue Huang, Fu‐Rong Li
Journal: Cancer Communications (2019)

Abstract Lung cancer is the leading cause of cancer mortality worldwide. Dendritic cells (DCs) are the key factors providing protective immunity against lung tumors and clinical trials have proven that DC function is reduced in lung cancer patients. It is evident that the immunoregulatory network may play a key role in the failure of the immune response to terminate tumors. Lung tumors likely employ numerous strategies to suppress DC‐based anti‐tumor immunity. Here, we summarize the recent advances in our understanding on lung tumor‐induced immunosuppression in DCs, which affects the initiation and development of T‐cell responses. We also describe which existing measures to restore DC function may be useful for clinical treatment of lung tumors. Furthering our knowledge of how lung cancer cells alter DC function to generate a tumor‐supportive environment will be essential in order to guide the design of new immunotherapy strategies for clinical use.