tbuckley/cabot-search huggingface dataset:
Sedentary people are advised to do at least one hour of moderate activity a day
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Doing at least an hour a day of moderate physical activity, such as brisk walking or cycling, seems to eliminate the increased risk of death associated with sitting for more than eight hours a day, a study published in the Lancet shows.1

Researchers used data from 16 studies that had looked at physical activity, sedentary time, and mortality. They analysed the raw study data according to a harmonised protocol that categorised the reported sitting and television viewing time into four standardised groups and the physical activity into quartiles, and they combined the data.

The analysis included data on 1 005 791 …
Abstract 1672: Photodynamic therapy using photosensitizer and light emitting diodes (LEDs) demonstrates oncolytic activity against prostate cancer
Authors: Taher Gheewala, Troy Skwor, Gnanasekar Munirathinam
Journal: Cancer Research (2016)

Abstract Prostate cancer (PCa) affects over 2 million Americans and its treatment options include surgery, anti-hormonal drugs for androgen sensitive tumors, and radiotherapy. However, patients undergoing androgen deprivation therapy develop resistance leading to development of castration resistant or androgen independent PCa. It is clear there is an urgent need to find an effective treatment strategy to manage aggressive PCa. An alternative treatment is the use of photodynamic therapy (PDT), which involves the activation of a photosensitizer by a defined wavelength of light in the presence of oxygen, generating transient concentrations of reactive oxygen species. We hypothesize that PDT via a photosensitizer (pheophorbide) in combination with light emitting diodes (LEDs) [670 nm] will demonstrate oncolytic activity against PCa cells, thus suggesting an alternative, less toxic cancer treatment. To test our hypothesis, we used C4-2 and DU-145 PCa cell lines as an in vitro model in this study. To explore the anti-cancer effects of PDT on PCa, cell viability assay and wound healing assay were performed. Western blotting was employed to identify the signaling molecules modulated by PDT. Our cell viability assay results demonstrated significant oncolytic activity against PCa cell lines using PDT with pheophorbide as a photosensitizer combined with 670 nm LEDs in as little as an 88 second pulse with increased lytic activity correlating with elevated energy intensities. We also observed variability in cell line PDT susceptibility; wherein, C4-2 cells were more susceptible than DU-145 PCa cells. The wound healing assay results with pheophorbide and 670 nm LEDs demonstrated significant inhibition of migration abilities of both C4-2 and DU-145 PCa cells. These findings implicate the anti-metastatic activity of PDT on PCa. Further, our mechanistic analysis showed activation of BiP/GRP78, an endoplasmic reticulum (ER) chaperone, in C4-2 as well as DU-145 PCa cells. This suggests that the anti-cancer activity of PDT with pheophorbide and 670 nm LEDs is via ER stress. In conclusion, our results show PDT using pheophorbide and 670 nm LEDs as a promising therapeutic strategy for PCa. Citation Format: Taher Gheewala, Troy Skwor, Gnanasekar Munirathinam. Photodynamic therapy using photosensitizer and light emitting diodes (LEDs) demonstrates oncolytic activity against prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1672.
Significant 99mTc-MDP but Unimpressive 18F-NaF Gastric Activity in a Patient With Multiple Myeloma
Authors: Shumao Zhang, Yue Chen, Zhanwen Huang, Liang Cai, Yin Zhang
Journal: Clinical Nuclear Medicine (2016)

A 69-year-old man with a history of low back pain for more than 4 months underwent Tc-MDP bone scan to determine the cause of the symptoms. In addition to the osseous lesions, significant activity in the stomach wall was noted. However, a subsequent F-NaF PET/CT only revealed bone lesion without increased activity in the stomach wall. The cause of the back pain was eventually confirmed due to multiple myeloma.
Abstract 518: Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation
Authors: Kalpana Mujoo, Raj K. Pandita, Anjana Tiwari, Vijay Charaka, Walter N. Hittelman, Murlidhar Hegde, Haibo Wang, Clayton R. Hunt, Bhuvanesh Dave, Jenny Chang, E Brian Butler, Tej K. Pandita
Journal: Cancer Research (2016)

