tbuckley/cabot-search huggingface dataset:
Amelioration of Autoimmune Arthritis in Mice Treated With the DNA Methyltransferase Inhibitor 5′‐Azacytidine
Authors: Dániel M. Tóth, Timea Ocskó, Attila Balog, Adrienn Markovics, Katalin Mikecz, László Kovács, Meenakshi Jolly, Aleksandra A. Bukiej, Andrew D. Ruthberg, András Vida, Joel A. Block, Tibor T. Glant, Tibor A. Rauch
Journal: Arthritis & Rheumatology (2019)

Disease-associated, differentially hypermethylated regions have been reported in rheumatoid arthritis (RA), but no DNA methyltransferase inhibitors have been evaluated in either RA or any animal models of RA. The present study was conducted to evaluate the therapeutic potential of 5'-azacytidine (5'-azaC), a DNA methyltransferase inhibitor, and explore the cellular and gene regulatory networks involved in the context of autoimmune arthritis.A disease-associated genome-wide DNA methylation profile was explored by methylated CpG island recovery assay-chromatin immunoprecipitation (ChIP) in arthritic B cells. Mice with proteoglycan-induced arthritis (PGIA) were treated with 5'-azaC. The effect of 5'-azaC on the pathogenesis of PGIA was explored by measuring serum IgM and IgG1 antibody levels using enzyme-linked immunosorbent assay, investigating the efficiency of class-switch recombination (CSR) and Aicda gene expression using real-time quantitative polymerase chain reaction, monitoring germinal center (GC) formation by immunohistochemistry, and determining alterations in B cell subpopulations by flow cytometry. The 5'-azaC-induced regulation of the Aicda gene was explored using RNA interference, ChIP, and luciferase assays.We explored arthritis-associated hypermethylated regions in mouse B cells and demonstrated that DNA demethylation had a beneficial effect on autoimmune arthritis. The 5'-azaC-mediated demethylation of the epigenetically inactivated Ahr gene resulted in suppressed expression of the Aicda gene, reduced CSR, and compromised GC formation. Ultimately, this process led to diminished IgG1 antibody production and amelioration of autoimmune arthritis in mice.DNA hypermethylation plays a leading role in the pathogenesis of autoimmune arthritis and its targeted inhibition has therapeutic potential in arthritis management.
Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model
Authors: Yueqin Zhou, Sharon Carmona, A.K.M.G. Muhammad, Shaughn Bell, Jesse Landeros, Michael Vazquez, Ritchie Ho, Antonietta Franco, Bin Lu, Gerald W. Dorn, Shaomei Wang, Cathleen M. Lutz, Robert H. Baloh
Journal: Journal of Clinical Investigation (2019)

Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.
A Prospective Study of the Development of Inflammatory Arthritis in the Family Members of Indigenous North American People With Rheumatoid Arthritis
Authors: Stacy Tanner, Brenden Dufault, Irene Smolik, Xiaobo Meng, Vidyanand Anaparti, Carol Hitchon, David B. Robinson, William Robinson, Jeremy Sokolove, Lauren Lahey, Elizabeth D. Ferucci, Hani El‐Gabalawy
Journal: Arthritis & Rheumatology (2019)

