tbuckley/cabot-search huggingface dataset:
A multi-institution phase I trial of ruxolitinib in chronic myelomonocytic leukemia (CMML).
Authors: Eric Padron, Amy Elizabeth Dezern, Kris Vaddi, Peggy A Scherle, Qing Zhang, Yan Ma, Maria Balasis, Sara Tinsley, Hanadi Ramadan, Casandra Zimmerman, David P. Steensma, Gail J. Roboz, Jeffrey E. Lancet, Alan F. List, Mikkael A. Sekeres, Rami S. Komrokji
Journal: Journal of Clinical Oncology (2015)

7021 Background: CMML is a lethal myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by peripheral monocytosis and bone marrow (BM) dysplasia with limited therapeutic options. Preclinical studies have identified the JAK2 inhibitors as therapeutic candidates. We conducted the first phase 1 clinical trial exploring the safety and efficacy of ruxolitinib, an FDA approved JAK1/2 inhibitor, in patients with CMML. Methods: All CMML WHO subtypes were included without regard to previous therapy. Key exclusion criteria included an ANC < 0.25x103 c/dL and a platelet count < 35x103c/dL. The use of GM-CSF analogs was prohibited. Four cohorts were enrolled using a “rolling six” study design, with doses ranging from 5mg BID to 20mg BID in 5mg dose escalations. Descriptive statistics were used to report baseline characteristics and response rates. The study was registered at clinicaltrials.gov NCT01776723 Results: Between March 2013 and January 2015, 19 patients (pts) were enrolled and treated with ruxolitinib. The Median age was 71 years and all pts had CMML-1. MPN-CMML by FAB criteria constituted 67% of pts and 47% had higher-risk disease by the Global MD Anderson Scoring System. Eleven pts (58%) received prior therapy and 8 pts (42%) received a prior hypomethylating agent. No dose limiting toxicities for ruxolitinib were identified. One subject had Grade (G)3 thrombocytopenia with no other drug-associated G3 or G4 adverse events. The mean duration of therapy was 122 days (range, 28-409 days). Of 15 pts evaluable for response, 3 had hematologic improvement and one pt had a partial response per 2006 IWG criteria. Six of 9 pts with splenomegaly had a > 50% reduction in spleen size. Fourteen of 15 pts with reported B-symptoms had clinically meaningful or complete resolution on ruxolitinib. There was no change in allelic burden of somatic mutations in responders; broad spectrum cytokine profiling will be available at the time of presentation. Conclusions: The recommended phase 2 dose of ruxolitinib is 20mg BID. We demonstrate that ruxolitinib has promising activity in CMML with particular benefit in those with disease related B-symptoms. A phase 2 study is planned to further test the efficacy of ruxolitinib in CMML. Clinical trial information: NCT01776723.
Abstract 1536: In silico discovery of target genes and pathways associated with breast cancer brain and bone metastases
Authors: Su-Ni Tang, Peixin Jiang, Xinli Liu
Journal: Cancer Research (2016)

Abstract Metastasis is the primary cause of death from breast cancer. Bone and brain are the most frequent sites for breast cancer metastasis. The aim of this study was to explore candidate genes associated with breast cancer bone and brain metastases. We compared the gene expression profiles of bone and brain metastases with primary tumors by compiling 55 microarray data sets from Gene Expression Omnibus (GEO: GSE12763, primary tumor n = 30; GSE14017, bone metastasis n = 10, brain metastasis n = 15). A total of 160 differentially expressed genes were screened with a two-fold change, among which 109 genes were up-regulated and 51 genes were down-regulated in bone metastasis. Pathway analysis showed these differentially expressed genes were significantly related to bone development and cell adhesion (p&amp;lt;0.01). Similarly, a total of 150 differentially expressed genes were identified in brain metastasis, 36 genes were up-regulated and 114 genes were down-regulated, which were enriched in immune response (p&amp;lt;0.01). Moreover, protein-protein interaction analysis revealed highly connected hub genes that are expected to play an important role in brain and bone metastases. These hub genes were FOS, EGR1, CTNNB1, DCUN1D1, HIST1H4E, VIM, UBD, EGFR in bone metastasis, and HIST1H4E, DCUN1D1, CDC42, ESR1 in brain metastasis. Interestingly, two genes, DCUN1D1 and HIST1H4E were both up-regulated in bone and brain metastases. It is known that DCUN1D1 could induce extracellular matrix invasion while HIST1H4E played a critical role in regulating chromosomal accessibility and stability. These findings reveal potential biomarkers and therapeutic targets of breast cancer bone and brain metastases, which provide a molecular basis for our future in vitro and in vivo studies. Citation Format: Su-Ni Tang, Peixin Jiang, Xinli Liu. In silico discovery of target genes and pathways associated with breast cancer brain and bone metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1536.
Oncogenic B-RafV600E up-regulates the mitotic checkpoint kinase Mps1 in human melanoma cells
Authors: Cui Yongping, Thomas Guadagno
Journal: Cancer Research (2007)

