tbuckley/cabot-search huggingface dataset:
A first-in-human dose phase 1 study of LY3009120 in advanced cancer patients.
Authors: David S. Hong, Antoine Hollebecque, Michael S. Gordon, Keith T. Flaherty, Geoffrey Shapiro, Jordi Rodon, Michael Millward, Nina Ramdas, Wei Zhang, Ling Gao, Amanda Sykes, Melinda D. Willard, Danni Yu, Andrew Schade, Daniel Lee Flynn, Michael Kaufman, Sheng-Bin Peng, Ilaria Conti, Ramon Velasquez Tiu, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2017)

2507 Background: LY3009120, a pan-Raf and dimer inhibitor, demonstrates inhibition of phospho-Mek/Erk and tumor growth inhibition in several non-clinical cancer models with BRAF, NRAS, or KRAS mutations. This is the first-in-human phase 1 study of LY3009120 in patients (pts) with advanced cancer. Methods: The safety and tolerability of LY3009120 was evaluated in pts with cancer aged 18 years or older who had an ECOG performance status ≤1, at least 1 unidimensionally measurable lesion (RECIST 1.1), and adequate organ function (NCT02014116; I6X-MC-JBDA; Eli Lilly &amp; Co.). The study sought to determine a recommended phase 2 dose using the toxicity band method and the safety, pharmacokinetic, and preliminary efficacy of LY3009120. Pharmacodynamic (PD) biomarkers, including pERK, p27 and Ki67, were evaluated in tumor tissue. The dose escalation phase evaluated dosages from 50 mg to 500 mg by mouth twice daily in pts with advanced cancers. Results: 34 pts (3 at 50 mg, 4 at 100 mg, 3 at 200 mg, 15 at 300 mg, 7 at 400 mg, and 2 at 500 mg) in dose escalation and 1 pt in dose expansion (1 at 300 mg) received at least one dose of LY3009120 by January 2, 2016 (median age = 47.4 yrs, range: 26-82 ). Most pts had a gene mutation (BRAF, n = 7; N/KRAS, n = 18); the most common cancer types included colon (n = 9), non–small cell lung cancer (n = 8), and pancreatic (n = 5). There were 6 dose-limiting toxicities in the dose escalation phase: 2 pts at 300 mg (G3 dermatitis acneiform [n = 1] and G2 blurred vision [n = 1]); 2 pts at 400 mg (G2 increased ALT with G3 hyperbilirubinemia [n = 1] and G3 increased ALT [n = 1]); 2 pts at 500 mg: (G3 arthralgia/myalgia [n = 1] and G3 stomatitis/pain [n = 1]). Based on these data, the maximum tolerated dose for LY3009120 was determined to be 300 mg twice daily. Treatment-emergent adverse events related to LY3009120 occurring in ≥10% of pts included fatigue (34%), nausea (31%), decreased appetite (20%), and dermatitis acneiform (20%) (Grade 1,2). A dose proportional increase in exposure was observed, but not at the 400 mg dose. The best response was stable disease in 5 pts. PD effect by rtPCR was not observed in tested paired tumor samples. Conclusions: LY3009120 is well tolerated at doses of 300 mg twice daily. Updated data from dose expansion will be presented in the meeting. Clinical trial information: NCT02014116.
An outbreak of non-typeable MRSA within a residential care facility
Authors: E Fanoy, W L van der Vaart, L C Helmhout, K Weijdema, M G van Santen-Verheuvel, S F Thijsen, A  J de Neeling, W J van Wamel, S H Maňásková, J L Kingma-Thijssen
Journal: Eurosurveillance (2009)

In a household setting within a residential care facility for visually and intellectually disabled people, a resident (index case) was diagnosed with dermal abscesses caused by a methicillin-resistant Staphylococcus aureus (MRSA) which was non-typeable by standard pulsed-field gel electrophoresis. In the process of 'search and destroy', all residents and staff in contact with the index case (a total of 200 people) were screened for MRSA. Five people (three personnel and two residents) carried non-typeable MRSA and were treated with antibiotics to eradicate the infection. The 'search and destroy' efforts did not result in the identification of a source. Goats and rabbits which were kept on the premises tested negative for MRSA. The condition of the index case is improving. Further restrictive measures were implemented within the facility to prevent wider spread of the MRSA. This discovery and spread within a residential care facility of a non-typeable MRSA which is often associated with livestock, is remarkable.
Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants
Authors: Brandie D. Wagner, Ana E. Babinec, Charlie Carpenter, Samantha Gonzalez, Grace O’Brien, Kara Rollock, Kayla Williamson, Peter M. Mourani, Steven H. Abman
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Quantitative single-cell analysis of target protein expression relative to human/murine tissue distribution in human xenografts for optimizing development of gene expression modulating therapeutics
Authors: Barbara Pratscher, Doris Losert, Hubert Pehamberger, Markus Mueller, Volker Wacheck
Journal: Cancer Research (2005)