Objective To determine the incidence of inflammatory arthritis and autoantibody prevalence in Indigenous North American people. Methods Unaffected relatives of Indigenous North Americans with rheumatoid arthritis ( RA ) from central Canada and Alaska were systematically monitored from 2005 to 2017. Rheumatoid factor ( RF ) and anti–citrullinated protein antibodies ( ACPA s) were tested at every visit, and a subset was tested for ACPA fine specificity using a custom multiplex assay. Multistate models based on all available study visits were developed to determine the likelihood of transitioning between autoantibody states, or to inflammatory arthritis. Results Eighteen of 374 relatives (4.8%) developed inflammatory arthritis during follow‐up (after a mean ± SD of 4.7 ± 2.4 years), yielding a transition rate of 9.2 cases/1,000 person‐years. Thirty percent of those who developed inflammatory arthritis were seronegative at baseline, but all were seropositive at inflammatory arthritis onset. Although 30% of ACPA / RF double‐seropositive individuals developed inflammatory arthritis (after 3.2 ± 2.2 years), the majority of these individuals did not develop inflammatory arthritis. Multistate modeling indicated a 71% and 68% likelihood of ACPA and RF seropositive states, respectively, reverting to a seronegative state after 5 years, and a 39% likelihood of an ACPA / RF double‐seropositive state becoming seronegative. Fine specificity testing demonstrated an expansion of the ACPA repertoire prior to the development of inflammatory arthritis. Conclusion Despite a high incidence of inflammatory arthritis in this cohort of at‐risk relatives of Indigenous North Americans with RA , a large proportion of autoantibody‐positive individuals do not develop inflammatory arthritis and revert back to an autoantibody‐negative state.
Patient Outcomes After Hospital Discharge to Home With Home Health Care vs to a Skilled Nursing Facility
Authors: Rachel M. Werner, Norma B. Coe, Mingyu Qi, R. Tamara Konetzka
Journal: JAMA Internal Medicine (2019)

Use of postacute care is common and costly in the United States, but there is significant uncertainty about whether the choice of postacute care setting matters. Understanding these tradeoffs is particularly important as new alternative payment models push patients toward lower-cost settings for care.To investigate the association of patient outcomes and Medicare costs of discharge to home with home health care vs discharge to a skilled nursing facility.A retrospective cohort study used Medicare claims data from short-term acute-care hospitals in the United States and skilled nursing facility and home health assessment data from January 1, 2010, to December 31, 2016, on Medicare beneficiaries who were discharged from the hospital to home with home health care or to a skilled nursing facility. To address the endogeneity of treatment choice, an instrumental variables approach used the differential distance between the beneficiary's home zip code and the closest home health agency and the closest skilled nursing facility as an instrument.Receipt of postacute care at home vs in a skilled nursing facility.Readmission within 30 days of hospital discharge, death within 30 days of hospital discharge, improvement in functional status during the postacute care episode, and Medicare payment for postacute care and total payment for the 60-day episode.A total of 17 235 854 hospitalizations (62.2% women and 37.8% men; mean [SD] age, 80.5 [7.9] years) were discharged either to home with home health care (38.8%) or to a skilled nursing facility (61.2%) during the study period. Discharge to home was associated with a 5.6-percentage point higher rate of readmission at 30 days compared with discharge to a skilled nursing facility (95% CI, 0.8-10.3; P = .02). There were no significant differences in 30-day mortality rates (-2.0 percentage points; 95% CI, 0.8-10.3; P = .12) or improved functional status (-1.9 percentage points; 95% CI, -12.0 to 8.2; P = .71). Medicare payment for postacute care was significantly lower for those discharged to home compared with those discharged to a skilled nursing facility (-$5384; 95% CI, -$6932 to -$3837; P < .001), as was total Medicare payment within the first 60 days after admission (-$4514; 95% CI, -$6932 to -$3837; P < .001).Among Medicare beneficiaries eligible for postacute care at home or in a skilled nursing facility, discharge to home with home health care was associated with higher rates of readmission, no detectable differences in mortality or functional outcomes, and lower Medicare payments.
Abstract P421: Cardiovascular Death Trends in Minnesota From 2000-2017
Authors: Yariv Gerber, Susan Weston, Sheila Manemann, Suzette Bielinski, Alanna Chamberlain, Jill Killian, Chandrasagar Dugani, Veronique L Roger
Journal: Circulation (2019)

