tbuckley/cabot-search huggingface dataset:
Trends in Maternal and Fetal Outcomes Among Pregnant Women With Systemic Lupus Erythematosus in the United States
Authors: Bella Mehta, Yiming Luo, Jiehui Xu, Lisa Sammaritano, Jane Salmon, Michael Lockshin, Susan Goodman, Said Ibrahim
Journal: Annals of Internal Medicine (2019)

Although pregnancy in systemic lupus erythematosus (SLE) carries a high risk for mother and fetus, outcomes may be improving.To assess nationwide trends and disparities in maternal and fetal complications among pregnant women with SLE.Retrospective cohort study.United States, 1998 to 2015.Adult pregnant women with and without SLE who had hospitalizations recorded in the National Inpatient Sample (NIS) database.Outcome measures were in-hospital maternal mortality, fetal mortality, preeclampsia or eclampsia, caesarean sections, non-delivery-related admissions, and length of stay. To assess whether trends in outcomes over time differed between patients with SLE and those without SLE, logistic or linear regression with an interaction term between year and SLE (yes or no) was used. Nationwide population estimates incorporating sampling and poststratification weights were obtained.An estimated 93 820 pregnant women with SLE and 78 045 054 without SLE were hospitalized in the United States from 1998 through 2015. Outcomes improved during those 18 years. In-hospital maternal deaths (per 100 000 admissions) declined among patients with as well as those without SLE (442 vs. 13 for 1998 to 2000 and <50 vs. 10 for 2013 to 2015), although the decrease was greater in women with SLE (difference in trends, P < 0.002). The percentage of patients with SLE in all pregnancy-related, as well as delivery-related, admissions increased significantly.The sample for this analysis was identified by using diagnostic codes; detailed information on hospital-specific trends, SLE disease activity, and medications was not available. Race trends could not be analyzed. Given that NIS uses weighted estimates, the incidence of outcomes reported may not be exact.In this large study examining SLE and non-SLE pregnancies over 18 years, in-hospital maternal mortality and overall outcomes improved markedly, particularly among women with SLE. However, improvement is still needed, because SLE pregnancy risks remain high.None.
The Level of Circulating Myeloma Cells at Diagnosis Correlates with a Plasma Cell Leukemia-like Phenotype of the Corresponding Myeloma Cells in Bone Marrow
Authors: Davine Hofste Op Bruinink, Vincent van der Velden, Mark van Duin, Berna Beverloo, Jeroen te Marvelde, Chelsea den Hollander, Rowan Kuiper, Michel Delforge, Martin H van Vliet, Niels Wcj van de Donk, Hervé Avet-Loiseau, Philippe Moreau, Pieter Sonneveld
Journal: Blood (2017)
Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease
Authors: Jacob T. Cain, Shibi Likhite, Katherine A. White, Derek J. Timm, Samantha S. Davis, Tyler B. Johnson, Cassandra N. Dennys-Rivers, Federica Rinaldi, Dario Motti, Sarah Corcoran, Pablo Morales, Christopher Pierson, Stephanie M. Hughes, Stella Y. Lee, Brian K. Kaspar, Kathrin Meyer, Jill M. Weimer
Journal: Molecular Therapy (2019)

CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a chicken β-actin (CB) hybrid promoter. Intrathecal delivery of scAAV9.CB.hCLN6 into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 4-year-old non-human primates was safe, well tolerated, and led to efficient targeting throughout the brain and spinal cord. A single intracerebroventricular (i.c.v.) injection at post-natal day 1 in Cln6 mutant mice delivered scAAV9.CB.CLN6 directly into the CSF, and it prevented or drastically reduced all of the pathological hallmarks of Batten disease. Moreover, there were significant improvements in motor performance, learning and memory deficits, and survival in treated Cln6 mutant mice, extending survival from 15 months of age (untreated) to beyond 21 months of age (treated). Additionally, many parameters were similar to wild-type counterparts throughout the lifespan of the treated mice.
Th17 responses to autologous dendritic cell vaccine.
Authors: Gabriel I. Nistor, Aleksandra J. Poole, Candace Hsieh, Hans S. Keirstead, Robert O. Dillman
Journal: Journal of Clinical Oncology (2019)