3841   Human tumor xenografts are essential for preclinical “proof of concept” studies. In particular, for the development of gene expression modulating anti-cancer treatment strategies (e.g. antisense oligonucleotides, siRNA) quantitative data about the range of target protein modulation and fraction of cancer cells affected is crucial for optimization of dosing and scheduling of these compounds. So far, target regulation was mainly measured in total tissue extracts by PCR/Western blotting or by immunohistochemical staining (IHC). Whereas analysis of total tissue extracts does not provide any data of the percentage of cells affected, IHC allows only semi-quantitative analysis of the extent of target modulation and the human/murine tissue spreading in the xenograft. We therefore were interested to establish a reliable method to quantify expression of any protein of interest on single cell level relative to the human/murine tissue distribution in human melanoma xenografts. Human melanoma cells expressing GFP as selected protein of interest were inoculated subcutaneously into the left lower flank of female C.B-17 mice (6 mice/time point) . After 7, 14, 21, 28 and 35 days post inoculation excised tumors were analysed by FACS, IHC and PCR for human/murine tissue distribution and GFP expression. For FACS analysis, tumor homogenates were stained by CD146 melanoma specific antibody. IHC was performed using specific MHC class I and lectin antibodies identifying murine and human cells, respectively. Analysis of human/murine tissue distribution revealed an unexpected low number of about 34% human cells after 7 days of tumor growth, further decreasing to only 9% after 35 days. However, even much lower than in vitro, expression of GFP remained constantly in the range of 30% of human melanoma cells at all time point examined (vs. 98% in vitro). These data were reflected by IHC and PCR analysis. Intensity of GFP in individual melanoma cells diminished gradually over time. Of note, IHC analysis of excised tumors showed an inhomogeneous human/murine tissue distribution with an increasing number of murine cell layers surrounding the human melanoma cells during the course of the study. In conclusion, the FACS analyses provided a fast and quantitative method for determining on the single cell level expression of a selected protein of interest relative to human/murine tissue distribution in a human melanoma xenograft model. Alterations of human/murine tissue distribution over time did not influence the percentage of the protein of interest detected by FACS. This method of xenograft analysis seems to be well suited for pre-clinical “proof of concept” studies in order to optimize dosing, scheduling and route of administration of gene expression modulating therapeutics targeting any gene of interest.
Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases.
Authors: Grace Prince, Allison Mary Deal, Megan Jean McKee, Dimitri G. Trembath, Kevin Keith, Juanita Ramirez, Bentley Randall Midkiff, Kimberly L. Blackwell, Jose Pablo Leone, Ronald L. Hamilton, Adam Brufsky, Aki Morikawa, Edi Brogi, Andrew David Seidman, Matthew G. Ewend, Lisa A. Carey, Stergios J. Moschos, Benjamin Garrett Vincent, Carey K. Anders
Journal: Journal of Clinical Oncology (2017)

