tbuckley/cabot-search huggingface dataset:
Abstract P3-06-02: Imprint of parity and age at first pregnancy on the genomic landscape of subsequent breast cancer
Authors: B Nguyen, D Venet, M Lambertini, C Desmedt, R Salgado, HM Horlings, F Rothe, C Sotiriou
Journal: Cancer Research (2019)

Abstract Background: Although parity and age at first pregnancy are among the most known extrinsic factors that modulates breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. In this study, we investigated the imprint of parity and age at first pregnancy on the pattern of somatic mutations, somatic copy number alterations (SCNAs), transcriptomic profiles, and tumor immune microenvironment by assessing infiltrating lymphocytes (TILs) levels of subsequent breast cancer. Methods: A total of 313 patients with primary breast cancer with available whole genome, RNA sequencing and TILs data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first pregnancy as a cut-off value. PABC was defined as patients diagnosed up to 10 years postpartum. Results: Genomic alterations of breast cancer were associated with age at first pregnancy but not with parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7%; Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; Padj = 0.010), MYC amplification (28% vs. 7%; Padj = 0.008), and a lower prevalence of mutational signature 2, putatively associated with APOBEC activity. PABC were associated with increased TILs infiltration (Padj = 0.0495). Conclusions: These findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. This work advocates that reproductive history should be routinely collected in future large scale genomic studies addressing the biology of female cancers. Citation Format: Nguyen B, Venet D, Lambertini M, Desmedt C, Salgado R, Horlings HM, Rothe F, Sotiriou C. Imprint of parity and age at first pregnancy on the genomic landscape of subsequent breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-02.
Abstract P6-05-04: NEAT1 enhances drug sensitivity by inhibiting cancer stem-like cells in triple-negative breast cancer
Authors: A Kwong, J Chen, J Siu, I Chuek, V Shin
Journal: Cancer Research (2019)

Abstract Background: Accumulating evidence showed that long non-coding RNAs (lncRNAs) dysregulation is the hallmark of cancer. Nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to overexpress in many cancers, and promote cell growth and disease progression. However, the role of NEAT1 on drug sensitivity and stem-cell like property in triple-negative breast cancer is largely unknown. Methods: LncRNA expression profile were compared between breast cancer patients and healthy individuals using lncRNA array. Large scale validation of NEAT1 expression in blood samples were performed by real-time PCR. Triple-negative breast cancer (TNBC) cells, MDA-MB-231 and its cisplatin resistance subline (MDA-MB-231/cis) were used. Stable transfection of cells with NEAT1 knockdown by shRNA, and evaluated single cell clonogenic assay, aldehyde dehydrogenase (ALDH) activity, CD44+/CD24- and other cancer stem cell (CSC) markers. Drug sensitivity assay, flow cytometry analysis, immunofluorescence staining and xenograft model were used to assess the functional role of NEAT1. Results: Array data showed that NEAT1 was the top upregulated lncRNAs in the plasma of breast cancer patients. Consistent with the array data, validation of larger cohort of patients and healthy individuals (n=369) also demonstrated a higher expression of NEAT1 in breast cancer patients, in particular TNBC subtype. Knockdown of NEAT1 by shRNA sensitized breast cancer cells to cisplatin and taxol treatment. Cell proliferation and colony formation abilities were reduced with S-phase cell cycle arrest in shNEAT1 cells. Flow cytometry analysis revealed an induction of apoptosis with increased cleaved caspase-3. Cells expressing shNEAT1 abrogated ALDH activity, CD44+/CD24- subpopulation and expression of CSC markers (SOX2, NANOG and OCT4). More importantly, shNEAT1 cells retarded tumor growth in xenograft mice model and reduced CSC markers. Conclusion: Taken together, NEAT1 expression is differentially expressed in breast cancer patients, and particularly higher in patients with TNBC. These findings suggest a potent therapeutic target to improve drug sensitivity in patients with TNBC. Citation Format: Kwong A, Chen J, Siu J, Chuek I, Shin V. NEAT1 enhances drug sensitivity by inhibiting cancer stem-like cells in triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-04.
Abstract P1-06-01: Regulation of BRCA1 by SIRT2
Authors: EV Minten, H Zhang, C Li, PE Head, DS Yu
Journal: Cancer Research (2019)