132 Background: Dendritic cells (DC) loaded with autologous tumor antigens in vitro, can induce a Th17 phenotype preceding a Th1 type response. We examined this in patients with metastatic melanoma who had been treated in a randomized trial with either DC loaded with autologous tumor antigens (ATA) from self-renewing tumor cells (DCV) or irradiated tumor cells (TCV). Methods: Blood samples were obtained at baseline, one week before three weekly vaccinations (week-0), and at week-4, (one week after the third vaccination). They were analyzed for growth factors, tumor markers and biomarkers using a quantitative, multiplex ELISA. Monocytes, lymphocytes, loaded and unloaded DC were analyzed for cytokine production and intercellular responses using mixed lymphocyte co-cultures (MLC). Results: When compared to baseline or the TCV arm, DCV-treated patients showed reductions in tumor markers, inflammation and angiogenesis in parallel with Th17 pathway activation, IL12 p70 heterodimer expression was detected in monocytes and DC only after antigen loading. The IL12 p40 fraction was present after differentiation and was enhanced after antigen loading. Similarly, the p19 component of IL23 was expressed before DC loading and later enhanced. MLC showed induction of Th17, Th1 and CD8 subpopulations. In the presence of antigen-loaded DCs, the FOXp3 cells were reduced in number, an effect that was canceled by neutralizing the IL12p40 subunit or by the adding tumor cells alone in the MLC. Conclusions: DC produced ex vivo can activate multiple cytotoxic pathways depending on IL12 subunits. Expression of IL23p19 and the shared IL12p40 fraction are responsible for Th1 priming (IL12 incomplete) and Th17 induction (IL23 complete), determinants of the reactive phenotype of naïve DCs. IL12 p70 heterodimer expression after DC loading enables a targeted Th1 type response while neutralizing the IL12 subunit p40, enhances Foxp3 positive T-regs. DC vaccines produced ex vivo could induce a Th1/Th17 cytotoxic response against tumors. In the absence of antigens, however, The Th17 phenotype can become tolerizing in the microenvironment. The findings are important for applications in settings in which tumor infiltration with Th17 correlates with survival, such as in advanced ovarian cancer. Clinical trial information: NCT00436930.
Cytogenetic changes in metastatic renal cell carcinoma: Basis for sensitivity and resistance to everolimus.
Authors: Imogen Rose Caldwell, Paul Oei, Daniel Ng, Beth Caudwell, Peter C.C. Fong, Reuben James Broom
Journal: Journal of Clinical Oncology (2012)

e15050 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to benefit from these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of benefit from everolimus therapy. Methods: 10 pts with clear cell mRCC treated with everolimus therapy were enrolled. 2 pts had both primary &amp; metastatic specimens. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) &amp; clinical data including Progression-free Survival (PFS) (RECIST 1.1) were obtained. The gene probes chosen for this analysis were: VHL, FHIT, PDGFβ, PDGFRβ, FGFR1, FGFR3, EGFR, MYC, PTEN &amp; IGH@. Results: Results are displayed in the table. The median PFS was 7.5 months (mo), including 4 pts who remain on treatment. 8 pts were treated 1st-line, one 2nd-line &amp; one 3rd-line. The longest responder (PFS 28 mo, 3rd-line) had a normal VHL status but loss of FHIT. 2 pts with the longest PFS had gain of both PDGFβ &amp; PDGFRβ. Changes were observed between the primary &amp; metastatic specimens including the acquisition of gain of PDGFβ &amp; MYC (these pts remain progression-free on treatment). Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFβ &amp; PDGFRβ was observed in 5 pts including 2 with prolonged benefit. Acquisition of gains in gene status suggests evolution of genetic changes between primary &amp; metastatic specimens. [Table: see text]
Promotion of human multiple myeloma cell growth in vitro and bone marrow invasion in vivo by Notch receptors and the CXCR4/SDF1 axis.
Authors: Maurizio Chiriva-Internati, Leonardo Mirandola, Elisa Lazzari, Michela Colombo, Marialuigia Lancellotti, Everardo Cobos, Yuefei Yu, Jose A. Figueroa, Charles Saadeh, Raymond Wade, Kristopher Zepeda, Jesse Mer, Venu Konala, Saba Radhi, Amardeep Aulakh, Marjorie Jenkins, Cynthia A. Jumper, Raed Alalawi, Raffaella Chiaramonte
Journal: Journal of Clinical Oncology (2013)

