bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of amplification of xenobiotic detoxification pathways genes on survival in lung adenocarcinoma versus squamous cell carcinoma bases on the Cancer Genome Atlas provisional database.
Authors: Shanshal Mohamed , Tijani Lukman Aderoju , Hardwicke Fred L. , Kaleem Hassan , D'Cunha Nicholas C. , Igid Henry Palangdao , Khan Muhammad Saad , Jones Catherine , Awasthi Sanjay , Radhi Saba 
Published: September 2018

e14093 Background: Ral interacting protein (RLIP76) is a stress-responsive anti-apoptotic efflux transporter of the mercapturic acid pathway (MPy). The MPy enzymes are an essential component of the broader xenobiotic detoxification pathways (XDP) that are regulated by p53 (TP53) in response to xenobiotic/oxidative stress. Homozygous Rlip knockout (Rlip-/-) mice are resistant to benzopyrene induced adenocarcinoma and have constitutive activation of p53. The cancer-resistant phenotype of Rlip-/- mice is the diametric opposite of p53 homozygous knockout mice (p53-/-) mice, which die before the age of 24 weeks of spontaneous malignancy. Methods: Our preliminary studies show that creating Rlip deficiency through pharmacological or genetic methods caused all p53-/- mice to remain cancer-free at an unprecedented age of 32 weeks. This degree of cancer prevention has never been observed with any previous pharmacological or genetic intervention in p53-/- mice. Transcriptomic and epigenomic profiling of the cancer-free p53-/- mice revealed that the direction of change in expression of a network of Rlip-linked XDP enzymes and signaling proteins was identical to that in the cancer-resistant Rlip-/- mice. Results: We hypothesized that the activity of this Rlip-linked subset of the XDP enzymes/signaling proteins (designated XMN1) is a determinant of carcinogenic susceptibility caused by p53 loss. To examine this possibility, we queried the TCGA (The Cancer Genome Atlas) database to determine whether components of XMN1 were differentially expressed in human malignancy, and whether this was associated with overall survival. We focused on non-small cell lung cancer because of the high incidence of p53 mutations in these cancers. To our surprise, we found amplification or upregulation of XMN1 components conferred a reduced survival in lung adenocarcinoma but prolonged survival in squamous cell carcinoma. Conclusions: The mechanisms underlying this remarkable diametrically opposite effect on prognosis of are unknown and suggest opposed functions of XMN1 in Squamous verses Adenocarcinoma.
Pediatric oncology phase 1 trial efficiency in the era of targeted and biological therapies.
Authors: Cooney Tabitha , Tran Duy C , Onar-Thomas Arzu , Norris Robin Elizabeth 
Published: September 2018

e14100 Background: Prior reviews have assessed the conduct and efficiency of pediatric phase 1 trials evaluating conventional chemotherapy. Additional analyses are now needed to evaluate the conduct and design of pediatric phase 1 trials of targeted and biologic agents. Methods: A systematic review of pediatric oncology phase 1 trials published between 2000-2015 was performed. Patient characteristics, study design, and trial endpoints were evaluated. When available, the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) was compared to the adult MTD/RP2D. Results: 166 pediatric phase 1 trials meeting pre-defined selection criteria were identified. Sixty-six trials evaluated conventional chemotherapeutic agents and 100 evaluated biologic agents. Of the 4,763 enrolled patients, 1933 were female and 2487 were male (ratio 1:1.3). Race or ethnicity data was included in only 31.3% of published articles. Seventy-five percent of trials used a 3+3 dose escalation strategy. Eight percent of studies used an adaptive/Bayesian strategy and 7% used the rolling six design. Eighty-eight percent of trials cited the MTD as their primary endpoint and 10.8% of studies did not define an MTD/RP2D. The median (range) ratio of pediatric to adult RP2D for small molecule phase studies (n = 41) was 1.13 (0.45-11.9). The median (range) ratio for phase 1 studies of biologic agents (n = 6) was 1.15 (0.6-1.6). Conclusions: Consistent with prior reports, more males than females were enrolled on pediatric phase 1 studies and racial and ethnic characteristics continued to be underreported. The majority of trials used the MTD as the primary endpoint. While there was some variability based on evaluated agent, the pediatric RP2D of the small molecule and biologic agent was similar to that determined in the adult population. These results are consistent with similar evaluations of pediatric phase 1 studies of conventional chemotherapy.
Phase I/II, first in human trial of the Bruton’s tyrosine kinase inhibitor (BTKi) M7583 in patients with B cell malignancies.
Authors: Rule Simon , Tucker David , Kalapur Anup , Sarholz Barbara , Scheele Jürgen , Zinzani Pier Luigi 
Published: September 2018