5213  B-Raf is mutated in approximately 70% of human cutaneous melanomas. The most frequent mutation in B-Raf is a glutamic acid for valine substitution at residue 600 (V600E), which produces a constitutively active kinase that is oncogenic through its ability to promote constant activation of ERK. Currently, the mechanisms through which B-RafV600E mediates melanoma development are poorly understood. Preliminary studies in our laboratory indicate that the status of the B-RafV600E mutation in melanoma cell lines correlates with high levels of the mitotic checkpoint kinase Mps1. Therefore, we asked whether B-RafV600E expression was directly responsible for regulating Mps1 levels in melanoma cells. Transient expression of the B-RafV600E mutant, but not the wild type B-Raf, led to increased levels of Mps1 protein (3-4 fold) and kinase activity (6-8 fold). Real-time PCR experiments showed that B-RafV600E expression did not change hMps1 mRNA levels indicating that B-RafV600E signaling regulates hMps1 at the posttranscriptional level. Co-immunoprecipitation assays showed that B-Raf associates with hMps1 in human melanoma cells. Consistent with these results, phospho-B-Raf(Thr599/Ser602) staining co-localized with Mps1 at the kinetochores in metaphase cells. We then examined whether B-RafV600E signaling regulated Mps1 protein stability by performing time-course experiments with cycloheximide treatment to shut off protein synthesis. The results from these experiments showed that expression of the B-RafV600E mutant led to a substantial stabilization of Mps1 protein. Specifically, the half-life of Mps1 protein was prolonged to 12 hrs. in melanoma cells that expressed the B-RafV600E mutant compared to 1.5 hrs for control cells with wild type B-Raf. The stabilization of Mps1 protein was further supported by immunofluorescence studies that showed elevated Mps1 staining in interphase and mitotic cells. In summary, our work demonstrates a link between oncogenic B-RafV600E and the mitotic checkpoint kinase Mps1. Since the checkpoint function of Mps1 is sensitive to its dosage, we propose that higher hMps1 activity in melanoma cells carrying the B-RafV600E mutation may promote spindle checkpoint errors and contribute to chromosome instability- a hallmark in many cancers.
Abstract 5115: Pre-clinical development of next generation inhibitors of the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase as cancer immunotherapies
Authors: Alan Wise, Barry E. McGuinness, Sarah C. Trewick, Thomas J. Brown, Phillip M. Cowley
Journal: Cancer Research (2016)