Abstract We are constantly exposed to a variety of both external and internal DNA damaging agents, such as UV light from the sun and reactive oxygen species created as by-products of aerobic respiration. As a result, our DNA accumulates thousands of instances of damage per cell per day. DNA damage response (DDR) pathways, which include DNA repair and cell-cycle checkpoints, are responsible for the repair of DNA damage and are critical for protecting against mutagenesis and maintaining genome integrity. DNA double-stranded breaks (DSBs) are the most deleterious type of DNA damage and are repaired by one of two pathways: Non-homologous end-joining (NHEJ), an error-prone mechanism of repair active throughout the entire cell cycle, or homologous recombination (HR), considered to be an 'error-free' method for DSB repair that occurs in the S and G2 phases of the cell cycle. Deficiencies in NHEJ or HR can result in genomic instability via genomic incorporation of chromosomal aberrations, which can ultimately lead to an increased risk of cancer. However, in many cases, the mechanisms by which defects in these pathways lead to an increased risk of developing cancer is unknown, making preventative care and treatment of resulting cancers more difficult. Breast Cancer 1 (BRCA1), an established tumor suppressor, is a protein necessary for the proper repair of DNA DSBs through the HR pathway. Defects in BRCA1, whether genetically inherited or spontaneously developed, have been linked to different types of cancer in both men and women, including breast, ovarian, and pancreatic cancer. Yet, the regulation of BRCA1 in HR is not well understood and thus highlights a major a gap in our understanding of how deficiencies in HR contribute to the development of cancer. Our lab has discovered that SIRT2, a class III NAD+ dependent histone deacetylase and putative human tumor suppressor, plays a crucial role in the DDR and repair of DNA DSBs. We have shown that depletion of SIRT2 impairs HR and increases cell sensitivity to ionizing radiation in a deacetylase-dependent manner. A mass spectrometry analysis showed SIRT2 interacts with several proteins involved in DDR, including BRCA1. We validated the interaction between SIRT2 and BRCA1 and found SIRT2 deacetylates BRCA1 both in vitro and in cells. Depletion of SIRT2 and subsequent deacetylation of BRCA1 decreases BRCA1 protein levels in cells, impairing HR. Our results show SIRT2 is a novel regulator of BRCA1 and is critical for the repair of DNA DSBs through HR. These findings provide invaluable insights into how to exploit the interplay between SIRT2 and BRCA1 as a novel therapeutic approach for the prevention and treatment of cancer. Citation Format: Minten EV, Zhang H, Li C, Head PE, Yu DS. Regulation of BRCA1 by SIRT2 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-01.
Long-term tapering versus standard prednisolone therapy for the treatment of the initial episode of childhood nephrotic syndrome: national multicentre double-blind phase III randomised controlled trial and economic evaluation
Authors: Nicholas J. A. Webb, Rebecca Woolley, Tosin Lambe, Emma Frew, Elizabeth Brettell, Emma Barsoum, Richard S. Trompeter, Carole Cummins, Jonathan Deeks, Keith Wheatley, Natalie Ives
Journal: BMJ (2019)
How are medical schools widening participation in medicine?
Authors: Flavia Munn
Journal: BMJ (2017)

When Shaun Hang started medical school, the only academic difference between him and his peers was on paper. His A level grades were slightly lower than most of his cohort—but his ability was not. The son of two takeaway chefs, Hang is the first in his family to go to university. He entered medicine via Birmingham University’s Routes to the Professions (R2P) programme. The course is one of the UK’s widening participation initiatives, which help students from less privileged backgrounds into medicine by providing mentoring, support with applications, and “contextual” lower grade offers that take into account applicants’ socioeconomic backgrounds. Contextual factors can include criteria such as whether the applicant comes from a neighbourhood with a low rate of participation in higher education, whether their parents went to university, and whether the applicant has access to extracurricular activities.

Now in his second year, Hang says, “People wouldn’t know [my route into medicine] unless they asked me about my grades, because I got three As and the grade boundary was A* AA.”

“But once I got here and started studying, the difference narrowed, and I don’t feel I am struggling in comparison.”

The R2P course helped Hang gain work experience in a pharmacy and guaranteed him a medical school interview at Birmingham, provided he achieved ABBB grades at AS level.

The need to improve diversity 

Despite schemes such as R2P, a 2016 government report on the state of social mobility in the UK found that medicine still “remains one of the most inaccessible professions.”1

In 2014, the Medical …
Dr Putin or how I learnt to stop whining and love the NHS
Authors: Joseph O’Keeffe
Journal: BMJ (2016)

Before medical school, I studied Russian at university. After a year of lectures on obscure grammatical points, I was dispatched to an industrial town north of Moscow to study at the local university. Two months into the course, I fell ill. A couple of days’ rest and I’d be fine, I thought. How wrong I was.