e14101 Background: BTK is a cytoplasmic tyrosine kinase expressed in cells of hematopoietic origin that is involved in innate and adaptive immunity. BTK inhibition blocks B-cell functions including proliferation, antigen presentation, antibody production, and cell migration. The B-cell receptor pathway is implicated in the pathogenesis of B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and B-cell chronic lymphocytic leukemia (CLL). Small molecule BTKis are a new class of agent against B-cell malignancies; ibrutinib has recently been approved for the treatment of resistant/refractory CLL, MCL, and Waldenström’s macroglobulinemia (WM). This ongoing phase I/II clinical trial (NCT02825836) is designed to determine the safety, tolerability, PK, BTK occupancy, and preliminary antitumor activity of the highly selective BTKi M7583 in patients (pts) with refractory/resistant B cell malignancies. Methods: The trial is in two parts: a dose-escalation part for which pts with refractory/resistant B cell malignancies are eligible; and a dose-expansion part for which pts with DLBCL (ABC subtype) or MCL who have failed 1-3 prior lines of therapy are eligible. Pts in the dose-escalation part will be enrolled to sequential dose escalation, with ascending once-daily M7583 doses starting at 80 mg (3 initial days)/160 mg (full 28-day cycle) and increasing according to an adaptive Bayesian design. Results: Three pts have been enrolled to treatment with M7583 80/160 mg (Table). All 3 patients have had an objective response or stable disease and relevant clinical benefit.Conclusions: M7583 appears to have a favorable benefit:risk profile, with an efficacy signal at a dose of 80 mg (3 initial days)/160 mg (full cycle) with objective response or clinical benefit. Clinical trial information: NCT02825836. [Table: see text]
Targeting polo-like kinase 1 and TRAIL to enhance apoptosis in non-small cell lung cancer (NSCLC) cells.
Authors: Noor Alfiah , Umelo Ijeoma Adaku , Kronenberger Peter , Teugels Erik , De Greve Jacques 
Published: September 2018

e14104 Background: TNF-related apoptosis-ligand (TRAIL) can selectively induce apoptosis in cancer cells without causing damage to normal cells. However, some tumors are resistant to TRAIL monotherapy and clinical studies assessing targeted agents towards the TRAIL receptor have failed to show robust therapeutic activity. A number of studies have reported that the combination of targeted agents against the TRAIL receptor with standard systemic therapy and another targeted therapy considerably increased anti-tumor activity in experimental NSCLC models. Polo like kinase 1 (PLK1) is an emerging anti-mitotic target for NSCLC with high selectivity. Depleting PLK1 has been shown to reduce cell proliferation and induce apoptosis in NSCLC cells but not in normal cells. Both PLK1 and TRAIL-induced apoptosis pathways are important in supporting the malignant phenotype. We postulated that inhibiting PLK1 could enhance TRAIL-induced apoptosis. We therefore combined human recombinant TRAIL (rhTRAIL) and the PLK1 inhibitor RO3280, and studied the effect of combinatorial treatment on NSCLC cells. Methods: Cell growth was assessed by MTS assay and apoptotic activity by FACS and western blot analysis. The effect of combinatorial treatment on MAPK/ERK, PI3K/Akt and JAK/STAT signaling pathways that play an essential role in the survival of NSCLC cells were investigated by western blot analysis. Results: In this study, we demonstrate that the combination of a rhTRAIL with RO3280 synergistically reduces cell growth and strongly increases apoptotic activity in NSCLC cells. In response to RO3280 treatment, STAT3 activity is inhibited, possibly contributing to the sensitization of NSCLC cells to TRAIL-induced apoptosis. Blockade of STAT3 activity with a STAT3 inhibitor (stattic) and siRNA-mediated knockdown of STAT3 significantly enhances TRAIL-induced apoptosis in NSCLC cells. Conclusions: Our results suggest that this synergistic effect might occur through the inhibition of STAT3 activity which in turn may further contribute to the sensitization of the NSCLC cells to TRAIL therapy. Taken together, our results support the further exploration of PLK1 inhibitors in combination with TRAIL therapy in the treatment of NSCLC.
A novel function of SMC1 as a transporter of xenobiotics.
Authors: Yendala Rachana , Tijani Lukman , Thein Kyaw Zin , Igid Henry Palangdao , Shanshal Mohamed , Awasthi Sanjay , Hardwicke Fred L. 
Published: September 2018