Abstract The enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO1) catalyse oxidation of the essential amino acid tryptophan (Trp) leading to the formation of immunosuppressive kynurenine (Kyn) pathway metabolites that dampen the immune response in the tumor microenvironment. Both IDO1 and TDO have been shown to be up-regulated in a variety of cancers and blockade of their activity has been shown to stimulate the anti-tumour immune response in pre-clinical animal models. We have discovered and optimized multiple novel chemical series of both highly selective and dual-acting inhibitors of IDO1 and TDO. We describe the characterization of molecules that we are progressing into the clinic. We have characterized the IDO1 and TDO-selective inhibitors and dual-acting inhibitors which demonstrate nM potencies. In IFNγ-stimulated A172 glioblastoma cells expressing both enzymes, the dual-acting molecules fully inhibit Kyn production, whilst selective inhibitors yield only a partial response, demonstrating the utility of dual enzyme blockade in cancer cells. The compounds also relieve inhibition of T-cell proliferation in cancer cell conditioned media/T-cell co-culture assays and demonstrate highly favourable physico-chemical and pharmacokinetic properties. These properties translate to superior PK/PD effects following oral dosing in rodents with profound and sustained modulation of plasma Kyn levels, combined with an exceptional safety profile. In a mouse model of LPS-induced IDO1 activation, our IDO1 inhibitors fully ablate elevation of Kyn in both plasma and lung in a dose-dependent manner. Following oral administration, the IOmet IDO1 inhibitors provide excellent single-agent tumor growth control in PAN02 pancreatic adenocarcinoma syngeneic models. In addition, combining IOmet IDO1 inhibitors with standard-of-care chemotherapy (gemcitabine/abraxane) in the PAN02 model completely inhibits tumor growth. In summary, we describe the characterization of novel potent, selective and dual-acting IDO1 and TDO inhibitors. These candidate molecules demonstrate excellent rodent in vivo PK/PD, safety and anti-tumor profiles, supporting their progression into the clinic. Citation Format: Alan Wise, Barry E. McGuinness, Sarah C. Trewick, Thomas J. Brown, Phillip M. Cowley. Pre-clinical development of next generation inhibitors of the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase as cancer immunotherapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5115.
A Novel Therapy of Clofarabine in Combination with Etoposide and Cyclophosphamide Shows Activity in Pediatric Patients with Refractory or Relapsed Acute Leukemia.
Authors: Nobuko Hijiya, Paul Gaynon, Manuel Fernandez, Michael Rytting, Roland Chu, Elly Barry, Blythe Thomson, Todd Cooper, Richard Kadota, Stanley Chaleff, Peter Steinherz, Rekha Abichandani, William Carroll
Journal: Blood (2007)
Corticosteroids as an adjunct to propranolol for infantile haemangiomas complicated by recalcitrant ulceration
Authors: E. Lie, K.B. Püttgen
Journal: British Journal of Dermatology (2016)

A small subset of patients with infantile haemangiomas (IHs) can present with serious complications, the most common of which is ulceration. Ulcerated IHs can be extremely painful and always result in scarring. Numerous studies support the efficacy and reduced side-effects of propranolol relative to systemic corticosteroids, which led to the adoption of propranolol as the mainstay of IH treatment. However, in certain cases of IH with complex ulceration, propranolol monotherapy may not be sufficient. In this case report, we present two cases that illustrate the effectiveness of the adjunctive use of oral corticosteroids for the treatment of select IHs with recalcitrant painful ulceration, which were refractory to conservative wound care, laser therapy and oral propranolol. We suggest a continuing niche role for the brief use of corticosteroids as an effective adjunct to oral propranolol in managing a subset of complex IHs complicated by intractable ulceration.
Impact of race/ethnicity and health insurance status on quality of care for cancer.
Authors: K. Copley-Merriman, G. Peltz, G. Pohl, E. Liu, J. A. Kaye
Journal: Journal of Clinical Oncology (2010)

e16540 Background: Quality of care for cancer could be impacted by a variety of factors. The objective of this study was to identify aspects of the impact of race/ethnicity and health insurance status on the quality of care for cancer patients. Methods: A systematic literature review regarding perceptions of the quality of cancer care in the United States was conducted in PubMed, EMBASE, and Cochrane Reviews for the last 10 years, English-only articles. Oncology medical subject heading (MESH) terms were cross-matched with quality of care MESH terms to obtain 875 abstracts. Of these, 140 publications were selected for full-article review based on defined inclusion/exclusion criteria. Results: Most of the articles on race/ethnicity (n = 6) were for breast cancer. Several papers found that, after controlling for age and status of disease, black patients had significantly different care from white patients. Black women are more likely than white women to have delays in administration of chemotherapy, reductions in doses, and premature discontinuations of therapy. Black patients also significantly differed from whites on their health insurance, hospital, and physician characteristics and these factors were associated with the patterns of care. Black patients were more likely than white patients to have either Medicaid or no insurance. Among various races, black women were the least likely to perceive their care as excellent, and being black was significantly and negatively associated with patient perception of excellent quality care (adjusted relative risk = 0.47; 95% CI = 0.21-0.88) in a multivariate model (Franco et al., 2009). Similar findings were reported in Asian/Pacific Islander patients and Hispanic patients in a study examining patient perceptions of quality of care by race, ethnicity, and language. Conclusions: Economic barriers faced by minorities could impact the quality of cancer care, including lower incomes, lack of work flexibility to make appointments, and less health insurance to pay for treatments. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly
Abstract 397: Brain natriuretic peptide (BNP) as molecular marker for bladder, ovarian, and glioblastoma cancers
Authors: Cynthia Lee, William Yeh, Dongwoon Lee, Samuel Dixon, Vuong Trieu
Journal: Cancer Research (2016)