2072 Background: Brain metastases (BM) are an increasingly common consequence of breast cancer (BC). Knowledge of the microenvironment in primary BC and its impact on prognosis is evolving. A similar understanding of the microenvironment of BC metastases is lacking, particularly for the brain, where unique immune regulation governs stroma composition. Such features of the peri-tumoral landscape, i.e. high immune infiltrate and low hemorrhage, offer prognostic value in BM from melanoma. This study reports on 4 biomarkers, gliosis (glio), immune infiltrate (immune), hemorrhage (hem) and necrosis (nec), and their prognostic significance in BCBM. Methods: A biobank of 203 patients (pts) who underwent craniotomy between 1989-2013 was created across 4 sites. Glio, immune, and hem (grouped 0 v 1-3) and nec (0-2 v 3) were scored via H&amp;E stain (0-3). Overall survival (OS (years)) from craniotomy was estimated using the Kaplan-Meier method; log-rank tests compared OS. Cox proportional hazards regression was used to evaluate prognostic value of the 4 biomarkers. Results: Mean age at primary BC diagnosis was 48 years (range 26-77). BCBM subtype (n = 158) was 36% HER2+, 26% HR+/HER2-, 38% HR-/HER2- (TN). Across all samples, expression was 82% glio, 45% immune, 82% hem, and 13% nec. Subtype differences were seen for nec (higher in TN, p &lt; 0.01). Across all pts, expression of glio, immune, and hem was associated with improved OS (years): 1.08 v 0.62 (p = 0.03), 1.31 v 0.93 (p = 0.03), 1.07 v 0.92 (p = 0.1), respectively. Nec was associated with inferior OS: 0.38 v 1.12 (p = 0.01). The association with improved OS was maintained for glio in TN (p = 0.02), and immune (p = 0.001) and hem (p = 0.07) in HER2+. In a multivariable model for OS, adding the 4 biomarkers to traditional clinical variables (age, race, subtype) significantly improved the model fit (p &lt; 0.001). Conclusions: Nec is a poor prognostic finding in BCBM across all subtypes. Glio confers superior prognosis in TN, while immune and hem correlate with superior prognosis in HER2+. A deeper understanding of the rich BCBM microenvironment both refines prognostic considerations for this pt population and may lead to future investigations of targeted immunotherapies in select subtypes of BCBM.
Encouraging survival with Toca 511 and Toca FC compared to external lomustine control.
Authors: Timothy Francis Cloughesy, Manish K. Aghi, Clark Chen, J. Bradley Elder, Santosh Kesari, Steven N. Kalkanis, George Kaptain, Joseph C. Landolfi, Tom Mikkelsen, Jana Portnow, Joan M. Robbins, Derek Ostertag, Asha Das, Alice Chu, Michael A. Vogelbaum
Journal: Journal of Clinical Oncology (2016)

2030 Background: Recurrent glioblastoma (GBM) has an unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector, encodes the transgene cytosine deaminase. Toca 511 selectively infects, persists and spreads in cancer cells. Subsequent oral administration of extended-release 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, leading to robust antitumor immune responses in animal models. In 2 Phase 1 studies, Toca 511 was administered by surgical resection and injection into the cavity wall (NCT01470794) or intratumoral injection by biopsy needle (NCT01156584). To provide context to the results observed, patients were compared to an external lomustine treated control (Courtesy Denovo Biopharma; Wick 2010). Methods: Demographics, overall survival (OS) and safety profile of Toca 511/Toca FC treated subjects with GBM in 1st or 2nd recurrence were compared to the lomustine control. Results: Toca 511/Toca FC treated patients were comparable to the lomustine control. Imbalances in KPS in favor of Toca 511/Toca FC treated patients were offset by younger age, higher number of subjects at 1strecurrence and lower steroid requirement in the lomustine control. Treatment with Toca 511/Toca FC, which was pooled from 2 Phase I studies, showed significant improvement in OS HR = 0.48, p < 0.001 with similar effect in the setting of surgical resection (OS HR 0.45, p = 0.003) and nonsurgical resection with a biopsy needle (OS HR 0.56, p = 0.060). Fewer related Grade ≥ 3 adverse events (AEs) were reported for Toca 511/Toca FC (2.5%) vs. lomustine (36.9%). There was a virtual absence of hematologic toxicity for Toca 511/Toca FC vs. lomustine (Grade ≥ 3 thrombocytopenia 23.8%). Discontinuations for AEs occurred in 0% for Toca 511/Toca FC vs. 4.8% for lomustine. Toca 511 is surgically delivered and treatment-emergent AEs regardless of attribution included incision site pain (20%), procedural pain (12.5%), and wound infection (5%) vs. 0%, 1.2%, 1.2% respectively for lomustine. Conclusions: Toca 511/Toca FC significantly improved survival and safety relative to lomustine. A Phase 2/3 trial has launched (NCT02414165)
Skin reactions from gold jewelry contaminated with radon deposit
Authors: N. Simon
Journal: JAMA (1967)