Abstract Embryonic as well as induced pluripotent stem cells (ESC/iPSC) have a robust DNA damage response to facilitate efficient repair of DNA strand breaks as well as interstrand cross-links (ICLs). Stem cell abundance in tumors can impact the efficacy of the therapeutic agents, and such agents also have an impact on the normal tissue toxicity. Therefore, it is important to compare DNA damage repair in progenitor stem cells and their differentiated lineages since the normal tissues surrounding the tumor predominantly contain differentiated cells. We therefore asked whether the DNA damage response is altered during differentiation of embryonic as well as induced pluripotent stem cells and found that sensing of ionizing radiations, interstrand cross-linking or hydroxyurea induced DNA damage was minimally altered by cellular differentiation. Furthermore, DNA DSB repair by non-homologous end joining was minimally impacted. However, the homologous recombination of DSB repair or ICL repair was significantly reduced in differentiated cells. In addition, differentiated cells showed a reduction in the frequency of new origins of replication and increased stalled replication forks. Interestingly, similar to ESC or iPSC lines, breast tumor stem cells also exhibited a decrease in DNA damage repair by homologous recombination in differentiated cells. The defect in DNA damage repair by homologous recombination was reversed in de-differentiated cells, supporting the argument that differentiation can influence homologous recombination repair of DSBs as well as repair of ICLs. These studies have implications in modulating the therapeutic efficacy of DNA damage inducing tumor-killing agents. Citation Format: Kalpana Mujoo, Raj K. Pandita, Anjana Tiwari, Vijay Charaka, Walter N. Hittelman, Murlidhar Hegde, Haibo Wang, Clayton R. Hunt, Bhuvanesh Dave, Jenny Chang, E Brian Butler, Tej K. Pandita. Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 518.
Abstract 707: High expression of Pol é promotes invasion and metastases in esophageal squamous cell carcinoma
Authors: Shitao Zou, Jinchang Wu, Wei-Qun Ding, Jundong Zhou
Journal: Cancer Research (2016)

Abstract . DNA polymerase iota (Pol iota) is an error-prone DNA polymerase involved in translesion DNA synthesis (TLS) that may play a significant role in the accumulation of DNA mutations. Our previous studies identified the elevated expression of Pol iota in human esophageal squamous cell cancer (ESCC) tissues and revealed that Pol iota contributes to ESCCs’ progression. The present study aimed to investigate the molecular mechanism by which Pol iota enhances the invasiveness and metastasis of ESCC cells. We found that the expression of Pol iota was higher in ESCCs with lymph node metastasis compared to those without lymph node metastasis. Kaplan-Meier analysis revealed a negative correlation between the expression of Pol iota and patients’ prognosis. Furthermore, the expression of matrix metalloproteinase-2(MMP-2) and matrix metalloproteinase-9(MMP-9), both being essential regulators for cells invasion, were associated with that of Pol iota in ESCCs tissue samples. The wound healing and transwells assay revealed that over-expression of Pol iota enhances motility and invasiveness of ESCC cells. In vivo, up-regulation of Pol iota promoted the colonization of ESCC cells in the liver, lung and kidney. Signaling pathway analysis showed that Pol iota induces the expression of MMP-2/9 and enhances the ESCCs progression via JNK-AP-1 cascade. Altogether, our finding demonstrated the underlying mechanism by which Pol iota promotes ESCCs’ development. Citation Format: Shitao Zou, Jinchang Wu, Wei-Qun Ding, Jundong Zhou. High expression of Pol é promotes invasion and metastases in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 707.
Abnormal Glucose Tolerance in Infants and Young Children with Cystic Fibrosis
Authors: Yaling Yi, Andrew W. Norris, Kai Wang, Xingshen Sun, Aliye Uc, Antoinette Moran, John F. Engelhardt, Katie Larson Ode
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