Background: The decline in cardiovascular disease (CVD) mortality in the United States noted since the mid 1970s has recently leveled off. This has generated concern and a need for further analyses to understand geographic variation, cause-specific deaths, location of death, and age-specific trends. Methods: Death certificate data obtained from the Minnesota Department of Health were used for analysis. The American Heart Association (AHA) classification was applied to the underlying cause of death to generate the following CVD categories: coronary heart disease (CHD), non-CHD diseases of the heart, and non-cardiac circulatory diseases. Temporal trends in death rates were explored by negative binomial regression, which enables estimates of age- and sex-adjusted average annual percentage changes (AAPCs). Differences in AAPCs between 2000-2009 and 2010-2017 were tested overall and across demographic, CVD, and location of death categories. Results: CVD mortality rates, which were declining in 2000-2009, have leveled off in 2010-2017 (Table). These trends were observed across all subgroups. After adjusting for sex, the age group that drove the decline in rates from 2000-2009 was the 65-84 year old group, which experienced no change in rates from 2010-2017. Across CVD categories, after adjusting for age and sex, the decline in rates from 2000-2009 was largely attributable to steep reductions in CHD and non-cardiac circulatory diseases, with lesser reduction in non-CHD diseases of the heart. In 2010-2017, CHD and non-cardiac circulatory diseases rates showed no change, whereas the rate of non-CHD diseases of the heart increased. The rates for in- and out-of-hospital deaths improved in 2000-2009 with no further improvement observed in 2010-2017. Conclusions: CVD mortality rates are no longer declining in Minnesota, paralleling national trends. These trends are particularly concerning for non-CHD diseases of the heart.
Abstract P412: Increased Forward and Backward Arterial Wave Reflections Are Found in Adolescents With Obesity or Obesity-Related Type 2 Diabetes Mellitus
Authors: Andrew H Tran, Thomas R Kimball, Phil R Khoury, Lawrence M Dolan, Elaine M Urbina
Journal: Circulation (2019)

Introduction: Pulse wave analysis provides an estimation of central (aortic) pressure and arterial wave reflections which relate to LV dysfunction and risk of CV events in adults. Recent adult studies suggest separation of the forward and backward waves may provide improved risk stratification for CV events. Data in youth are lacking. Hypothesis: We hypothesized that a significant difference in arterial wave reflections would be identified in young subjects with adverse CV risk factors. Methods: Vital signs, fasting lipids, glucose, insulin, HbA1c, and CRP were obtained in 551 patients aged 10-24 years in a study comparing vascular health among lean (L= 199), obese (O=173) and subjects with type 2 diabetes (T=179). Wave separation analyses were performed on pressure tracings obtained from radial artery tonometry. Group differences in CV risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. Results: A more adverse CV risk profile was found in O and T subjects compared to L (higher BMI, SBP, DBP, LDL, TG, CRP, lower HDL in O and T vs L; all p≤0.0003). The T group had higher glucose, insulin, and HbA1c compared to the L and O groups (all p≤0.0001). The forward pulse wave amplitude (Pf) and the backward pulse wave amplitude (Pb) were significantly higher (P&lt;0.0001) in the O and T groups compared to the L subjects (figure). The independent determinants of Pf included age, sex, waist-to-hip ratio (WHR), height, SBP, DBP, and HR (R2=0.24, p&lt;0.0001). Independent determinants of Pb included group, WHR, SBP, HR, and log insulin (R2=0.43, p&lt;0.0001). Conclusions: Adolescents and young adults with obesity and T2DM have altered forward and backward arterial wave reflections compared to lean controls related to adiposity, BP, and insulin levels. These new parameters may be useful in risk stratifying patients with adverse cardiovascular risk factors.
Development of a Trojan horse oncolytic virus for treatment of myeloma.
Authors: Simon Tazzyman, Munitta Muthana, Jack Harrison, Claire Lewis, Joe Conner, Andrew Chantry
Journal: Journal of Clinical Oncology (2015)