e14107 Background: Structural Maintenance of Chromosome 1 (SMC1) is a component of the cohesin complex involved in the DNA-damage repair. Studies have shown that it is overexpressed in Colon Ca, Glioblastoma ,Triple-negative breast cancer (TNBC) and contributes to their characteristic drug resistance. Because of its structural homology to the ABC-membrane transporter proteins (mediate multi-drug resistance in cancer cells by catalyzing ATP-dependent efflux of many structurally unrelated amphiphilic xenobiotics) and because of its marked over-expression in tissues of knockout mice lacking the other known transporter RLIP76 (RALBP1), the present studies were directed at determining whether SMC1 was present in plasma membrane and could function as a multi-drug transporter capable of mediating multi-drug resistance. Methods: The intracellular localization of SMC1 was performed by immunocytochemistry in fixed and live H358 cells (human non small cell lung cancer cells). We demonstrated, for the first time that SMC1 can be purified to apparent homogeneity using a GS-E affinity chromatography method. Transport activity of SMC1 was tested by reconstituting purified SMC1 into artificial liposomes, later transfected into H358 and TNBC cells with confirmed SMC1 overexpression. Accumulation and efflux of amphiphilic chemo drugs were compared to control cells. Results: Immunofixation studies demonstrated no detectable immunological cross-reactivity between SMC1 and Ralbp1.SMC1 was found in the plasma membrane ,cytosol and nucleus.The uptake of Doxorubicin and Vinblastine in transfected cells was significantly lower and were two-fold resistant to DOX as compared with controls. These cells, when treated with SMC1 antibody/antisense also confirmed increased drug cytotoxicity as well as apoptosis. Conclusions: This study provides convincing evidence for the distribution of SMC1 in the plasma membrane, cytosol, and nucleus. It functions as a drug-transporter reducing intracellular accumulation of chemotherapy drugs in cancer cells.These findings indicate a dual role in defending these from apoptosis and suggest that strategies aimed at inhibiting SMC1 could be useful in reversing intrinsic or acquired drug-resistance of cancer cells.
Tracking the interplay between circulating and tumor-infiltrating T cells using AmpliSeq-based Ion Torrent TCRβ immune repertoire sequencing.
Authors: Looney Timothy , Lowman Geoffrey , Linch Elizabeth , Topacio Denise , Miller Lauren , Lin Lifeng , Pankov Aleksandr , Au-Young Janice , Andersen Mark , Mongan Ann , Hyland Fiona 
Published: September 2018

e14518 Background: TCRβ immune repertoire analysis by next-generation sequencing is emerging as a valuable tool for research studies of the tumor microenvironment and potential immune responses to future cancer immunotherapy. Here we describe a multiplex PCR-based TCRβ sequencing assay that takes advantage of the exceptionally low base-call error rate and long read capability of the Ion S5 530 chip. The S530 chip provides > 15M reads, allowing for sample sequencing in multiplex. The research assay utilizes AmpliSeq technology and Framework 1 and Constant gene targeting primers to provide comprehensive coverage of TCRβ CDR 1, 2 and 3 from RNA input with a hands-on time of less than 30 minutes. CDR region sequences reveal the antigen specificity of the receptor and may be genetically modified to increase TCR affinity for tumor antigen. Methods: We evaluated assay performance by sequencing TCRβ rearrangements from normal donor peripheral blood leukocyte (PBL) cDNA that had been spiked with 30 reference rearrangements taken from the literature. We then used our assay to evaluate the extent of clonal overlap between matched tumor infiltrating lymphocyte (TIL) and peripheral blood leukocyte repertoires in an individual with squamous cell carcinoma of lung. Results: Results from sequencing of spike-in reference rearrangements indicate that the assay is accurate and sensitive over 5 logs of input template amount while showing minimal amplification bias. Sequencing of matched PBL and TIL repertoires revealed that a subset of the PBL repertoire (8%) consisted of clones also found in TIL. Technical replicates showed high concordance (r > .96) in the frequency of detected clones, indicating that the results were reproducible and samples were sequenced to an appropriate depth. Conclusions: In summary, these data suggest that AmpliSeq-based multiplex PCR and Ion Torrent sequencing provide unbiased, reproducible, scalable, complete, and accurate information for immune repertoire research sequencing applications.
Hyponatraemia as an unrecognised risk factor in non-small cell lung cancer (NSCLC) treatment with nivolumab.
Authors: Grohe Christian , Gwynn Simon , Evans Richard 
Published: September 2018