8591 Background: Multiple myeloma (MM) originates from post-germinal center B cells, and is caused by malignant plasma cells accumulating in the bone marrow. Interactions of MM cells with the bone marrow stroma promote tumor growth, migration and drug resistance. The chemokine receptor CXCR4 and its ligand SDF1 are critical regulators of this process. MM cells frequently hyper-express CXCR4 and respond to SDF1,2 enhancing MM cell infiltration, proliferation and osteolysis. Notch receptors similarly promote MM cell growth, drug resistance and the associated osteolytic process. We hypothesized that the CXCR4/SDF1 axis mediates the effects of Notch signals in MM. Methods: We used real-time PCR, flow-cytometry, E.L.I.S.A. and chemotaxis assay to explore the effects of CXCR4 in cultured human MM cell lines after Notch inhibition or over-stimulation. Additionally, we validated our findings in a NOD/SCID murine model xenografted with human MM cells. Results: Our results show that Notch blocking reduced CXCR4 and SDF1 expression by MM cells. Further, Notch activation was required for MM cell chemotactic and proliferative response to SDF1 in vitro. We then investigated the outcome of anti-Notch treatment on human MM cells bone invasion in NOD/SCID mice. Interfering with Notch activity dramatically reduced xenografted MM cell ability to infiltrate the bone marrow, ultimately resulting in diminished tumor burden. Notably, such effect was associated with a decrease of CXCR4 expression. Conclusions: This was the first time that Notch receptors were reported to regulate the CXCR4/SDF1 axis and bone marrow invasion in human MM. These findings indicate that specific Notch-tailored therapies may effectively hamper CXCR4-mediated bone infiltration and associated lesions, and are expected to significantly improve treatment outcome and survival.
Correction: Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond
Authors: C. S. Chim, S. K. Kumar, R. Z. Orlowski, G. Cook, P. G. Richardson, M. A. Gertz, S. Giralt, M. V. Mateos, X. Leleu, K. C. Anderson
Journal: Leukemia (2019)

Following the publication of this article the authors noted that the MRD data under the Table 1 column "Remark" of Aspire should go to that of Pollux. The authors wish to apologize for any inconvenience caused. The corrected table is attached to this correction.
In vitro and in vivo inhibitory effects of TLR4 agonist, glucopyranosyl lipid A (GLA), on allergic rhinitis caused by Japanese cedar pollen
Authors: Koji Matsumoto, Hideaki Kouzaki, Sayuri Yamamoto, Hirotaka Kikuoka, Ichiro Tojima, Jan H. ter Meulen, Takeshi Shimizu
Journal: Allergy (2019)