e14035 Background: Multiple myeloma remains an essentially incurable malignancy tumour bulk may be substantially reduced however, disease re-accumulates and patients eventually succumb. Novel strategies to eliminate residual plasma cells are urgently needed. Recently, a novel Trojan horse macrophage-based, viral therapy designed to augment conventional anti-cancer therapies has shown therapeutic efficacy in murine models of prostate cancer. We have adopted a similar strategy for treatment of myeloma. Methods: Two engineered oncolytic viruses (Adenovirus and HSV1716) were tested for their ability to induce cell death in myeloma cell lines 1-7 days post infections. Both viruses are engineered to replicate specifically in the tumour environment. Cell death was assessed using cell counts and flowcytometric analysis. We then assayed viral infection and release from primary macrophages by viral titre assays. The ability of the released virus to induce cell death in myeloma cell lines was assessed as before. To test if we could use a murine model to study our Trojan horse system, tumour sections were stained for macrophage infiltration and such environmental factors as hypoxia (HIF-1alpha staining). Finally HSV1716 infected macrophages were then injected in to a murine model of myeloma and the therapeutic effect assessed by histology. Results: We found that both Adenovirus and HSV1716 induced significant increases in cell death in two myeloma cell lines while leaving a number of normal cells unaffected. HSV1716 successfully infected human macrophages and was released 4 days after infection with a marked increase in viral production observed in hypoxia. The macrophage released virus induced potent cell death in two myeloma cell lines after 4 days. Our murine model of myeloma showed macrophage infiltration and profound hypoxia. Treatment of these mice with HSV1716 bearing macrophages showed a trend for a reduction in myeloma associated bone disease. Conclusions: Two oncolytic viruses show potential for therapeutic treatment of myeloma. Macrophage are capable of carrying HSV1716 and delivering it to tumour cells resulting in tumour cell death providing a mechanism to better target myeloma tumours by preventing immune rejection of systemic virus
Potential markers of response and resistance to programmed cell death-1 blockade in first-line therapy of cisplatin-inilegible advanced urothelial cancer.
Authors: Alberto Carretero-Gonzalez, Blanca Homet Moreno, Marta Dueñas, Mónica Martínez-Fernández, Ray Manneh, Alejandra Bernardini, Carolina Rubio, Felipe Villacampa, Rosa M. García Martín, Ramón García Escudero, José L. Rodríguez Peralto, Daniel Rueda, Guillermo De Velasco, Daniel E. Castellano, Jesús M Paramio
Journal: Journal of Clinical Oncology (2019)

449 Background: Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit in advanced urothelial cancer (UC) patients. An alert was issued about a decrease in survival for bladder cancer patients with PD-L1-low status receiving immunotherapy versus chemotherapy as first-line therapy. We studied a small series of UC patients treated with first-line PD-1 checkpoint inhibition in order to analyze their characteristics and patterns of response to therapy. Methods: Eleven UC samples were obtained from patients before undergoing therapy with ICIs. Patients were classified according to their benefit from therapy in responders (n=5) and non-responders (n=6). Genomic and immunohistochemistry analyses were performed. Results: Both luminal and basal UC subtypes showed benefit from ICIs. Tumors from non-responders showed increased mutations in chromatin remodelling genes and the amplification of 3q26-28 region. Transcriptome analyses showed that tumors from responders displayed a significant enrichment of genes associated with interferon γ and α response, TNFα via NFκB, genes upregulated by MYC or E2F1, genes involved in G2/M checkpoint and epithelial-mesenchymal transition compared to non-responders. Specific immune cell subsets were present in the tumor microenvironment of tumors from responders and non-responders. Immunohistochemistry showed that none of the immune cell markers analyzed individually was sufficient to discriminate between responders and non-responders. However, the increase in FOXP-3, PD-L1, PD-1, CD8, β2 microglobulin and CD68 and the decrease in CD4 and CD163 cells identified UC patients that responded to ICIs. Conclusions: Our findings confirm that the evaluation of pre-treatment UC tumor samples provides valuable information that could influence treatment decisions. Despite the clinical benefit of PD-1/PD-L1 inhibition in UC, only a fraction of patients benefit from therapy. Our data suggest that responders and non-responders display diverse genomic and transcriptome changes as well as specific immune cell subsets in the tumor microenvironment that can be identified by conventional IHC staining.
Impact of treatment and insurance on socioeconomic disparities on the survival of renal cancer patients in Thailand.
Authors: Phichai Chansriwong, Piyaporn Srikaew, Suchin Worawichawong
Journal: Journal of Clinical Oncology (2019)

