tbuckley/cabot-search huggingface dataset:
2-Deoxy-D-glucose kills select tumor cell types under normoxia: reversal by mannose indicates interference with glycosylation
Authors: Metin Kurtoglu, Johnathan C. Maher, Awtar Krishan, Waldemar Priebe, Theodore J. Lampidis
Journal: Cancer Research (2005)

2375  Cells growing under hypoxia are solely dependent on glucose metabolism via glycolysis for energy production. Consequently, when this pathway is blocked, with 2-deoxy-D-glucose (2DG), they die. In contrast, under normoxia when glycolysis is blocked most cells survive since fats and proteins can substitute as energy sources to fuel mitochondrial oxidative phosphorylation. Here, utilizing trypan blue exclusion assays, as well as flow cytometric analysis of DNA content, we find that 500 μg/ml of 2-DG kills a variant of the human breast carcinoma cell line, SKBR3, even when growing under normal oxygen tension. Previous studies demonstrated that 2-DG, under normal oxygen conditions, interferes with the process of N-linked glycosylation in viral coat glycoprotein synthesis, which can be reversed by addition of exogenous mannose. Thus, our results which show that 2-DG toxicity in SKBR3 variants growing under normoxia, can be completely reversed by low dose mannose (180 μg/ml) implicates glycosylation and not glycolysis as the mechanism responsible for this phenomenon. Moreover, mannose is not able to reverse the toxicity of 2-DG in tumor cells that are sensitive to it under hypoxic conditions. Additionally, 2-fluro-deoxy-D-glucose (2-FG) containing a fluoro group in the gluco configuration, which prevents it from resembling mannose, is not toxic to SKBR3 cells under normoxia at equivalent 2-DG doses. 2-FG, however, is as good or better than 2-DG in killing hypoxic tumor cells via blockage of glycolysis. To investigate the effect of 2-DG on glycoprotein synthesis, we measured an over-expressed glycoprotein in the SKBR3 variant, ErbB2, by western blot analysis and found it to be inhibited. Furthermore, the inhibition of ErbB2 synthesis by 2-DG could be reversed by mannose. However, SKOV3, an ovarian cancer line that also over-expresses Erb2 is found to be resistant to 2-DG under normoxic conditions suggesting that ErbB2 is not the sole target of -2DG in SKBR3. Overall, our results raise the possibility that in the appropriate tumor cell types, 2-DG could be used clinically as a single agent to selectively kill both the aerobic (via interference with glycosylation) as well as the hypoxic (via inhibition of glycolysis) cells of a solid tumor.
Preclinical testing supports combined BET and BRAF inhibition as a promising therapeutic strategy for melanoma.
Authors: Luca Paoluzzi, Douglas Hanniford, Elena Sokolova, Igor Dolgalev, Adriana Heguy, Iman Osman, Farbod Darvishian, Jinhua Wang, James E. Bradner, Eva Hernando
Journal: Journal of Clinical Oncology (2014)

9072 Background: Manipulation of key epigenetic regulators is emerging as a new therapeutic strategy in cancer. Our group recently reported a role for BRD4, a Bromodomain-containing protein and BET family member, in melanoma maintenance (Segura MF et al, Cancer Research 2013). BET inhibition impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo. Here we investigated the effect of combining the BET inhibitor JQ-1 with the B-RAF inhibitor Vemurafenib in in vitro and in vivo models of B-RAF mutated melanoma. Methods: We performed cytotoxicity and apoptosis assays, and a xenograft mouse model to explore the in vitro and in vivoactivity of JQ-1 alone or in combination with Vemurafenib in melanoma. We conducted RNA sequencing of xenograft tumors, quantitative RT-PCR and immunoblottings to investigate the mechanisms underlying the effects of combined BET and B-RAF inhibition. Results: In vitro, the BET-inhibitor JQ-1 exhibited time and concentration-dependent cytotoxicity against a panel of B-RAF mutant melanoma cell lines. When combined with JQ-1, Vemurafenib showed synergism and significant apoptosis in vitro. In a xenograft mouse model of melanoma, the addition of JQ-1 to Vemurafenib enhanced the ability of either drug alone to suppress tumor growth and significantly improved survival. Tumors treated with BET and B-RAF inhibitors had reduced proliferative index, as revealed by Ki67 immunostaining. Pathway analysis of RNA sequencing data of mouse tumor tissues showed a significant impact on transcriptional programs controlling cell growth, proliferation, angiogenesis, cell-cycle regulation and differentiation. Conclusions: Collectively, our data provide a rationale for combined BET and B-raf inhibition as a novel strategy for the treatment of melanoma.
Comparative study of content of certain tumor markers in skin melanoma and nevi tissues.
Authors: Victoriya Pozdnyakova, Elena Frantsiyants, Ekaterina Komarova, Valeriya Bandovkina, Olga Khokhlova
Journal: Journal of Clinical Oncology (2014)

