In article number 1701527, Sangeeta N. Bhatia and co-workers engineer an antibacterial by fusing two peptide domains to target and kill bacteria and then encapsulate them in a biodegradable porous silicon nanoparticle. These nanomaterials kill bacteria and improve animal survival after treatment of a lung-infection model. This approach represents a new strategy for the development of antibacterials to combat the rising incidence of antibiotic resistance in the clinic.
The understanding of the growth kinetics of conductive filaments in soft polymers is crucial to achieve controllable and reliable resistive random access memory (RRAM). A simple solution-processed and cone-shaped contact method is developed by Mingdong Yi, Linghai Xie, Wei Huang, and co-workers in article number 1701333. The nanoscale engineering of a resistance-switching layer opens the possibility of high-performance flexible memory.
Hot spots with significantly enhanced electric field are generally found in plasmonic systems composed of metallic nanoparticles/nanostructures. The combination of efficient photoluminescence and polarization and wavelength sensitivity offers the opportunity to encode such hot spots for optical memory, which is a promising way of storing big data. In article number 1701918, Sheng Lan, Shaolong Tie, Min Gu, and co-workers numerically analyze the impact of hot spots on the nonlinear optical response of metallic nanoparticles/nanostructures and demonstrate multidimensional optical data storage with ultrahigh density and ultralow energy.
A hybrid voltage inverter is made with two field-effect transistors, one using quantum dots as active material and the other polymer-wrapped carbon nanotubes. In article number 1701764, Maria A. Loi and co-workers demonstrate that different solution-processable, low-dimensional materials can be combined to obtain high-performance, low-cost, and low-voltage electronics.
Quaternary alloying (mixing of four elements) provides the flexibility to engineer the optical bandgap of atomically thin transition-metal dichalcogenide (TMD) materials. Such alloying also influences the growth temperature. In article number 1702457, Boris I. Yakobson, Chandra Sekhar Tiwary, Pulickel M. Ajayan, and co-workers describe the quaternary alloying of Mo, W, S, and Se to produce alloys where the bandgap can be tuned from 1.61 to 1.85 eV.
Owing to the lower cost and easy accessibility of potassium, potassium-ion batteries are considered as potential substitutes for lithium-ion batteries. A porous carbon monolith with ultrahigh pyridinic N content is successfully synthesized by Yu Chen, Chenglin Yan, and co-workers in article 1702268, which exhibits excellent electrochemical performance, especially in terms of reversible capacity, for both K+ half-cells and full-cells.
Publication date: Available online 14 September 2017
Source:Women and Birth
Author(s): Marjorie Atchan, Deborah Davis, Maralyn Foureur
BackgroundAustralia experiences high breastfeeding initiation but low duration rates. UNICEF introduced the global breastfeeding strategy, the Baby-Friendly Hospital Initiative, to Australia in 1992, transferring governance to the Australian College of Midwives (ACM) in 1995. In 2017 23% of facilities were registered as 'baby-friendly' accredited.AimTo examine the introduction and dissemination of the Baby-friendly Hospital Initiative into the Australian national setting.MethodsAn instrumental case study was conducted containing two components: analysis of historical documents pertaining to the Initiative and participant's interviews, reported here. A purposive sampling strategy identified 14 participants from UNICEF, ACM, maternity and community health services, the Australian government and volunteer organisations who took part in in-depth interviews. Thematic analysis explored participants' perceptions of factors influencing the uptake and future of the since renamed Baby Friendly Health Initiative (BFHI) and accreditation programme, BFHI Australia. Two broad categories, enablers and barriers, guided the interviews and analysis.FindingsParticipants revealed a positive perception of the BFHI whilst identifying that its interpretation and expansion in Australia had been negatively influenced by intangible government support and suboptimal capacity building. BFHI's advocacy agenda competed with BFHI Australia's need for financial viability. Widespread stakeholder collaboration and tangible political endorsement was seen as a way to move the strategy forward.ConclusionDissemination of BFHI Australia is hampered by multi-level systems issues. Prioritisation, stakeholder collaboration and adequate resourcing of the BFHI is required to create a supportive and enabling environment for Australian women to determine and practice their preferred infant feeding method.