e14526 Background: The investigation, diagnosis and management of hyponatraemia is often inadequate in cancer patients. In a retrospective analysis of 3,357 cancer patients hyponatraemia was noted in up to 47%. A strong and independent association between hyponatremia and longer length of stay with higher mortality was highlighted and associated with standard chemotherapy. No pooled data, however are available on the effect of immuno-oncology (IO) treatment options such as nivolumab on HN in lung cancer patients. Methods: Key publications and data registries concerning the incidence, evaluation and management of hyponatraemia in patients with NSCLC and treated with nivolumab were analysed. Our data show that hyponatraemia is a common side effect and around 5.2% of patients treated with nivolumab progressed from baseline to a Grade 3 / 4 adverse event. Results: The aetiology of hyponatraemia in cancer patients is complex, appearing to be a negative prognostic indicator. Existing data show that effective treatment of hyponatraemia in cancer patients may be associated with reduced mortality. In addition, the role of sodium on the cancer cell cycle requires further investigation. It has been shown in vitro that a hypotonic environment is pro-tumorigenic, whereas a slightly hypertonic environment may have a negative impact on clonogenicity in prostate cancer cells. This may suggest a more complex interaction impacting on cancer patients other than a simplistic mortality association with hyponatraemia. Nivolumab treatment is associated with HN and particular attention should be paid to the correction of symptomatic HN in these patients. Conclusions: Hyponatraemia is the most commonly occurring electrolyte disturbance in cancer patients and may represent a modifiable risk factor impacting patient survival. The clinician should be aware of the potential for IO therapies to precipitate hyponatraemia. Consideration of the correct diagnosis and management of hyponatraemia may further enhance the prognosis of NSCLC patients treated with IO agents.
Hyponatraemia as a risk factor in renal cell carcinoma treatment with nivolumab.
Authors: Grohe Christian , Gwynn Simon , Evans Richard 
Published: September 2018

e14528 Background: In the general hospital population, the incidence of hyponatraemia is reported at varying levels up to 40%. In a retrospective analysis of 3,357 cancer patients (4,702 admissions) hyponatraemia was noted in 47%. A strong and independent association between hyponatraemia and longer length of stay with higher mortality was highlighted. The investigation, diagnosis and management of hyponatraemia is often inadequate in cancer patients. This poster offers recommendations for the improved diagnosis and management of hyponatraemia patients with renal cell carcinoma treated with nivolumab. Hyponatraemia occurs in 20% of patients with renal cell carcinoma and is associated with reduced survival. Patients with hyponatraemia before treatment had a median overall survival of 5.5 months compared with 18.6 months for those with normal sodium values. Methods: Key publications concerning the incidence, evaluation and management of hyponatraemia in patients with RCC as well as unpublished data from Phase III registration studies were reviewed and the data examined to consider impacts on current oncology practice Results: Hyponatraemia is a negative prognostic indicator in cancer. Data show that effective treatment of hyponatraemia in cancer patients reduces mortality. It has been shown in vitro that a hypotonic environment is pro-tumorigenic, whereas a slightly hypertonic environment may have a negative impact on clonogenicity. This may suggest a more complex impact on outcomes in cancer patients than simply the mortality associated with hyponatraemia. The presentation of hyponatraemia in cancer patients is complex and may be caused by the direct impacts of disease, iatrogenic factors or different treatment approaches Conclusions: Hyponatraemia is the most commonly occurring electrolyte disturbance in cancer patients, potentially representing a modifiable risk factor, with resultant impact on patient survival. The clinician should be aware of the potential for Immuno-oncology agents to precipitate hyponatraemia and consider that the correct diagnosis and management of hyponatraemia may further enhance efficacy and survival.
Correlation of QNBC immune and basal signature to targeted therapies and race.
Authors: Hughley Raymond Wesley , Dean-Colomb Windy Marie , Tripathi Shweta , Davis Melissa , Yates Clayton Clopton 
Published: September 2018