In cystic fibrosis, abnormal glucose tolerance is associated with decreased lung function and worsened outcomes. Translational evidence indicates that abnormal glucose tolerance may begin in early life.To determine whether very young children with cystic fibrosis have increased abnormal glucose tolerance prevalence compared with control subjects. The secondary objective was to compare area under the curve for glucose and insulin in children with cystic fibrosis with control subjects.This is a prospective multicenter study in children ages 3 months to 5 years with and without cystic fibrosis.Oral glucose tolerance testing with glucose, insulin, and C-peptide was sampled at 0, 10, 30, 60, 90, and 120 minutes. Twenty-three children with cystic fibrosis and nine control subjects had complete data. All control subjects had normal glucose tolerance. Nine of 23 subjects with cystic fibrosis had abnormal glucose tolerance (39%; P = 0.03). Of those, two met criteria for cystic fibrosis-related diabetes, two indeterminate glycemia, and six impaired glucose tolerance. Children with cystic fibrosis failed to exhibit the normal increase in area under the curve insulin with age observed in control subjects (P < 0.01), despite increased area under the curve glucose (P = 0.02).Abnormal glucose tolerance is notably prevalent among young children with cystic fibrosis. Children with cystic fibrosis lack the normal increase in insulin secretion that occurs in early childhood despite increased glucose. These findings demonstrate that glycemic abnormalities begin very early in cystic fibrosis, possibly because of insufficient insulin secretion.
Abstract 3937: Nestin expression is associated with a basal-like phenotype and poor prognosis in breast cancer
Authors: Kristi Krüger, Elisabeth Wik, Tor Audun Klingen, Ying Chen, Turid Aas, Lars A. Akslen
Journal: Cancer Research (2016)

Abstract Background: Nestin, neuroepitheilal stem cell protein, is an intermediate filament protein first described in neural stem or progenitor cells, and its expression has been seen in several tissues, including different types of cancer. In breast cancer, Nestin expression has been linked to the triple negative and basal-like phenotypes. We here evaluated Nestin and its association with clinico-pathologic markers and survival in two prospective Norwegian breast cancer cohorts. Materials and methods: Series I includes 546 women (50-69 years) diagnosed with primary invasive breast cancer (403 screen-detected and 143 interval cancers) as part of the prospective and population-based Norwegian Breast Cancer Screening Program (NBCSP) during 1996-2003 (Hordaland county). Series II includes 282 women (50-69 years) with invasive cancers (199 screen-detected and 83 interval cancers) diagnosed as part of the NBCSP during 2004-2009 (Vestfold County). Immunohistochemical staining of Nestin was done on tissue microarrays (TMAs). Expression in tumor cells was graded by a Staining Index (SI) (values 0-9). Results: Nestin positivity, observed in 9% and 13% of the breast cancer cases in Series I and II, was associated with higher histological grade (OR, odds ratio 14.3 and 8.1), high tumor cell proliferation by Ki-67 (OR 11.4 and 9.1), larger tumor diameter (OR 1.8 and 2.4), but not with lymph node status or HER2 status. Further, Nestin positivity was associated with negativity for estrogen (OR 14.9 and 11.9) and progesterone receptor (8.5 and 3.4), the triple negative phenotype (OR 29.1 and 17.4) and basal-like differentiation by positivity for Cytokeratin 5 (OR 9.1 and 8.7) or P-cadherin (OR 7.0 and 8.5). By univariate survival analysis, Nestin positivity was associated with reduced breast cancer specific (p = 0.002 and p = 0.076) and overall survival (p = 0.005 and p = 0.039). When including the standard variables tumor size, histologic grade and lymph node status in a multivariate analysis, Nestin was still significantly associated with reduced breast cancer specific survival in the largest cohort (Series I). Conclusion: We found that Nestin expression in breast cancer is associated with aggressive features, the triple negative phenotype, basal-like differentiation, and reduced breast cancer specific survival. Citation Format: Kristi Krüger, Elisabeth Wik, Tor Audun Klingen, Ying Chen, Turid Aas, Lars A. Akslen. Nestin expression is associated with a basal-like phenotype and poor prognosis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3937.
IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells
Authors: Yumeng Mao, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Andreas Lundqvist
Journal: Blood (2016)
Skin provocation tests may help to diagnose atopic dermatitis
Authors: T. Hawro, S. Lehmann, S. Altrichter, J. W. Fluhr, T. Zuberbier, M. K. Church, M. Maurer, M. Metz
Journal: Allergy (2016)