http://ift.tt/2xDoVTi
The 8th edition of the TNM was released in 2016 and included major revisions, especially for stage III. We aimed to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Clinical data from 1557 patients operated on for stage III gastric cancer according to the 7th edition between 2007 and 2014 were analyzed and compared using the 7th and 8th TNM classifications. A proposed staging system was established, and the three systems were compared in terms of prognostic performance. The stage shifted for 669 (42.96%) patients. It shifted from IIIA to IIIB (one patient, 0.06%), IIIB to IIIA (230 patients, 14.8%), IIIB to IIIC (94 patients, 6.0%), and IIIC to IIIB (344 patients, 22.1%). However, the new AJCC subgroupings did not prove distinctive for survival levels between T3N3aM0 (stage IIIB) and T3N3bM0 (stage IIIC) or between T4aN3aM0 (stage IIIB) and T4aN3bM0 (stage IIIC) when <30 lymph nodes (LNs) were resected. The performance of the 8th edition (c-index, 0.614; 95% confidence interval [CI], 0.596–0.633) revealed no relevant improvement compared to the 7th edition (c-index, 0.624; 95% CI, 0.605–0.643). The proposed staging system generated the best prognostic stratification. The 8th TNM edition may not provide better accuracy in predicting the prognosis of stage III gastric cancer. The proposed staging system, comprised of a combination of the number of LNs harvested and the 7th and 8th AJCC classifications, may improve predictive capacities for stage III gastric cancer.
The aim of this study was to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Furthermore, a proposed staging system was established, and the three systems were compared in terms of prognostic performance.
Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.
Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.
Results: The FGFR inhibitor–resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.
Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527–36. ©2017 AACR.
Purpose: Leptomeningeal metastases are more common in non–small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of leptomeningeal metastases.
Experimental Design: We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients.
Results: Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as MET amplification and ERBB2 mutation, were also identified in CSFCTCs.
Conclusions: CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases. Clin Cancer Res; 23(18); 5480–8. ©2017 AACR.
T-cell costimulation and coinhibition can be respectively exploited by blocking and agonist mAbs. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti–PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy. Clin Cancer Res; 23(18); 5326–8. ©2017 AACR.
See related article by Tolcher et al., p. 5349
Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.
Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.
Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders.
Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR.
See related commentary by Pérez-Ruiz et al., p. 5326
Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).
Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m2/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.
Results: There were neither G4–5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs.
Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358–65. ©2017 AACR.
Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.
Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.
Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P < 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P = 0.002), lymph node metastasis (P = 0.004), and advanced clinical stage (P = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion, and proliferation in vitro. Further study found that RCC2 induced epithelial–mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9.
Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK–JNK signaling. Clin Cancer Res; 23(18); 5598–610. ©2017 AACR.
Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.
Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.
Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTEN.
Conclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639–47. ©2017 AACR.
High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095–106. ©2017 AACR.
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Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.
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Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. Cancer Res; 77(18); 4741–4. ©2017 AACR.
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Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe (P < 0.0001) and intraoperative Pe (P < 0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long-term surveillance indicated that presence of clusters in preoperative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence. Cancer Res; 77(18); 5194–206. ©2017 AACR.
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In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745–54. ©2017 AACR.
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Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
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Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1–expressing CAFs that share phenotypic and functional characteristics with bone marrow–derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1–positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced in vitro neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs in vitro and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. Cancer Res; 77(18); 5142–57. ©2017 AACR.
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Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution; most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (∼3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predict the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and an elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The antitumor effects of chemotherapies can in part be due to the induction of genomic instability and increased passenger load. Cancer Res; 77(18); 4763–72. ©2017 AACR.
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Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1-null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer. Cancer Res; 77(18); 4773–84. ©2017 AACR.
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The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR–PARG axis as an opportunity to enhance PARPi-based therapies. Cancer Res; 77(18); 5011–25. ©2017 AACR.
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Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1–induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068–76. ©2017 AACR.
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Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797–808. ©2017 AACR.
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CTL–associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4–Tyk2–STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118–28. ©2017 AACR.
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Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage–restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B–expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program. Cancer Res; 77(18); 4809–22. ©2017 AACR.
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A cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer–derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer. Cancer Res; 77(18); 5169–82. ©2017 AACR.