e20010 Background: For the study of the pathogenesis of melanoma interest is a comparative study of tumor markers in melanoma tissue early stage and melanocytic nevi. Methods: 40 samples of early stage skin melanoma tissue (pT1-2N0M0) obtained in operative excision of tumors and 20 skin nevi samples were studied. The levels of sCD44std, neuron-specific enolase (NSE), stem cell factor (SCF), heat shock proteins (Hsp70 and Hsp27) were studied by the IFA method. Intact skin samples obtained of patients having no oncopathology were used as the control samples (n=30). Results: It has been found that the level of SCF in skin melanoma samples was 1.4 times higher than the one in intact skin. Similarly, SCF was 1.4 times higher in nevi tissue than in intact skin, however, it did not differ validly from the indicator in melanoma tissue (P1,2<0,05). The level of sCD44std expression in the melanoma tissue exceeded the control values in 4.8 times, and in 2.5 times in nevi tissue. The greatest differences were found in the level of NSE: its content in melanoma tissue was more than 250 times as high as that in intact skin, while the one in nevi tissue exceeded the control values in 40 times. The expression level of Hsp 70 exceeded the control values in 4.8 and 4 times both in melanoma tissue and in nevi tissue, respectively. The content of Hsp27 was 1.6 times as high in the melanoma tissue as in the intact skin, but that of the nevi tissue had no valid distinctions from the parameter of melanoma tissue. Conclusions: The expression level of sCD44std, NSE, SCF, Hsp70 and Hsp27 in the tissue of nevi falls between the intact skin and early stage melanoma tissue, which allows supposing possible nevi malignization mechanisms.
NHS 10 year plan pledges improvements in stroke, heart attacks, and mental health
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The NHS in England has published its much anticipated long term plan for the next decade, with a vow to improve outcomes for people with major physical conditions alongside a substantial increase in funding for mental health and primary care. The blueprint, due to be published today, sets out how the NHS will use the extra £20.5bn (€23bn; $26bn) a year by 2023-24 it will receive from the government to drive improvements in the service over the next 10 years. Many of the measures have been trailed over recent months, including:
Previous cancer of spouse as a predictor for mortality after personal diagnosis of cancer.
Authors: Tamar Peretz, Lea Baider, Gil Goldzweig, Jeremy M Jacobs, Aviad Zick, Yakir Rottenberg
Journal: Journal of Clinical Oncology (2014)

9564 Background: Previous experience may affect further coping with illness. The aim of the current study was to evaluate the association between prior cancer of spouse with mortality following a personal diagnosis of cancer. Methods: A historical prospective study, with cohort inception and baseline measurement of people participating in the Central Bureau of Statistics 1995 census, was designed. Cancer incidence was ascertained through the Israel Cancer Registry and followed up until 2011. Multivariate Cox proportional hazards models were used to assess hazard ratios for mortality among study subjects following cancer of their spouse, while controlling for age, sex, marital status and ethnicity. In order to exclude lead time bias and smoking effect, further analyses which restricted to stage IV cancers and models which excluded smoking associated cancers (lung, head and neck, renal, and bladder cancers) were carried. Results: A total of 133,550 cases of cancer and 61,048 deaths were reported during the study period. The effect on mortality was mediated by spouse’s survival at the time of self-diagnosis; mortality of spouse, at the time of personal diagnosis of cancer was associated with increased risk for death (HR=1.07, 95%CI: 1.02-1.12) compared with reduced risk of personal mortality following a diagnosis of cancer in spouse whose was alive at time of diagnosis (HR=0.90, 95%CI: 0.87-0.94). The gender effect was more prominent in stage IV patients; only males were susceptible to the negative effect after spouse mortality (HR=1.20, 95%CI: 1.06-1.36) while the protective effect of a spouse who was alive at time of self-diagnosis was significant only among females (HR=0.79, 95%CI: 0.71-0.89). These results were similar in the models which included only non-smoking associated cancers. Conclusions: Mortality followed cancer diagnosis is affected by prior diagnosis of cancer among the spouse. This effect is influenced by the survival of the spouse at the time of cancer diagnosis and gender.
Does gallbladder cancer behave differently in young patients?
Authors: Vishal Gupta, Abhijit Chandra, Saket Kumar, Rahul R, Hunaid Hatimi, Vivek Gupta
Journal: Journal of Clinical Oncology (2014)