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Mammographic findings in locally advanced breast carcinoma treated with neoadjuvant chemotherapy.
Authors: Carlos Castañeda, Raymundo Flores, Katerin Ingrid Rojas, Claudio J Flores, Zaida Morante, Christian Pacheco, Rossana Esther Ruiz, Gabriela Calderon, Henry Leonidas Gomez, Tatiana Vidaurre
Journal: Journal of Clinical Oncology (2013)

e12538 Background: Breast Cancer (BC) is a heterogeneous disease. Mammograpy images of BC has been associated with tumor features. We evaluated relationship between radiologic features of pre-neoadjuvant chemotherapy (NAC) lesions and clinico pathological tumor features. Methods: We evaluated mammography films and clinicopathological information of BC patient who received NAC followed by tumor resection at Instituto Nacional de Enfermedades Neoplásicas from 2000 to 2011. Results: 495 BC cases were selected. Most cases were staged in clinical Tumor size stage 4 (48.2%) and node stage 1 (58.7%); and had a GIII histological grade (51.2%). Breast density (BD) was classified as BIRADS grade 1 in 17%, grade 2 in 22%, grade 3 in 35% and grade 4 in 25.3%. High BD has been associated to younger age (p&lt;0.001) and obesity (p=0.012). An association between mammographic rounded shape and triple-negative (TN) phenotype was found (p=0.002). An association between the dusty microcalcification and HER2 group as well as between the casting and the TN BC group (p=0.001) is found. NAC included anthracyclines and taxanes in 422 (85.4%) cases. Four and 5 Miller Payne pathologic response (pR) in the primary lesion and absence of axilary lymph nodes involvement were found in14.8% of the whole population, and in 10.5% of luminal cases, 17.7% of HER2- enriched and 23% of TN BC. pCR was associated to patient age (p&lt;0.001), tumor grade (p&lt;0.001) and high breast density (p=0.001), as well as better DFS (p=0.05). Conclusions: Radiographic images are related to tumor features in pre-NAC BC cases. pCR is associated to high density breast as well as previously described clinicopathological features.
In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors
Authors: Danny N. Khalil, Nathan Suek, Luis Felipe Campesato, Sadna Budhu, David Redmond, Robert M. Samstein, Chirag Krishna, Katherine S. Panageas, Marinela Capanu, Sean Houghton, Daniel Hirschhorn, Roberta Zappasodi, Rachel Giese, Billel Gasmi, Michael Schneider, Aditi Gupta, James J. Harding, John Alec Moral, Vinod P. Balachandran, Jedd D. Wolchok, Taha Merghoub
Journal: Journal of Clinical Investigation (2019)

Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while sparing the intervening draining lymph node and spleen. Furthermore, patients with transcription changes like those induced by this therapy experienced improved progression-free survival with anti-PD-1 treatment. Dual CD40-TLR4 activation within a single tumor is thus an approach for overcoming resistance to PD-1 blockade that is unique in its ability to cause the loss of exhausted T cells within tumors while sparing nonmalignant tissues.
RRAS2 shapes the TCR repertoire by setting the threshold for negative selection
Authors: Ana Martínez-Riaño, Elena R. Bovolenta, Viola L. Boccasavia, Julia Ponomarenko, David Abia, Clara L. Oeste, Manuel Fresno, Hisse M. van Santen, Balbino Alarcon
Journal: The Journal of Experimental Medicine (2019)

Signal strength controls the outcome of αβ T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2−/− mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2−/− mice have reduced affinity for MOG/I-Ab tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2−/− mice, suggesting their involvement in autoimmunity.
Optimization of Ex Vivo Activation and Expansion of T Cells for Therapy of Lymphoma Via Antagonism of PI3K δ and Vasoactive Intestinal Peptide Signaling
Authors: Edmund K. Waller, Mojitabe Hassan, Anna B. Morris, Jasmin Jeffery, Kunhee Lee, Neera Jagirdar, Ashley D. Staton, Christopher Flowers, Cynthia Gaylor, Todd A. Sulchek, Christopher Thomas Petersen
Journal: Blood (2017)
Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
Authors: Anita M.A.P. Govers, Caroline R.M. Wiggers, Ruben van Boxtel, Michal Mokry, Edward E.S. Nieuwenhuis, Menno P. Creyghton, Marije Bartels, Paul J. Coffer
Journal: HemaSphere (2019)