e14537 Background: Triple Negative Breast Cancer has been identified as one of the most aggressive breast cancer subtypes. We previously identified a subtype of TNBC, which lacks the androgen receptor (AR), which we coined quadriple negative breast cancer (QNBC). We have shown that women with QNBC have a worse prognosis compared to those with just TNBC. Additionally, we have noted that African American (AA) women with TNBC have a greater chance of having QNBC (28%) and a higher rate of disease progression (25%) vs Caucasian Americans (CA). We also found these QNBC patients have a unique immune signature that correlates to the more aggressive basal subtype. Here, we explore individual genes and their correlation to race and immune therapies. Methods: We analyzed mRNA expression in 925 tumors from CA or AA women from The Cancer Genome Atlas. Samples were dichotomized as positive or negative using mean gene expression cutoff. Gene expression comparisons among groups were determined using standard t-tests, ANOVA, and odds ratios with a significance threshold alpha of 0.05. Therapy targets were selected from the list of significantly differentiated genes. Boxplots and heatmaps were made using R packages. Cumulative Incidence plots for time to progression were constructed using XLStats and Grays test for significance. Results: QNBC CA have higher expression of PDCD4 (p < .001), CD46 ( p < .001), CD3EAP ( p = .04) and CD84 ( p = .07) compared to QNBC AA. CD47 ( p = .63) and PD1 (p = .96) express no significant differences in race. QNBC AA show higher expression of NFKB ( p < .001), CCL2 ( p < .001), and IL12 ( p < .001) compared to QNBC CAs. Interestingly, QNBCs with high expressions of CD47 ( p = .04) have poor prognosis. Thus, QNBC patients with low expression of CD46 (p = .025), PDCD4 ( p < .001), and CD3EAP ( p < .001) have poor prognosis and overall survival. Conclusions: Current immune targeted therapies like CD47 and PD1 looks favorable for treatment in some QNBC patients. Race appears to effect other major therapy target gene expressions in the QNBC immune basal signature as well. This may imply that QNBC AA and CA have different immune response which may explain racial progression differences. Assessment of immune markers may contribute to more accurate prognosis.
Effect of BL-8040, high-affinity CXCR4 antagonist, on T-cell infiltration, tumor growth, and synergy with immunomodulatory agents.
Authors: Abraham Michal , Mishalian Inbal , Harel Yaniv , Klein Shiri , Pereg Yaron , Oberkovitz Galia , Wald Hanna , Eizenberg Orly , Bulvik Baruch , Vainstein Haras Abi , Aharon Arnon , Peled Amnon 
Published: September 2018

e14544 Background: Cancer cells affect their micro-environment by recruiting immune cells that support tumor growth, metastasis and inhibition of anti-tumor effector T and NK cell recruitment. In this study, we investigated the role of BL-8040, a CXCR4 antagonist in cancer immunotherapy and its ability to modulate the immunosuppressive tumor micro-environment. Methods: The effect of BL8040 on tumor micro-environment was tested in 3 different cancer mouse models: lung cancer, pancreatic cancer and melanoma. The mobilization of immune cells to the periphery in response to BL8040 was tested, as well as the accumulation of immune cells both within and surrounding the tumor in the pancreatic cancer mouse model. Results: BL8040 was found to be a potent and robust mobilizer of immune cells. Immunophenotyping of the mobilized cells revealed that the mobilization of CD4 and CD8 T lymphocytes, as well as of dendritic cells (DC), was significantly increased in the cancer-bearing mice compared to their naïve counterparts. Importantly, a significant mobilization of effector CD8 T cells and activated CD8 T cells in the cancer-bearing mice was also detected following BL8040 treatment. Concomitantly, in the pancreatic cancer mouse model, treatment with BL8040 increased CD8 T cell accumulation within the tumor and inhibited tumor growth. Conclusions: The immune cell population that is mobilized in response to BL8040 treatment is different in cancer mouse models and naïve mice. The ability of BL8040 to induce mobilization of leukocytes, cytotoxic and activated CD8 T cells and DCs is affected by the presence of a tumor. In our models of pancreatic cancer, mobilization of immune cells from the bone marrow into the circulation and their accumulation within the tumor and tumor microenvironment resulted in inhibition of tumor growth. These results indicate that BL8040 may affect the tumor microenvironment and therefore can potentially synergize with immunomodulatory agents. In vivo pre-clinical studies as well as clinical studies are currently ongoing for testing the combination of BL8040 with immunomodulatory agents in different cancer models.