Abstract Background Atopic dermatitis ( AD ) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. Objective To test whether the results of skin provocation with cowhage, an established model of histamine‐independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD . Methods Twenty‐two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. Results Patients with AD , compared with healthy controls, exhibited significantly smaller histamine‐induced flares ( P &lt; 0.01) and markedly longer itch persistence after provocation with cowhage ( P &lt; 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic ( ROC ) curve 0.78 and 0.80, respectively). The persistence of cowhage‐induced itch for at least 30 min and a histamine‐induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD . If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. Conclusion The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage‐induced itch and diminished histamine‐induced flare in nonlesional skin may support diagnosis of AD .
Abstract 652: Establishment of a novel mouse model of intrahepatic cholangiocarcinoma by liver-specific Kras activation and Pten deletion
Authors: Yumi Terakado, Tsuneo Ikenoue, Kiyoshi Yamaguchi, Yoichi Furukawa
Journal: Cancer Research (2016)

Abstract The mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K) pathway are intracellular signaling pathways that are involved in carcinogenesis. Various studies suggest that these pathways are important for the development of liver tumors. To investigate the effect of coactivation of MAPK and PI3K pathways in liver tumorigenesis, we generated three types of mouse models by crossbreeding conditional KrasG12D knockin mice and/or conditional Pten knockout mice with Alb-Cre mice (Alb-Cre KrasG12D/+ Pten flox/flox mice, Alb-Cre KrasG12D/+ Pten flox/+ mice, and Alb-Cre KrasG12D/+ mice). Among the three models, mice carrying liver-specific oncogenic Kras knockin and homozygous Pten deletion (Alb-Cre KrasG12D/+ Pten flox/flox) frequently demonstrated weight loss, abdominal distension, and jaundice with median survival of eight weeks. Macroscopic analysis detected diffuse and firm tumorous lesions mainly in the hepatic hilum. Histological examination of the Alb-Cre KrasG12D/+ Pten flox/flox mice disclosed bile duct hyperplasia at four weeks of age, precancerous lesions of intrahepatic cholangiocarcinoma (ICC) at five weeks of age, and advanced ICC lesions that resemble human ICC at seven weeks of age. On the other hand, the Alb-Cre KrasG12D/+ Pten flox/+ mice, the second model, developed ICCs as well as hepatocellular carcinomas (HCCs), and their average survival was eight months. The third mice model, the Alb-Cre KrasG12D/+ mice, developed HCCs but not ICCs, and survived more than one year. Immunohistochemical analysis of the ICCs in the Alb-Cre KrasG12D/+ Pten flox/flox mice corroborated the activation of the Mapk and the Pi3k pathways in the tumor cells. These data suggest that activity of Pi3k pathway might dictate the fate determination of hepatotumorigenesis into biliary or hepatocyte cell lineage. In addition, oncogenic Kras expression and homozygous Pten deletion cooperate to induce exclusively ICCs. Since a limited number of mouse ICC models have been reported, the Alb-Cre KrasG12D/+ Pten flox/flox mouse model should be a useful tool for the analysis of molecular mechanism(s) underlying ICC. Citation Format: Yumi Terakado, Tsuneo Ikenoue, Kiyoshi Yamaguchi, Yoichi Furukawa. Establishment of a novel mouse model of intrahepatic cholangiocarcinoma by liver-specific Kras activation and Pten deletion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 652.
Challenges facing the health secretary in new Cabinet
Authors: Chris Ham
Journal: BMJ (2016)