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Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res; 77(18); 4823–34. ©2017 AACR.
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This study examines the prevalence of trauma experiences and traumatic stress in a diverse group of Asian American middle school students from a large urban school district. Descriptive statistics document the mean number of self-reported trauma experiences and posttraumatic stress subscale scores and how these rates differ by students' gender and Asian ethnic subgroups (including Chinese, Filipino, Japanese, Korean, Samoan, Southeast Asian, and Other). Furthermore, we assess the degree to which 1 or more traumatic events is associated with students' self-reported symptoms of severe traumatic stress and the types of traumatic events that are the most powerful predictors of elevated stress. These in-depth findings underscore the need for routine, school-based screening to identify and bring culturally competent, trauma-informed support and interventions to Asian American middle school students experiencing traumatic stress. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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Help-seeking and coping behaviors for emotional distress in Asian Americans were examined with Asian values, perceived emotional intelligence, and optimism as predictors. Participants were 160 self-identified Asian American college students. Out of 6 identified coping methods, disengagement and meditation/exercise were reported to be the more predominant help-seeking strategies. Asian values and the perceived ability to manage others' emotions predicted the reported use of family supports. The perceived ability to manage one's own emotions predicted reported use of meditation/exercise and substance use as coping methods; however, this predictor strongly overlapped with optimism. Utilization of professional supports, such as psychologists and other mental health professionals, were predicted by past use of counseling services. Management of one's emotions and optimism distinguished those who had used counseling services from those who had not. Implications are made for adapting professional services to be culturally sensitive, in order to better address mental and emotional health needs in the Asian American community. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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This study is a qualitative analysis of the writings of 40 Korean American adopted adults around the topic of birth family and culture. Utilizing grounded theory analysis, one main theoretical construct of "searching for connection—finding resolution" emerged from the writings. This construct represents a unique aspect of the transnational, transracial adoption identity journey. Within this main construct, there were four themes: (a) authentic self, (b) genetic connection to birth family and children), (c) adoptive family, and (d) cultural connection. The construct and themes add to the understanding of identity for adopted adults. These results also provide valuable information for mental health practitioners working with this population. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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Employment has been established as an important component of recovery from psychiatric disabilities, but little is known about the perspectives and experiences of working among ethnic minority populations, such as Asian Americans. Asian Americans with psychiatric disabilities have been largely underrepresented in the academic literature on recovery from mental illness and finding meaningful roles in the community. We developed the Meaning of Work Scale to compare the perspectives of Asian Americans with psychiatric disabilities (n = 53) regarding work with those of White Americans with psychiatric disabilities (n = 96). We further explored the perspectives of Asian American individuals (n = 53) regarding work using an open-ended qualitative questions. Data comparing the 2 groups were analyzed using t tests while qualitative data were analyzed using grounded theory methodology. The results revealed significant differences in the intrinsic meaning of work between White Americans and Asian Americans. Major themes derived from qualitative results included barriers that affect work, cultural values and expectations that influence work, and helpful strategies, services, and supports to deal with work-related challenges. These findings have important implications for providers of clinical and rehabilitation services working with Asian Americans diagnosed with psychiatric disabilities. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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This study examined the association between rural-to-urban migration in combination with other stressful life events and levels of depression and physical well-being in parents of first-grade children in Shanghai China (n = 2,077). The study also explored the buffering effects of resources previously identified in prior studies, such as socioeconomic status, social support, and marital satisfaction. Respondents who had migrated were found to have the highest levels of depression and physical ailments, particularly in combination with having experienced other stressful life events. Family socioeconomic status and social support were found to moderate the consequences of migration and other stressful life events on individuals' psychological and physical well-being. Although marital satisfaction was related to physical and psychological well-being, it had no moderating role for individuals who had migrated from rural areas to Shanghai. Implications for practice and policy as well as future research directions are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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Growing up in a White family does not necessarily protect internationally adopted Korean Americans raised in White families from the pernicious effects of discrimination. Emotion regulation strategies may buffer