Abstract Background: BNP has been reported as molecular marker for ovarian cancer. This study evaluated BNP as a molecular marker for bladder, ovarian, glioblastoma, and pancreatic cancers. Methods: Serum samples collected at the time of diagnosis were tested using rapid and quantitative point-of-care (POC) devices for BNP blood biomarkers and the data was evaluated using JMP® 11.2.1 statistical analysis software. Samples were collected from bladder cancer patients (48 transitional cell carcinoma of the bladder), glioblastoma patients (51), pancreatic cancer patients (39 adenocarcinoma, 1 mucinous adenocarcinoma), ovarian cancer patients (24 serous adenocarcinoma, 20 serous papillary adenocarcinoma, 7 endometrioid adenocarcinoma, 3 clear cell carcinoma, 1 endometrial adenocarcinoma, 1 endometrioid papillary carcinoma, 1 serous papillary carcinoma), and normal subjects (n = 60). Results: Compared to normal subjects, bladder patients are more likely to be smokers (p = 0.0064). All four patient groups were more likely to be hypertensive (bladder, p = 0.0165; glioblastoma, p&amp;lt;0.0001, ovarian, p = 0.0002; pancreatic, p &amp;lt; 0.0001). No significant differences among the groups versus normal for weight were observed. Significant differences between the groups versus normal for BMI (ovarian, p = 0.0061), age (bladder, p = 0.0006; pancreatic = 0.0085), BNP (ovarian, p = 0.0012; glioblastoma, p = 0.0016; bladder, p = 0.0112) were noted. There was positive correlation between age and BNP level among all four cancer groups (bladder, p = 0.0133; glioblastoma, p = 0.0629; ovarian, p = 0.0304; pancreatic, p = 0.0172); whereas there was a negative correlation between age and BNP level among normal controls (p = 0.0109). Age-adjusted BNP level was highly significant different versus normal (bladder, p &amp;lt;0.0001; ovarian, p = 0.0013; glioblastoma, p = 0.0047). Neither BNP nor age-adjusted BNP level was significantly different from normal for pancreatic cancer patients. Hypertensive condition had no impact on BNP or age-adjusted BNP. Conclusions: Bladder, ovarian, and glioblastoma cancers are associated with significant reduction in BNP and age-adjusted BNP blood levels. Pancreatic cancer was an exception. BNP level could be useful in the monitoring of treatment efficacy in which the BNP POC device described here would be highly appropriate due to its ease in deployment at the patient's home or doctor's office. Citation Format: Cynthia Lee, William Yeh, Dongwoon Lee, Samuel Dixon, Vuong Trieu. Brain natriuretic peptide (BNP) as molecular marker for bladder, ovarian, and glioblastoma cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 397.
Interleukin 2 Receptor-α (CD25) Expression Is Associated with Shortened Overall Survival and Resistance to Induction Therapy with Plerixafor and Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)
Authors: John N. Allan, Gail J. Roboz, Eric J. Feldman, Joseph M. Scandura, Ellen K. Ritchie, Linda Lam, Wen Xie, Hsiao-Ting Hsu, Duane C Hassane, Monica L. Guzman
Journal: Blood (2014)
How can we make the learning curve of endoscopic submucosal dissection for (Western) endoscopists less steep?
Authors: Alanna Ebigbo, Helmut Messmann
Journal: Endoscopy (2016)

Endoscopic submucosal dissection (ESD) is a difficult-to-learn method for the treatment and resection of early gastrointestinal cancers and precancerous lesions. In the hands of an expert, ESD is a highly efficient means of achieving complete en bloc resection, producing impressive rates of curative R0 resection coupled with low recurrence and complication rates, especially when compared with standard methods such as endoscopic mucosal resection [1].
Randomised sham-controlled trial of transcutaneous electrical stimulation in obstructive sleep apnoea
Authors: Martino F Pengo, Sichang Xiao, Culadeeban Ratneswaran, Kate Reed, Nimish Shah, Tao Chen, Abdel Douiri, Nicholas Hart, Yuanming Luo, Gerrard F Rafferty, Gian Paolo Rossi, Adrian Williams, Michael I Polkey, John Moxham, Joerg Steier
Journal: Thorax (2016)