Valuing staff and supporting them to improve care should be the priority

The immediate challenge facing Jeremy Hunt, who has been reappointed as health secretary in the new Cabinet, is to confront the parlous state of NHS finances in England. The aggregate deficit of £1.85bn (€2.2bn; $2.5bn) in 2015-16 was the largest in NHS history and resulted from increasing demands on providers at a time of constrained funding.1 Savings from other parts of the Department of Health’s expenditure may help to offset NHS overspending but cannot be relied on to do the same in future.

Almost all of last year’s deficit was concentrated in acute hospitals and was driven by the appointment of additional clinical staff, many recruited from agencies, in response to the failures of patient care at Mid Staffordshire NHS Foundation Trust2 and concerns about Care Quality Commission inspections. The regulator of NHS providers, NHS Improvement, has intervened to control the costs of agency staff and has signalled that providers should cut the number of clinical staff they employ to restore financial balance.3 …
Abstract 4722: Selective inhibition of DNA methyltransferases and efficacy of novel DNMT inhibitors in leukemia xenografts
Authors: Dat Nguyen, Melinda Hollingshead, Larry Rubinstein, James Doroshow, Sherry X. Yang
Journal: Cancer Research (2016)

Abstract Background. DNA methyltransferase (DNMT) 1 plays an important role in tumorigenesis and is responsible for maintenance and propagation of DNA methylation patterns, and DNMT3A and DNMT3B are involved in de novo DNA methylation. 4’-Thio-5-aza-2’-deoxycytidine (5-aza-T-dCyd) and 4’-thio-2’-deoxycytidine (T-dCyd) are novel DNMT inhibitors in development. In this investigation, we test the hypothesis that DNMTs are differentially modulated by DNMT inhibitors that may contribute to treatment efficacy. Methods. Animals (5 per group) bearing HL-60 leukemia cell xenografts were treated with saline or aza-T-dCyd at 2 mg/kg with and without 100 mg/kg tetrahydrouridine (ThU) for 5 days weekly for 2 weeks and cycle repeat after 9-day rest. Two other groups were dosed with T-dCyd at 4 mg/kg and decitabine at 0.75 mg/kg, respectively. Tumor growth was assessed by measuring tumor size. Expression of DNMT1, DNMT3A and DNMT3B was examined by immunohistochemistry in paraffin-embedded tumors resected at day 11. Results. Expression of DNMT1 was high, DNMT3B intermediate, and DNMT3A at low levels in saline control group. Significant growth delay was achieved in the aza-T-dCyd (86%) and aza-T-dCyd plus ThU cohorts (45%), compared with the controls. In the aza-T-dCyd treated xenografts, histological examination confirmed a significant reduction (77%) in tumor area (P = 0.002). Expression of DNMT1 and DNMT3B (n = 2 in aza-TdCyd group) was reduced in aza-T-dCyd cohort (P = 0.01 and P = 0.04) as well as aza-T-dCyd in combination with ThU group (P = 0.01 and P = 0.03). In contrast, no growth inhibition but decrease in DNMT3A and DNMT1 were observed by dosing with decitabine. There were neither delays for tumor growth nor changes of all three DNMTs by T-dCyd treatment with the dose administered. Conclusions. Aza-T-dCyd and aza-T-dCyd plus ThU treatments result in significant tumor growth inhibition in HL-60 leukemia xenografts. The anti-tumor activity is associated with simultaneous inhibition of the two drug targets — DNMT1 and DNMT3B. The preclinical results provide compelling evidence to advance aza-T-dCyd for clinical development and perhaps in the context of companion biomarker approach. Citation Format: Dat Nguyen, Melinda Hollingshead, Larry Rubinstein, James Doroshow, Sherry X. Yang. Selective inhibition of DNA methyltransferases and efficacy of novel DNMT inhibitors in leukemia xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4722.