e15097 Background: Gallbladder cancer (GBC) is usually diagnosed after 60 years of age. Behavior of GBC in young patients is largely unknown. Objective of study was to assess the relationship between age and clinicopathological characteristics of GBC. Methods: Patients with GBC admitted to the hospital between January 2009 and December 2013 were included in the study while those managed in outdoor clinic were excluded. Young (≤40 years) patients were compared with patients > 40 years of age with respect to different clinicopathological parameters. Statistical analysis was performed using t test and χ2or Fisher’s test, and survival was assessed using Kaplan-Meir method and log-rank test was used to analyze the difference between survival curves. Results: 257 patients (mean age 50.51±11.97 years, 188 females) of GBC were included in the study. At presentation 79.7% patients had abdominal pain (mean duration 4.65±9.32 months), 54.4% had jaundice (mean duration 2.07±2.79 months), 70 (27.3%) had metastatic disease and 73 (28.4%) had locally advanced unresectable (LAUR) disease. At surgical exploration (n=114) 36 patients had metastatic and 21 had LAUR disease. Finally 57 patients (22.1%) underwent curative resection. With respect to age (≤40 vs > 40), no significant difference was found in sex (females 73.8% vs 73%, p=0.9), presence of pain (81.9% vs 79%, p= 0.71) or its duration (mean 4.5± 10.7 vs 4.68±9.04 months, p=0.9), jaundice (59% vs 54%, p=0.59) or its duration (mean 2.18±1.66 vs 2.02±3.04 months, p=0.76), anorexia (26.2% vs 31.6%, p=0.52), weight loss (19.7% vs 21.9%, p=0.85), fever (19.7% vs 25.5%, p=0.39), gallstones (60.7% vs 67.3%, p=0.42), advanced (N1/T4) disease (23.5% vs 27.5%, p=1.00) and tumor grade (well vs moderate/poor, 55% vs 41.3%, p=0.42). While no significant difference was found in metastatic disease (47.5% vs 39.3 %, p 0.99) and resectability (27.9% vs 20.4%, p= 0.22), unresectability due to local infiltration was significantly lower in young patients (24.4% vs 40.3%, p=0.032). Median survival was 38 months in each group with no significant difference in survival curves (p=0.7). Conclusions: Clinicopathological parameters of GBC do not differ in patients ≤40 years of age suggesting its behavior similar in young and elderly patients.
A Phage Display-Generated Fully Human Anti-IL-7Rα Antibody Shows Anti-Tumor Activity Against T-Cell Acute Lymphoblastic Leukemia
Authors: Padma Akkapeddi, Ana Rita Fragoso, Julie Hixon, Mariana Oliveira, Tânia Carvalho, Andreas Gloger, Mattia Matasci, Francisco Corzana, Scott Durum, Dario Neri, Gonçalo Bernardes, Joao Barata
Journal: Blood (2018)
Complementary approaches using cancer classification and mutational profiling for molecular characterization of clinically challenging tumors.
Authors: Brock Schroeder, Theresa N. Operana, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2014)