the effects of discrimination on psychological adjustment, yet little research has been conducted on these links. To fill this gap, we examined the relationship between emotion regulation, discrimination and psychological adjustment in a sample of adopted Korean American adolescents (N = 115). Using both parent and adopted child reports across 2 waves of data (7 years apart), we addressed 2 questions. First, what are the different emotion regulation profiles and how do they correspond to psychological adjustment? Second, controlling for adjustment in childhood, do these emotion regulation profiles moderate the association between discrimination and psychological adjustment? We found 3 distinct profiles using cluster analysis: high reappraisal/low suppression (HR/LS), high reappraisal/moderate suppression (HR/MS), and moderate reappraisal/moderate suppression (MR/MS). The HR/LS profile showed the best adjustment, whereas the MR/MS profile reported the most adjustment problems. However, emotion regulation profiles did not moderate the association between perceived discrimination and psychological adjustment. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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The present study identified profiles of acculturation in Asian Americans and explored their implications for health. Pointing out the upward selection bias of Asian Americans in English-only surveys, the study calls attention to the importance of obtaining Asian American samples that reflect the group's cultural and linguistic diversities. Data were drawn from 2,602 participants (age range = 18–98) in the 2015 Asian American Quality of Life (AAQoL) Survey, conducted in central Texas. To reach out to diverse groups of Asian Americans, culturally and linguistically sensitive approaches (e.g., survey questionnaire in Asian languages, bilingual/bicultural recruiters and survey assistants, and partnerships with key individuals and organizations within ethnic communities) were employed, resulting in a sample almost half of which were surveyed in their native languages. Latent profile analysis based on acculturation-related variables (nativity, proportion of life lived in the United States, English speaking ability, familiarity with host culture, familiarity with heritage culture, identity toward ethnic origin, and sense of belonging to the community of ethnic origin) identified a 4-cluster solution: fully bicultural, moderately bicultural, alienated from host culture, and alienated from heritage culture. The fully bicultural group was most advantaged in terms of self-ratings of physical, oral, and mental health. The alienated from heritage culture group demonstrated a particular risk for physical and mental health, whereas the alienated from host culture group was at risk for oral health. Findings not only help understand the heterogeneity of acculturation in Asian Americans but also provide implications for health interventions. (PsycINFO Database Record (c) 2017 APA, all rights reserved)
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Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and non-surgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN-17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated non-operatively. This article is protected by copyright. All rights reserved.
Kenji Kabashima | Takashi Nomura
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Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC). Experimental Design:SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-β-activated kinase 1 (TAK1) and NF-B signaling by SAFB. The role of SAFB in invasion, metastasis and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results:SAFB was down-regulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The down-regulation of SAFB activated NF-B signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo. The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1 and NF-B-related genes.Conclusions:Our results show that SAFB regulated the activity of NF-B signaling in CRC by targeting TAK1. This novel mechanism provides a comprehensive understanding of both SAFB and the NF-B signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-B axis is a potential target for early therapeutic intervention in CRC progression.
Purpose: Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors. Experimental Design: Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro. Bevacizumab internalization, trafficking and effects on cell survival were analyzed using multi-label confocal microscopy, immunoblotting and cytotoxicity assays in the presence/absence of inhibitors. Results: In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+-tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival. Conclusions: We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A.
Purpose: Mutation of the Kirsten ras sarcoma viral oncogene homolog (KRAS) and loss of p53 function are commonly seen in non-small cell lung cancer (NSCLC). Combining therapeutics targeting these tumor defensive pathways with cisplatin in a single nanoparticle platform are rarely developed in clinic. Experimental Design: Cisplatin was encapsulated in liposomes which multiple polyelectrolyte layers including siKRAS and miR-34a were built on to generate multifunctional layer-by-layer nanoparticle. Structure, size, and surface charge were characterized, in addition to in vitro toxicity studies. In vivo tumor targeting and therapy was investigated in an orthotopic lung cancer model by microCT, fluorescence imaging, and immunohistochemistry. Results: The singular nanoscale formulation, incorporating oncogene siKRAS, tumor suppressor stimulating miR-34a, and cisplatin, has shown enhanced toxicity against lung cancer cell line, KP cell. In vivo, systemic delivery of the nanoparticles indicated a preferential uptake in lung of the tumor-bearing mice. Efficacy studies indicated prolonged survival of mice from the combination treatment. Conclusion: The combination RNA-chemotherapy in an LbL formulation provides an enhanced treatment efficacy against NSCLC, indicating promising potential in clinic.