The clinical use of histone deacetylase inhibitors (HDACi) for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last decades. Nonetheless, their effects on normal myelopoiesis remain poorly evaluated. Here, we treated cord blood derived CD34+ progenitor cells with two chemically distinct HDACi inhibitors MS-275 or SAHA and analyzed their effects on the transcriptome (RNA-seq), epigenome (H3K27ac ChIP-seq) and functional and morphological characteristics during neutrophil development. MS-275 (entinostat) selectively inhibits class I HDACs, with a preference for HDAC1, while SAHA (vorinostat) is a non-selective class I/II HDACi. Treatment with individual HDACi resulted in both overlapping and distinct effects on both transcriptome and epigenome, whereas functional effects were relatively similar. Both HDACi resulted in reduced expansion and increased apoptosis in neutrophil progenitor cells. Morphologically, HDACi disrupted normal neutrophil differentiation what was illustrated by decreased percentages of mature neutrophils. In addition, while SAHA treatment clearly showed a block at the promyelocytic stage, MS-275 treatment was characterized by dysplastic features and skewing towards the monocytic lineage. These effects could be mimicked using shRNA-mediated knockdown of HDAC1. Taken together, our data provide novel insights into the effects of HDAC inhibition on normal hematopoietic cells during neutrophil differentiation. These findings should be taken into account when considering the clinical use of MS-275 and SAHA, and can be potentially utilized to tailor more specific, hematopoietic-directed HDACi in the future.
Embryonic Stem Cells Modulate the Cancer-Permissive Microenvironment of Human Uveal Melanoma
Authors: Jiahui Liu, Zheqian Huang, Liu Yang, Xiaoran Wang, Shoubi Wang, Chaoyang Li, Ying Liu, Yaqi Cheng, Bowen Wang, Xuan Sang, Xiongjun He, Chenjie Wang, Tengfei Liu, ChengXiu Liu, Lin Jin, Chang Liu, Xiaoran Zhang, Linghua Wang, Zhichong Wang
Journal: Theranostics (2019)

The currently used anti-cancer therapies work by killing cancer cells but result in adverse effects and resistance to treatment, which accelerates aging and causes damage to normal somatic cells.On one hand, chicken and zebrafish embryos can reprogram cancer cells towards a non-tumorigenic phenotype; however, they cannot be used in the clinical practice.On the other hand, embryonic stem cells (ESCs) mimic the early embryonic microenvironment and are easily available.We investigated the therapeutic efficacy of the ESC microenvironment (ESCMe) in human uveal melanoma in vitro and in vivo.Methods: Human uveal melanoma C918 cells co-cultured with ESCs were used to measure the levels of mRNA and protein of the phosphoinositide 3-kinase (PI3K) pathway.Cell proliferation, invasiveness, and tumorigenicity of C918 cells were also analyzed.To mimic the tumor microenvironment in vivo, we co-cultured C918 cells and normal somatic cells with ESCs in a co-culture system and evaluated the therapeutic potential of ESCMe in both cell types.For an in vivo study, a mouse tumor model was used to test the safety and efficacy of the transplanted ESC.Elimination of the transplanted ESCs in mice was carried out by using the ESC-transfected with a thymidine kinase suicidal gene followed by administration of ganciclovir to prevent the formation of teratomas by ESCs.Results: In vitro studies confirmed that ESCMe inhibits the proliferation, invasiveness, and tumorigenicity of C918 cells, and the PI3K agonist abolished these effects.ESCMe suppressed the various malignant behaviors of uveal melanoma cells but enhanced the proliferation of normal somatic cells both in vitro and in vivo.Further, we demonstrated that ESCMe suppressed the PI3K pathway in tumor cells but activated in somatic cells. Conclusions:The ESCMe can effectively suppress the malignant phenotype of uveal melanoma cells and modulate the tumor-promoting aging environment by preventing the senescence of normal cells through the bidirectional regulation of the PI3K signaling.Our results suggest that ESC transplantation can serve as an effective and safe approach for treating cancer without killing cells.