576 Background: Access to care is an important aspect of high-quality cancer care. Patients' health insurance status is a factor influencing an individual's ability to access high-quality cancer care. The increased costs of cancer care are negatively impacting patients. 75% of Thai people use the Thailand’s Universal Coverage Scheme (UCS), about 15% use the Civil Servant Medical Benefit Scheme (CSMBS) or the Social Security Scheme (SSS). Only CSMBS can reimburse cost of the targeted therapy. Multiple new therapies have emerged for the treatment of metastatic renal cell carcinoma (mRCC) that showed OS increased in following introduction of targeted therapies and immunotherapy. However, many patients lack access to affordable, high-quality cancer care. Aim: To determine the relationship between treatment affordability, insurance status and RCC cancer survival. Methods: Retrospectively reviewed 281 medical records of RCC patients at the Ramathibodi hospital between January 2009 and December 2017. We searched the Surveillance, Epidemiology, and End Results dataset. Kaplan–Meier methods and multivariable Cox regression models were used to analyze survival outcomes and risk factors. Results: 281 RCC patients, and 127 metastasis were identified. Median age was 59.1 years, and 74.7% were male gender. There were clear cell carcinoma (77.9%), and non-clear cell was 17.1%. IMDC prognostic model categorized as favorable/intermediate/poor risk group as 14.2%/51.2%/29.1%. 41.7% has health insurance status as CSMBS, 7% in SSS and 50.9% in UCS. Only 50% of SSS and UCS paid out of their pocket of mRCC treatment. First line treatment for mRCC were targeted therapy with VEGFR TKI 73.9%, but 26.8% received only supportive care. Median OS was 24 months in the treatment group and only 4.1 months in the best supportive care group (p &lt;0.05). Health insurance status and medication affordability was confirmed as an independent prognostic factor for mRCC patients. Conclusions: Insurance status and medication affordability are important predictive factors for mRCC, and improving access to affordable targeted therapies is likely to improve outcomes in mRCC.
MRI-guided prostate brachytherapy dose escalation to the dominant intraprostatic lesions: A retrospective analysis of urinary toxicity and biochemical response.
Authors: George Wakil, Nicolas Côté, Timothy Lymberiou, Lorne Aaron, Elie Antebi, Philippe Arjane, Talar Derashodian, Vien Do, Marjory Jolicoeur, Mahmoud Nachabe, Thu Van Nguyen Huynh, Patricia Duguay-Drouin
Journal: Journal of Clinical Oncology (2019)

47 Background: Magnetic resonance imaging (MRI) allows for delineation of the dominant intraprostatic lesions (DIL) thus minimizing the risk of a geographic miss. At our center, using MRI planning following the brachytherapy implant, the DIL is defined as the gross tumor volume (GTV) and receives at least the prescribed dose. This retrospective analysis studies the biochemical response and urinary symptoms of a MRI-guided escalated dose to the DIL during prostate brachytherapy. Methods: Intermediate- or high-risk patients with a visible DIL on the diagnostic MRI, treated between 2013 and 2016, with combined external-beam radiation therapy (46 Gray) and a high-dose rate whole prostate brachytherapy (15 Gray), were analyzed. Baseline characteristics and dosimetric values were obtained as well as PSA and International prostate symptom score (IPSS) at baseline, 3, 6, 12, 18, 24, 36 and 48 months (mos). Results: A total of 117 patients were studied, of which 58% were intermediate-risk and 42% high-risk. Median follow-up was 31 months (10-69 months). The biochemical progession-free survival (bPFS) was 97.4%. The median GTV D100 (dose to 100% of the GTV) and CTV V100 (percentage of the clinical target volume, defined as the whole prostate, receiving 100% of the prescribed dose) were 119% and 97.97%. The median PSA at 12, 24, 36 and 48 months for all patients and for patients treated without androgen deprivation therapy (ADT), was 0.18, 0.11, 0.06, 0.07 μg/L, and 0.73, 0.35, 0.1, 0.08 μg/L, respectively. The median IPSS score at baseline was 6 and remained stable over time. Conclusions: MRI-guided dose escalation to the GTV during brachytherapy boost yields an excellent bPFS and a rapid PSA drop without an increase in urinary symptoms. [Table: see text]