The most comprehensive sequencing effort of sarcomatoid renal cell carcinoma (sRCC) to date reinforces the notion that the sarcomatoid component is closely related to the epithelial component of the cancer. This work also challenges the notion that sRCC evolves from low grade RCC and identifies potential mediators of sarcomatoid differentiation.
Purpose: Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. Experimental Design: To evaluate the effector function and expansion capacity of CAR.αPD1-T cells in vitro, we measured the production of IFN- and T cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.αPD1-T cells, CAR-T cells, and CAR-T cells combined with anti-PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism was investigated by analyzing the expansion and functional capacity of TILs. Results: Human anti-PD-1 CPIs secreted by CAR.αPD1-T cells efficiently bound to PD-1 and reversed the inhibitory effect of PD-1/PD-L1 interaction on T cell function. PD-1 blockade by continuously secreted anti-PD-1 attenuated the inhibitory T cell signaling and enhanced T cell expansion and effector function both in vitro and in vivo. In the xenograft mouse model, we demonstrated that the secretion of anti-PD-1 enhanced the antitumor activity of CAR-T cells and prolonged overall survival. Conclusions: With constitutive anti-PD-1 secretion, CAR.αPD1-T cells are more functional and expandable, and more efficient at tumor eradication than parental CAR-T cells. Collectively, our study presents an important and novel strategy that enables CAR-T cells to achieve better antitumor immunity, especially in the treatment of solid tumors.
Purpose: Despite tumor resection being the frontline clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intends to treat established GBM tumor. Characterizing cytoreductive surgery-induced immune-response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs. Experimental design: We developed syngeneic orthotopic mouse GBM models of tumor-resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNβ to enhance the its release from engineered mouse mesenchymal stem cells (MSC-IFNβ) and assessed whether surgical resection of intracranial GBM tumor significantly enhance the anti-tumor efficacy of targeted on-site delivery of encapsulated-MSC-IFNβ. Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSCs) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the anti-tumor efficacy of locally delivered encapsulated-MSC-IFNβ. IFNβ enhanced selective post-surgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells resulting in increased survival of mice. Utilizing encapsulated-MSC-IFNβ in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNβ induces cell-cycle arrest followed by apoptosis resulting in increased survival in immune-compromised mice despite their absence of an intact immune system. Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immune-therapeutic agents in treating cancer.
A 30-day-old female infant presented to the orthopedic emergency department with progressive upper limb paralysis over the last week, with no history of trauma or fever. She was born at term, cesarean delivery, with unremarkable physical examination at birth. The mother had adequate prenatal care, but the last trimester venereal disease research laboratory test result was not available. The infant had a markedly decreased spontaneous movement of the upper limbs, crying on active movement, with intense skin paleness.
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The diagnosis of secundum atrial septal defect often is delayed. For 310 patients with hemodynamically significant secundum atrial septal defect undergoing closure over a 5-year period at a single medical center, this study reviews the symptoms prompting referral, limitations of physical examination and electrocardiography, and basis for initially missing the diagnosis.
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A 15-year-old boy was admitted to our emergency department with pain in the hip and coccyx. He had sustained an injury from slipping on an icy road the day before. His medical history was unremarkable, and vital signs were within normal limits. Physical examination revealed focal tenderness in the left iliac area. On pelvic radiography, fracture of the left pelvic bone was suspected (Figure 1); however, pelvic computed tomography (CT) showed no evidence of acute fracture of the coccyx and pelvic bone.
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To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys.
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Objectives
To assess the extent to which participation in organised physical activity in the school or community outside school hours and neighbourhood play was associated with children's physical activity and sedentary time.
DesignCross-sectional study.
SettingChildren were recruited from 47 state-funded primary schools in South West England.
Participants1223 children aged 8–9 years old.
Outcome measuresAccelerometer-assessed moderate-to-vigorous-intensity physical activity (MVPA) and sedentary time.