GOLD JEWELRY may be contaminated sufficiently with radiation to represent a hazard to the wearer. The finding of gold rings containing decay products of radon has prompted this report. <h3>Report of Cases</h3> A professor and his wife were seen by us because of chronic skin lesions of their ring fingers and the recent finding of radioactivity in their wedding rings. In December 1940, 26 years ago, they were married in a double ring ceremony. They wore their rings constantly, and the bride noticed a rash under her ring after about a year. Subsequently a skin reaction also developed under the husband's ring. In those early years of their marriage they were living in Indiana, and the skin rashes were considered to be due to detergents which had just been available to the housewife. The itching, redness, and later blistering of the fingers finally forced both husband and wife to remove
An unusual appearance on cranial computed tomography
Authors: Rebecca Mortimer, Christopher Bano, David C Howlett
Journal: BMJ (2017)

A 65 year old woman had an in-hospital cardiac arrest after hip replacement, and had a prolonged period of hypoxia during resuscitation. Spontaneous circulation was achieved and she was transferred ventilated to intensive care. She remained unconscious and underwent cranial computed tomography (CT) (fig 1). What does the cranial CT show?



Fig 1 
Axial unenhanced computed tomography (CT) section at the level of the basal cisterns



There are changes of cerebral oedema with secondary apparent high density in basal cisterns and fissures—“pseudo-subarachnoid haemorrhage.”

### Discussion

Unenhanced CT shows generalised reduced attenuation of the brain parenchyma, with loss of grey/white matter differentiation and effacement …
The identification of novel genetic risk loci in uveal melanoma.
Authors: Tomas Kirchhoff, Esma Ucisik-Akkaya, Matjaz Vogelsang, Karan Rai, Robert Pilarski, Carlos N Martinez, Robert Ferguson, Esther Kazlow, Iman Osman, Frederick H Davidorf, Colleen M Cebulla, Mohamed Abdel-Rahman
Journal: Journal of Clinical Oncology (2016)

1543 Background: Uveal melanoma (UM) is the most common primary intraocular tumor in adult, but its etiology for the most part remains unclear. It has been suggested that the genetic susceptibility plays an important role in UM, but currently known germline mutations in BAP1 or CDKN2A, explain < 3% of UM familial risk. In general UM population the genetic risk factors are vastly unexplored. Because of previously reported association of UM and cutaneous melanoma (CM), we hypothesized that there is a shared genetic susceptibility to both phenotypes. Unlike UM, in which systematic GWAS has never been performed, the CM GWAS scans have established a portfolio of risk variants that can serve as surrogates for the discovery of novel genetic susceptibility to UM. Methods: We have tested 29 SNPs associated in previous and recent CM GWAS for their risk effect on UM. Twenty-nine SNPs were genotyped using Sequenom MassARRAY I-plex platform in 273 UM patients and 735 controls matched to cases by geographic location, gender and age. Both cases and controls were of European ancestry and ascertained at Ohio State University. Additional 1047 controls from prior multi-cancer GWAS were also included in the association analysis performed by logistic regression adjusted by age and gender. Results: We identified highly significant associations with UM risk, for multiple SNPs in HERC2/OCA2 region at 15q12, all reaching genome-wide level of significance: rs12913832 (OR = 0.5287, 95% CI 0.4151-0.6736; p = 6.576E-08), rs1129038 (OR = 0.5325, 95% CI 0.4185-0.6777; p = 9.264E-08), rs916977 (OR = 0.4647, 95% CI 0.3392-0.6365; p = 3.056E-07). Additional associations were also found for rs12203592 (OR = 1.467, 95% CI 1.182-1.822; p = 0.000656) in IRF4 locus at 6p25. Conclusions: Our study reveals novel genetic associations with UM risk, exhibiting association effects that surpass GWAS level of significance. The results also point to the genetic connection between CM and UM etiologies. Notably, the association of variants in HERC2/OCA2 region, involved in determination of eye pigmentation, suggest novel promising avenues for further molecular and genetic exploration of UM development.
Abstract P203: Nuclear PKA Compartmentation Manages Hypertrophic Responses to β-Adrenergic Signaling
Authors: Jason H Yang, Jeffrey J Saucerman
Journal: Circulation Research (2011)