<h3>Introduction</h3> Obstructive sleep apnoea (OSA) is characterised by a loss of neuromuscular tone of the upper airway dilator muscles while asleep. This study investigated the effectiveness of transcutaneous electrical stimulation in patients with OSA. <h3>Patients and methods</h3> This was a randomised, sham-controlled crossover trial using transcutaneous electrical stimulation of the upper airway dilator muscles in patients with confirmed OSA. Patients were randomly assigned to one night of sham stimulation and one night of active treatment. The primary outcome was the 4% oxygen desaturation index, responders were defined as patients with a reduction &gt;25% in the oxygen desaturation index when compared with sham stimulation and/or with an index &lt;5/hour in the active treatment night. <h3>Results</h3> In 36 patients (age mean 50.8 (SD 11.2) years, male/female 30/6, body mass index median 29.6 (IQR 26.9–34.9) kg/m<sup>2</sup>, Epworth Sleepiness Scale 10.5 (4.6) points, oxygen desaturation index median 25.7 (16.0–49.1)/hour, apnoea-hypopnoea index median 28.1 (19.0–57.0)/hour) the primary outcome measure improved when comparing sham stimulation (median 26.9 (17.5–39.5)/hour) with active treatment (median 19.5 (11.6–40.0)/hour; p=0.026), a modest reduction of the mean by 4.1 (95% CI −0.6 to 8.9)/hour. Secondary outcome parameters of patients9 perception indicated that stimulation was well tolerated. Responders (47.2%) were predominantly from the mild-to-moderate OSA category. In this subgroup, the oxygen desaturation index was reduced by 10.0 (95% CI 3.9 to 16.0)/hour (p&lt;0.001) and the apnoea-hypopnoea index was reduced by 9.1 (95% CI 2.0 to 16.2)/hour (p=0.004). <h3>Conclusion</h3> Transcutaneous electrical stimulation of the pharyngeal dilators during a single night in patients with OSA improves upper airway obstruction and is well tolerated. <h3>Trial registration number</h3> NCT01661712.
487. Non-Viral Silencing of Machado-Joseph Disease Through the Systemic Route
Authors: Mariana Conceicao, Liliana Mendonca, Célia Gomes, Pedro Costa, Conceição Lima, Luís Pereira de Almeida
Journal: Molecular Therapy (2015)

Machado-Joseph disease (MJD) is the most common dominantly-inherited ataxia worldwide and is caused by the over-repetition of a CAG tract in the coding region of the ATXN3/MJD1 gene, which confers a toxic gain-of-function to the ataxin-3 protein resulting in degeneration within different brain regions, particularly the cerebellum. There is currently no available treatment to modify disease progression. The most direct approach to treat MJD is to block the production of the mutant protein using silencing sequences. Our group and others already showed that silencing mutant ataxin-3 in MJD mouse models is beneficial, however these studies used an invasive intracranial injection of viral vectors. There is a need for a less invasive procedure and therefore the aims of this study were: a) to develop an efficient system to enable transvascular delivery of siRNAs to the brain, and b) to investigate if this approach could rescue the motor behavior deficits and neuropathological abnormalities of a severely impaired transgenic mouse model of MJD. To cross the blood-brain barrier a lipid-based formulation encapsulating siRNAs and targeted to the brain with a short peptide derived from rabies virus glycoprotein (RVG-9r) was developed. Flow cytometry and confocal microscopy studies revealed specific in vitro association of RVG-9r-targeted liposomes with neuronal cells. Moreover, this formulation efficiently knocked down target mRNA resulting in protein level reduction in a neuronal cell line. Upon intravenous (i.v.) injection NIR images show that, when compared to a control formulation, RVG-9r-targeted liposomes increased the accumulation of the NIR dye in the mouse brain but not in major organs such as heart, lungs, liver, spleen and kidneys. Moreover, flow cytometry revealed an increased fluorescence of FAM-labeled siRNAs in the cerebellum of transgenic animals injected with RVG-9r-targeted liposomes. Furthermore our results also show that, when compared to a control sequence of siRNA, i.v. administration of siRNA against mutant ataxin-3 (siMutAtx3) was able to decrease mRNA and aggregates levels of mutant ataxin-3 in the cerebellum of MJD transgenic mice. Importantly, i.v. administration of siMutAtx3 alleviated the motor impairments (beam walking, swimming and footprint pattern) and attenuated the neuropathological abnormalities in MJD transgenic mice (Purkinje cell number, aggregates levels and granular layer thickness). In summary, our results show that we have developed a promising nanoparticle-based system to deliver silencing sequences to the brain by i.v. administration. Altogether our studies open new avenues towards MJD therapy that can also be applied to other neurodegenerative diseases.