A week later, I felt more feverish, my throat was achingly swollen. I needed to see a doctor. Russia has two health systems: a state funded system and a variety of private insurance schemes. My Russian professor suggested I see a doctor privately, but I insisted on going to the local poliklinika, which is similar to a general practitioner walk-in clinic in the United Kingdom. During my three hour stay in the packed waiting room, I noticed that several of the windows were smashed, with bin bags taped over to keep out the −20oC temperatures. To add insult, quite literally, to injury, the outpatient orthopaedic clinic was up three flights of stairs with no lift. The experience left me feeling like a character …
Abstract P2-02-01: Inhibition of creatine kinase metabolism represses invasion and sensitizes estrogen-receptor negative breast cancer cells to standard chemotherapies
Authors: HP Barch, R Krutilina, DL Brooks, D Parke, TN Seagroves
Journal: Cancer Research (2019)

Abstract Dysregulated tumor cell metabolism is a hallmark of cancer progression and therapeutic resistance. In a screen for Hypoxia-Inducible Factor (HIF)-dependent genes regulating metabolism, we identified creatine kinase, brain isoform (CKB) as down-regulated in HIF-1 knockout mammary tumor cells. CKB is a member of a family of cytosolic and mitochondrial creatine kinases (CKs) that reversibly catalyze the transfer of a high-energy phosphoryl group from ATP to creatine, generating local stores of phosphocreatine in the forward reaction, and re-generating ATP in the reverse reaction. Creatine kinases are up-regulated in a variety of solid tumors, including breast cancers. CK activity is inhibited by cyclocreatine (cCr), a creatine kinase substrate that represses the CK-dependent generation of ATP from phosphocreatine &amp;gt;170-fold. Knockdown of CKB in tumor cells derived from the polyoma middle T (PyMT) transgenic model of metastatic breast cancer did not impair cell proliferation or wound healing, but potently suppressed invasion in vitro, suggesting utility for treating stage IV disease. When female FVB/Nj mice were injected with wild type PyMT cells in a tail vein assay and then treated with cCr, lung metastasis was repressed to the same extent as CKB gene knockdown. These data were validated using a variety of human estrogen receptor (ER)-negative breast cancer cell lines. CKB loss- and gain-of-function models were created and effects on cell proliferation, survival, wound healing and ATP production were compared to cCr treatment. Overall, whereas deletion of CKB had no effect on cell proliferation or survival in either adherent or suspension conditions, either deletion of CKB or cCr therapy potently reduced intracellular ATP levels, which was associated with reduced invasive potential. In contrast, over-expression of CKB enhanced chemotaxis to EGF and invasion towards serum. Whereas cCr monotherapy is generally cytostatic, combination with either doxorubicin or paclitaxel is synergistic to kill tumor cells. Together, these data suggest that inhibition of CK activity may be effective in treating stage IV breast cancer patients with established metastatic disease. We are currently exploring the cell signaling and cell survival pathways that are altered by CKB gene deletion or cCr treatment to understand how the creatine kinase arm of metabolism promotes tumor progression, metastasis and response to conventional chemotherapies. Citation Format: Barch HP, Krutilina R, Brooks DL, Parke D, Seagroves TN. Inhibition of creatine kinase metabolism represses invasion and sensitizes estrogen-receptor negative breast cancer cells to standard chemotherapies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-01.
Abstract LB-203: Phase I/II study of the androgen receptor antagonist MDV3100 in castration-resistant prostate cancer
Authors: Howard I. Scher, Thomasz Beer, Celestia S Higano, Daniel C Danila, Julia Shelkey, Mohammed Hirmand, David Hung, Michael J Morris, Steve M Larson, Charles L Sawyers
Journal: Cancer Research (2008)