Protein kinase A (PKA) directly mediates several cardiac behaviors in response to β-adrenergic stimulation. However, it remains unclear how PKA makes context-dependent decisions to select between contractile and hypertrophic β-adrenergic signaling responses. We have previously shown PKA activation by isoproterenol is spatially heterogeneous in neonatal rat cardiac myocytes, indicating subcellular β-adrenergic signaling compartmentation. We hypothesize hypertrophic β-adrenergic signaling responses are specifically regulated by nuclear compartmentation of PKA activity. We expressed spatially targeted FRET reporters for PKA activity and found PKA responses to isoproterenol to be slower and less sensitive in the nucleus than in the cytosol. To investigate mechanisms underlying these differences, we constructed a biochemically mechanistic computational model of cytosolic and nuclear PKA activity in rat cardiac myocytes. Using this model, we found that nuclear PKA dynamics are limited by diffusional transport barriers, whereas nuclear PKA sensitivity to isoproterenol is limited by protein kinase inhibitor (PKI) inhibition. Moreover, our model predicts these differences in compartmented PKA activity may help PKA select between different substrates, sensitive to the temporal characteristics of β-adrenergic stimulation. In the model, short, transient isoproterenol treatment fully phosphorylates phospholamban while CREB is only partially phosphorylated. In contrast, long, sustained isoproterenol treatment fully phosphorylates both phospholamban and CREB. To test the model prediction that compartmented PKA can regulate different cardiac behaviors, we over-expressed PKA targeted to the cytosol and nucleus. Myocytes over-expressing PKA in the nucleus were 24.8% larger than control (n = 908 cells, p = 0.0002), while myocytes over-expressing PKA in the cytosol were the same size as control cells (n = 987 cells, p = 0.9971). Together, these results highlight an important role for nuclear PKA compartmentation in selecting hypertrophic responses to β-adrenergic stimulation.
Prospero‐related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating interleukin‐8 expression
Authors: Yanfeng Liu, Yonglong Zhang, Shenghao Wang, Qiong‐Zhu Dong, Zhongliang Shen, Wei Wang, Shuai Tao, Chenjian Gu, Jing Liu, Youhua Xie, Lun‐Xiu Qin
Journal: Hepatology (2017)

Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero‐related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin‐specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin‐8 ( IL‐8 ) by epigenetically stimulating the IL‐8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti‐IL‐8 monoclonal antibody. Conclusions : We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti‐IL‐8 antibody in high PROX1 expression HCC patients. (H epatology 2017;66:1894–1909)
Irreversible panHER tyrosine kinase inhibitors (TKIs) to induce irreversible senescence in HER2 positive breast cancer cells.
Authors: Martina McDermott, Brigid Browne, Adam Szabo, John Crown, Norma O'Donovan
Journal: Journal of Clinical Oncology (2016)

e12092 Background: We have previously reported that lapatinib (L) induces reversible senescence in HCC1419 HER2 positive breast cancer cells (McDermott et al, ASCO 2011). In this study we examined induction of senescence in a panel of HER2 positive breast cancer cell lines and compared L, a reversible TKI, with the irreversible panHER TKIs neratinib (N) and afatinib (A). Methods: Five HER2 positive breast cancer cell lines were treated with L for up to 4 weeks and senescence-associated β-galactosidase (SA-β-gal) activity was measured by staining for β-gal at pH 6.0. HCC1419 cells were also tested with N and A, and combined treatment with L and trastuzumab (T) was tested in HCC1419 and SKBR3 cells. The ability of HCC1419 TKI-treated cells to exit senescence was assessed by treating the cells for 1 week with L, N and A followed by TKI withdrawal for up to 2 weeks and staining for SA-β-gal activity. Senescence-associated biomarkers were measured in L-treated HCC1419 cells by real-time qRT-PCR with primers for p15, p16, p21, p27 and GAPDH. Inhibitors of PI3K/Akt (LY294002) and MAPK (U0126) were also tested for induction of SA-β-gal activity. Results: In the 5 HER2 positive cell lines treated with L for up to 4 weeks we found increased SA-β-gal activity, suggesting induction of senescence. L-induced senescence was associated with elevated levels of p15 and p27, with no change in p16 or p21. Similar to L, both N and A treatment induced SA-β-gal activity in HCC1419 cells. L-induced senescence was reversed following L removal, whereas N- and A-induced senescence was not reversed following TKI removal for 2 weeks. SA-β-gal activity was not induced by T alone and addition of T to L did not alter L-induced senescence in HCC1419 or SKBR3 cells. LY294002 and U0126 as single agents and in combination induced senescence in HCC1419 cells, suggesting that inhibition of PI3K/Akt or MAPK signaling is sufficient to induce senescence. Conclusions: Therapy-induced senescence represents a novel mechanism of action of HER targeting TKIs. While L-induced senescence is reversible, the irreversible TKIs, N and A, cause irreversible senescence and thus may provide more long-term benefit for patients with HER2 positive breast cancer.