e22116 Background: Tumor profiling is increasingly important for patient stratification to identify mutations with available molecularly-targeted therapies. Clinical actionability relies on complementary molecular approaches to account for underlying disease complexity and heterogeneity. In this study, biomarker profiles following molecular diagnosis by the 92-gene assay were investigated in a large series of clinically challenging cases. Methods: 574 cases submitted for testing with the 92-gene assay (CancerTYPE ID, bioTheranostics) and subsequent biomarker profiling for clinically established gene mutations, translocations, copy number alterations, and protein markers (IHC, PCR, FISH; CancerTARGET ID, bioTheranostics) were included. 92-gene assay molecular predictions, biomarker testing frequency, and mutation rates were analyzed. Results: Of 574 cases evaluated, 76% consisted of tumor types and molecular subtypes with approved targeted therapies. Lung represented 28% (n=158), colorectal 21% (n=122), gastroesophageal 13% (n=77), breast 9% (n=54), melanoma 4% (n=23), and other tumor types 24% (n=140) of cases. Molecular profiling included 23 different tests for prognosis, response or resistance, and 76% had ≥2 predictive biomarkers tested. Consistent with clinical actionability, the frequency of biomarker testing for lung adenocarcinomas was 90% EGFR, 79% ALK, 64% ROS1, and 58% KRAS; positive mutational rates were 6% for EGFR, 4% for ALK rearrangement, 1% for ROS1, and 35% for KRAS. For colorectal cancers, the frequency of biomarker testing was 99% KRAS and 58% BRAF; positive mutational rates were 36% for KRAS and 3% for BRAF. Conclusions: Molecular diagnosis as a complementary approach to biomarker testing may provide a molecular bridge to clinical actionability. Tumor-specific mutational rates were similar to expected prevalence rates and further support the utility of this approach. Mutations Cases (%) Amplification Cases (%) KRAS 46 C-MET 29 PIK3CA 44 FGFR1 27 EGFR 39 HER2 21 BRAF 39 Overexpression ALK 22 TS 22 NRAS 13 HER2 20 EGFR S492R 12 C-MET 18 DDR2 6 EGFR 17 KIT 4 RRM1 17 PDGFRA 0 ERCC1 3 Rearrangement Deletion ALK 32 PTEN 43 ROS1 23 RET 11
Prognostic value of classical HLA class I and nonclassical HLA-E in Russian and Dutch patients with breast cancer stage I.
Authors: Irina Vladimirovna Kolyadina, Peter JK Kuppen, Cornelis J. H. Van De Velde, Irina Poddubnaya, N.G. Dekker-Ensink, A. Sajet, C. Engels, A. Karseladze, G. Frank, D. Komov, V. Ermilova
Journal: Journal of Clinical Oncology (2014)

e22095 Background: We suggested the same prognostic value of immune markers in Russian and Dutch women with breast cancer stage I. Methods: Our study included Russian (n=315) and Dutch (n=203) women with breast cancer stage I, treated in RCRC, RMAPE (1985-2009) and LUMC (1985-1994). Russian women were younger than the Dutch, with more aggressive tumors (G1-tumors was in 7% (Russian) and 27% (Dutch) patients); were treated less often with breast-conserving surgery (53% vs 65%), but received adjuvant system therapy more often (64% vs10%), p<0,05. Relapse-free survival (RFS) was some higher in Dutch than Russian women (5- and 10-years: 88% and 76% vs 79% and 70%); but overall survival (OS) was the same in Russian and Dutch patients (5- and 10-years: 91% and 76% vs 92% and 78% respectively), p>0,05. A Tissue Micro Array taken from tumor blocks of all women was constructed; sections were immunohistochemically stained for HLA-E and -G, HLA class I (HC10, HCA2), and Foxp3. HLA-E and -G were scored using the percentage of tumor cells with membranous multiplied by the intensity of staining (0-3) to provide a score of 0–300; HC10 and HCA2 - using the percentage positive tumor cells (0-100); FoxP3 - by counting the number of positive cells. We used median expression for result evaluation as positive (>median) or negative (< median); determined prognostic value of immune markers for RFS and OS for all groups and for women not systemically treated (Russian- 107, Dutch- 183 women). Results: We did not find any prognostic value of single immune markers for RFS and OS (p>0,05). However, we found that tumor relapse strongly associated with the combination of HLA class I loss (HC10 and HCA2 both negative) and HLA-E-positive expression in women not systemically treated. RFS in this immune marker combination was incredibly low: in Russian women it was 28% and 14% (5- and 10-years); in Dutch - 50% and 38% (5- and 10-years). In contrast to this data in any immune combination RFS was significant higher: in Russian women it was 68,5% and 58,1% (5- and 10-years); in Dutch - 92,3% and 85,1% (5- and 10-years), p=0,0001. Conclusions: Immune marker combination HLA class I with HLA-E plays important role for tumor relapse in breast cancer stage I.
Abstract 19288: Acute and Chronic Affects of Indoor Air Pollution on Endothelial Function
Authors: Catherine H Miele, Micaela Iantorno, Robert G Weiss, Robert H Gilman, Guelki Valdivia, Robert A Wise, Victor G Davila-Roman, William Checkley
Journal: Circulation (2015)