MethodsChildren wore an accelerometer, and the mean minutes of MVPA and sedentary time per day were derived. Children reported their attendance at organised physical activity in the school or community outside school hours and neighbourhood play using a piloted questionnaire. Cross-sectional linear and logistic regression were used to examine if attendance frequency at each setting (and all settings combined) was associated with MVPA and sedentary time. Multiple imputation methods were used to account for missing data and increase sample size.
ResultsChildren who attended clubs at school 3–4 days per week obtained an average of 7.58 (95% CI 2.7 to 12.4) more minutes of MVPA per day than children who never attended. Participation in the three other non-school-based activities was similarly associated with MVPA. Evidence for associations with sedentary time was generally weaker. Associations were similar in girls and boys. When the four different contexts were combined, each additional one to two activities participated in per week increased participants' odds (OR: 1.18, 95% CI 1.12 to 1.25) of meeting the government recommendations for 60 min of MVPA per day.
ConclusionParticipating in organised physical activity at school and in the community is associated with greater physical activity and reduced sedentary time among both boys and girls. All four types of activity contribute to overall physical activity, which provides parents with a range of settings in which to help their child be active.
Human Gene Therapy , Vol. 0, No. 0.
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Human Gene Therapy , Vol. 0, No. 0.
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NDRG1 inhibition sensitizes osteosarcoma cells to combretastatin A-4 through targeting autophagy
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.438
Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.446
POPX2 phosphatase regulates apoptosis through the TAK1-IKK-NF-κB pathway
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.443
Identification of 11(13)-dehydroivaxillin as a potent therapeutic agent against non-Hodgkin's lymphoma
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.442
Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.444
Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.425
Novel chimeric transcript RRM2-c2orf48 promotes metastasis in nasopharyngeal carcinoma
Cell Death & Disease, Published online: 14 September 2017; doi:10.1038/cddis.2017.402
Cancer Biotherapy & Radiopharmaceuticals Sep 2017, Vol. 32, No. 7: 258-265.
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Cancer Biotherapy & Radiopharmaceuticals Sep 2017, Vol. 32, No. 7: 229-238.
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Cancer Biotherapy & Radiopharmaceuticals Sep 2017, Vol. 32, No. 7: 247-257.
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Cancer Biotherapy & Radiopharmaceuticals Sep 2017, Vol. 32, No. 7: 266-273.
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High Altitude Medicine & Biology , Vol. 0, No. 0.
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By Dewayne Bevil Orlando Sentinel ORLANDO, Fla. — WonderWorks, a science-driven attraction on Orlando's International Drive, is offering discounts to Florida residents and free admission to first responders for a limited time. International Drive attraction WonderWorks will give free admission to first responders through October. There's a shorter-term deal for Florida residents in the ...
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The goal of this protocol is to isolate endothelial progenitor cells from umbilical cord blood. Some of the applications include using these cells as a biomarker for identifying patients with cardiovascular risk, treating ischemic diseases, and creating tissue-engineered vascular and heart valve constructs.
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Sensorimotor timing deficits are considered central to attention-deficit/hyperactivity disorder (ADHD). However, the tasks establishing timing impairments often involve interconnected processes, including low-level sensorimotor timing and higher level executive processes such as attention. Thus, the source of timing deficits in ADHD remains unclear. Low-level sensorimotor timing can be isolated from higher level processes in a finger-tapping task that examines the motor response to unexpected shifts of metronome onsets. In this study, adults with ADHD and ADHD-like symptoms (n = 25) and controls (n = 26) performed two finger-tapping tasks. The first assessed tapping variability in a standard tapping task (metronome-paced and unpaced). In the other task, participants tapped along with a metronome that contained unexpected shifts (±15, 50 ms); the timing adjustment on the tap following the shift captures pre-attentive sensorimotor timing (i.e., phase correction) and thus should be free of potential higher order confounds (e.g., attention). In the standard tapping task, as expected, the ADHD group had higher timing variability in both paced and unpaced tappings. However, in the pre-attentive task, performance did not differ between the ADHD and control groups. Together, results suggest that low-level sensorimotor timing and phase correction are largely preserved in ADHD and that some timing impairments observed in ADHD may stem from higher level factors (such as sustained attention).
To evaluate the association between levonorgestrel-releasing intrauterine system (LNG-IUS) use and breast cancer (BC) risk.