Abstract Introduction: Overexpression of the androgen receptor (AR) is believed to contribute to the progression of CRPC. MDV3100 is a small molecule AR antagonist with a novel mechanism of action that blocks nuclear translocation of AR, DNA binding, and has no agonist activity when AR is overexpressed. MDV3100 has been shown to be effective in preclinical models of CRPC. In July 2007, a multi-center first-in-man Phase 1-2 trial was initiated to determine safety, pharmacokinetics (PK), and antitumor activity including effects on prostate-specific antigen (PSA), bone and soft tissue metastases, and in selected pts fluorodeoxyglucose (FDG) and fluorodihydrotestosterone (FDHT) uptake by positron emission tomography (PET). Methods: Pts were administered MDV3100 orally, once daily, starting at 30 mg with sequential escalations in cohorts of 3 pts. Enrollment was expanded at 60 mg and above to include up to 12 chemotherapy-naïve and 12 post-chemotherapy pts, once the safety of a dose was established. PK parameters for the dose-escalation cohorts were estimated using a 2-compartment model. Results: 85 pts have been enrolled to date on doses up to 240 mg. 21 pts at 60 mg, and 22 pts at 150 mg have been followed for 12+ and 8+ weeks respectively. MDV3100 has been well-tolerated without dose-limiting toxicity. PK were dose-linear with a half-life of approximately one week. At doses of 30, 60, 150, and 240 mg, geometric mean steady state Cmax values were 2.8, 6.1, 17.3, and 23.7 µg/mL and AUC24hr were 61, 120, 361, and 480 µg*hr/mL, respectively. Effective AR blockade by MDV3100 has been shown by PSA declines and by PET findings. Evaluation at the 12 week timepoint for 21 pts at 60 mg showed 9 pts (43%) had &amp;gt;50% decline in PSA from baseline. To date, 8 pts have had FDG and FDHT PET at baseline of whom 4 have had 1 or more follow-up scans. All 8 had abnormal FDHT accumulation at baseline while 4 of 4 with follow-up scans had no FDHT accumulation. Conclusions: MDV3100 is a novel AR antagonist in clinical investigation. The observed PSA declines are consistent with the inhibition of AR signaling. The inhibition of FDHT accumulation demonstrates receptor blockade in vivo. MDV3100 has been well-tolerated to date and appears to be a promising candidate for the treatment of CRPC. Pt follow-up and dose escalation are continuing. The analysis of the association between PSA declines and clinical outcomes is ongoing and will be reported at a future date.
TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer
Authors: Jitka Fucikova, Jana Rakova, Michal Hensler, Lenka Kasikova, Lucie Belicova, Kamila Hladikova, Iva Truxova, Petr Skapa, Jan Laco, Ladislav Pecen, Ivan Praznovec, Michael J. Halaska, Tomas Brtnicky, Roman Kodet, Anna Fialova, Josephine Pineau, Alain Gey, Eric Tartour, Ales Ryska, Lorenzo Galluzzi, Radek Spisek
Journal: Clinical Cancer Research (2019)

In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial.We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ dendritic cells as well as by PD-1+, CTLA4+, LAG-3+, and TIM-3+ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach.High levels of PD-L1 and high densities of PD-1+ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust TH1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1+TIM-3+CD8+ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3+ cells improved patient stratification based on the intratumoral abundance of CD8+ T cells, the amount of PD-1+ cells failed to do so.Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.
Abstract LB-202: Phase 1 dose escalation trial of the novel vascular disrupting agent NPI-2358
Authors: Monica Mita, Matthew A Spear, Lorrin K Yee, K P Papadopoulos, Elisabeth Heath, Ofelia Romero, G Kenneth Lloyd, Gillian Cropp, Alain Mita, Patricia LoRusso
Journal: Cancer Research (2008)

Abstract Background: NPI-2358 is a novel vascular disrupting agent that inhibits tubulin polymerization leading to tumor vascular endothelial destabilization. NPI-2358 selectively induces tumor vascular collapse resulting in tumor regression and potentiates other oncology agents in preclinical tumor models. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity. Methods: In this study the dose of NPI-2358 was escalated from 2 to 30 mg/m2 in patients with advanced solid tumors and lymphomas. Patients were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. The study utilized a dynamic accelerated dose titration (DADT) design in which the dose of NPI-2358 was escalated in cohorts, in which any cohort could consist of 1 patient provided no ≥Grade 2 adverse event is reported in the prior cohort, otherwise the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO, and PK were obtained on day 1 and day 15. DCE-MRI were performed at baseline, day 2 then every other cycle and end of study as feasible, to assess changes in tumor blood flow and vascular permeability as reflected in the volume transfer constant (Ktrans). An improved two-compartment model is utilized which incorporates motion correction and an automated arterial input function. This is expected to improve the accuracy and reproducibility in the estimation of Ktrans by eliminating variability associated with subject motion, contrast injection, and cardiac output. Results: Twenty-five subjects were enrolled in the dose escalation phase. We selected 30 mg/m2 as the RP2D, based on adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient elevations in blood pressure. DCE-MRI demonstrated decreases in Ktrans beginning at 13.5 mg/m2, and a 16-82% decrease in patients evaluated at 30 mg/m2. Decreasing Ktrans over multiple treatment cycles was seen in the two patients that underwent repeat DCE-MRI imaging. Five patients had stable disease for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles), anal squamous cell carcinoma (3 cycles), adrenalcortical carcinoma (2 cycles), and melanoma (2 cycles). Average Cmax and AUCtotal have increased from 34 to 610 ng/ml, and from 101 to 3998 ng/ml/hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.8 ±3.2 h, CL was 34.1 ±26 L/h, and Vss was 211±61 L.Conclusions: At the RP2D NPI-2358 produced tolerable toxicities, while eliciting decreases in tumor blood flow by DCE-MRI. Maximum effect on Ktrans appeared to increase with increasing dose and time on treatment. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently proceeding into Phase Ib/II trials in solid tumor malignancies.