Objective: Pollution exposure has been linked to accelerated atherosclerosis. Endothelial dysfunction is a reversible indicator for early atherosclerosis, but it is unknown if indoor air pollution from biomass fuel cookstoves is associated with acute and chronic endothelial dysfunction. Methods: We enrolled 76 adults in Puno, Peru (3825 m above sea level); 56 from a rural community that almost exclusively use biomass fuels for cooking (biomass fuel users) and 20 from urban communities that use clean fuels for cooking (clean fuel users). We measured flow-mediated dilatation (FMD) of the brachial artery before and after cooking. We compared baseline FMD in biomass vs. clean fuel users and evaluated for acute effects of cooking by looking and changes in FMD before and after cooking with biomass vs. clean fuels Results: Mean age was 53 ± 9.1 years with 54% male. Biomass fuel users had similar age, blood pressure, and BMI but had lower LDL-cholesterol compared to clean fuel users (p&lt;0.05). Mean baseline FMD was 5.2 ± 2.3% vs. 6.3 ± 3.2% in clean vs. biomass fuel users respectively (p=0.22). Adjusting for age, sex, blood pressure, BMI, and LDL-cholesterol demonstrated no difference in baseline FMD between biomass and clean fuel users (p=0.92). Among biomass fuel users, mean FMD dropped to 3.8 ± 3.0% after one hour of biomass fuel smoke exposure from cooking (p&lt;0.001). This did not occur when FMD was repeated in clean fuel users one hour after baseline exam (FMD: 4.9 ± 2.9%, p=0.29). Conclusion: Biomass fuel smoke exposure causes acute decrease in endothelial function in this population with already abnormal function. However, we found no differences in baseline endothelial function in these two heterogeneous populations. Larger studies are needed to determine if biomass fuel exposure is associated with chronic endothelial dysfunction and if interventions aimed to decrease biomass fuel smoke exposure can improve endothelial function and thus cardiovascular mortality.
Lymphocyte-to-monocyte ratio (LMR) compared to sidedness of primary tumor to predict outcome of anti-EGFR monotherapy in metastatic colorectal cancer.
Authors: Lucjan Wyrwicz, Maciej Temnyk, Sebastrian Rybski, Mariola Winiarek, Katarzyna Kokoszyńska
Journal: Journal of Clinical Oncology (2018)

809 Background: In RAS-wild type metastatic colorectal cancer (mCRC) treatment with cetuximab or panitumumab is the standard of care. Previously, the association between overall survival (OS) and inflamatory biomarkers were reported in several studies in mCRC (NLR, LMR). According to recent observations, primary site location can predict the superior outcome of anti-EGFR agents in first line of treatment. Here we test the relationship between inflamatory biomarkers and sidedness on outcomes of anti-EGFR therapy. Methods: Total 186 consecutive patients treated with panitumumab (n = 106) or cetuximab (n = 80) in monotherapy in third or following lines of palliative treatment were identified via electronic survey of medical records of Maria Sklodowska-Curie Memorial Cancer Center, Poland. All identified patients were treated within the state reimbursment programme with pre-specified inclusion criteria (including ECOG 0-2 mCRC, failure of previous irinotecan, oxaliplatin and fluoropiridine, all RAS-wt tumors) and treatment was administered until RECIST progression. The pretreatment inflamatory biomarkers (NLR, dNLR, LMR, PLR) were obtained for all patients. Results: Median overall survival of the cohort was 31.5 months when calculated from the start of treatment, with no difference for left- and right-sided tumors (31.8 m. vs 29.5 m.; p = 0.58). In third line treatment no difference in PFS between left- and right-sided tumors were observed (p = 0.22; PFS left 4.82 m. vs PFS right 3.44 m.). No prognostic effect of either biomarker was noted on OS or time to failure of first two lines of treatment. Only a high lymphocyte-to-monocyte ratio (LMR &gt; 2.6) and low derived neutrocyte-to-lymphocyte ratio (dNLR &lt; 3.0) were associated with longer PFS on anti-EGFR treatment (5.5 m. in LMR &gt; 2.6; 2.5 m. in LMR &lt; 2.6; HR 0.53; p = 0.008). Notable, the patients with LMR &gt; 2.6 were more likely to be diagnosed with left sided tumor (p &lt; 0.001; 54% and 15% of left- and right-sided tumors respectively). Conclusions: High limfocyte-to-monocyte ratio may indicate the potential subpopulation of patients which can benefit mostly from anti-EGFR treatment in monotherapy in the refractory setting.