A cohort of all Maccabi Healthcare Services (MHS) female members aged 40–50 years between 1/2003 and 12/2013 was used to identify LNG-IUS users as "cases," and 2 age-matched non-users as "controls." Exclusion criteria included: prior BC diagnosis, prior (5 years pre-study) and subsequent treatment with other female hormones or prophylactic tamoxifen. Invasive tumors were characterized by treatments received (chemotherapy, hormonal therapy, trastuzumab, or combination thereof).
The analysis included 13,354 LNG-IUS users and 27,324 controls (mean age: 44.1 ± 2.6 vs. 44.9 ± 2.8 years; p < 0.0001). No significant differences in 5-year Kaplan–Meier (KM) estimates for overall BC risk or ductal carcinoma in situ occurrence were observed between groups. There was a trend towards higher risk for invasive BC in LNG-IUS users (5-year KM-estimate: 1.06% vs. 0.93%; p = 0.051). This difference stemmed primarily from the younger women (40–45 years; 0.88% vs. 0.69%, p = 0.014), whereas in older women (46–50 years), it was non-significant (1.44% vs. 1.21%; p = 0.26). Characterization of invasive BC by treatment demonstrated that LNG-IUS users had similar proportions of tumors treated with hormonal therapy, less tumors treated with trastuzumab, (7.5% vs. 14.5%) and more tumors treated with chemotherapy alone (25.8% vs. 14.9%; p = 0.041).
In peri-menopausal women, LNG-IUS was not associated with an increased total risk of BC, although in the subgroup of women in their early 40's, it was associated with a slightly increased risk for invasive tumors.
Organ-on-chip (OOC) platforms have attracted attentions of pharmaceutical companies as powerful tools for screening of existing drugs and development of new drug candidates. OOCs have primarily used human cell lines or primary cells to develop biomimetic tissue models. However, the ability of human stem cells in unlimited self-renewal and differentiation into multiple lineages has made them attractive for OOCs. The microfluidic technology has enabled precise control of stem cell differentiation using soluble factors, biophysical cues, and electromagnetic signals. This study discusses different tissue- and organ-on-chip platforms (i.e., skin, brain, blood–brain barrier, bone marrow, heart, liver, lung, tumor, and vascular), with an emphasis on the critical role of stem cells in the synthesis of complex tissues. This study further recaps the design, fabrication, high-throughput performance, and improved functionality of stem-cell-based OOCs, technical challenges, obstacles against implementing their potential applications, and future perspectives related to different experimental platforms.
Stem-cell-based organ-on-chips (OOCs) are powerful platforms for drug screening and development. This study discusses different OOCs (e.g., brain, liver, heart, tumor, and lung) with the emphasis on the critical role of stem cells. This further recaps the design, improved functionality, high-throughput performance, technical challenges, and future perspectives of stem-cell-based OOCs.
The last eight years (2009–2017) have seen an explosive growth of interest in organic–inorganic halide perovskites in the research communities of photovoltaics and light-emitting diodes. In addition, recent advancements have demonstrated that this type of perovskite has a great potential in the technology of light-signal detection with a comparable performance to commercially available crystalline Si and III–V photodetectors. The contemporary growth of state-of-the-art multifunctional perovskites in the field of light-signal detection has benefited from its outstanding intrinsic optoelectronic properties, including photoinduced polarization, high drift mobilities, and effective charge collection, which are excellent for this application. Photoactive perovskite semiconductors combine effective light absorption, allowing detection of a wide range of electromagnetic waves from ultraviolet and visible, to the near-infrared region, with low-cost solution processability and good photon yield. This class of semiconductor might empower breakthrough photodetector technology in the field of imaging, optical communications, and biomedical sensing. Therefore, here, the focus is specifically on the critical understanding of materials synthesis, design, and engineering for the next-stage development of perovskite photodetectors and highlighting the current challenges in the field, which need to be further studied in the future.
The fundamental optoelectrical properties of organic–inorganic perovskites in combination with low-cost solution processability, broad-band absorption, fast response, and high sensitivity make them very attractive candidates for the application in photodetection. However, insightful understanding on materials properties, device engineering, and internal photophysical processes is required to further advance perovskite photodetectors. Perovskite photodetectors are comprehensively reviewed.
