tbuckley/cabot-search huggingface dataset:
Leads from the MMWR. Antibodies to a retrovirus etiologically associated with acquired immunodeficiency syndrome (AIDS) in populations with increased incidences of the syndrome
Journal: JAMA (1984)

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CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma
Authors: Prabhavathi Maddineni, Ramesh B. Kasetti, Pinkal D. Patel, J. Cameron Millar, Charles Kiehlbauch, Abbot F. Clark, Gulab S. Zode
Journal: Molecular Neurodegeneration (2020)

Abstract Background Glaucoma is a leading neurodegenerative disease affecting over 70 million individuals worldwide. Early pathological events of axonal degeneration and retinopathy in response to elevated intraocular pressure (IOP) are limited and not well-defined due to the lack of appropriate animal models that faithfully replicate all the phenotypes of primary open angle glaucoma (POAG), the most common form of glaucoma. Glucocorticoid (GC)-induced ocular hypertension (OHT) and its associated iatrogenic open-angle glaucoma share many features with POAG. Here, we characterized a novel mouse model of GC-induced OHT for glaucomatous neurodegeneration and further explored early pathological events of axonal degeneration in response to elevated IOP. Methods C57BL/6 J mice were periocularly injected with either vehicle or the potent GC, dexamethasone 21-acetate (Dex) once a week for 10 weeks. Glaucoma phenotypes including IOP, outflow facility, structural and functional loss of retinal ganglion cells (RGCs), optic nerve (ON) degeneration, gliosis, and anterograde axonal transport deficits were examined at various stages of OHT. Results Prolonged treatment with Dex leads to glaucoma in mice similar to POAG patients including IOP elevation due to reduced outflow facility and dysfunction of trabecular meshwork, progressive ON degeneration and structural and functional loss of RGCs. Lowering of IOP rescued Dex-induced ON degeneration and RGC loss, suggesting that glaucomatous neurodegeneration is IOP dependent. Also, Dex-induced neurodegeneration was associated with activation of astrocytes, axonal transport deficits, ON demyelination, mitochondrial accumulation and immune cell infiltration in the optic nerve head (ONH) region. Our studies further show that ON degeneration precedes structural and functional loss of RGCs in Dex-treated mice. Axonal damage and transport deficits initiate at the ONH and progress toward the distal end of ON and target regions in the brain (i.e. superior colliculus). Most of anterograde transport was preserved during initial stages of axonal degeneration (30% loss) and complete transport deficits were only observed at the ONH during later stages of severe axonal degeneration (50% loss). Conclusions These findings indicate that ON degeneration and transport deficits at the ONH precede RGC structural and functional loss and provide a new potential therapeutic window for rescuing neuronal loss and restoring health of damaged axons in glaucoma.
Abstract 2347: Incidence and mortality rate of liver and intrahepatic bile duct cancer in the United States, 2000-2016
Authors: Michael Rutalira Koko, Glodi Mutamba
Journal: Cancer Research (2020)

Abstract Introduction: Liver and intrahepatic bile duct cancer is highly deadly. Incidence and mortality rates of Liver and intrahepatic bile duct cancer have increased significantly from 2000-2016 in the United States. The purpose of this study is to investigate the incidence and mortality rates of this cancer according to sex and race. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) 18 data to calculate age-adjusted incidence and mortality rates from 2000-2016. Annual Percent Change (APC) was obtained for incidence and mortality rates by sex and race. Results: Between 2000 and 2016, the incidence rate increased significantly for both male and female from 8.9 to 13.0 and 3.3 to 4.7 per 100,000 persons, respectively. Additionally, the highest incidence rates have been reported among Hispanic, non-Hispanic American Indian/Alaska Native and non-Hispanic Asian or pacific Islander with 13.5, 14.6 and 11.6 per 100,000 persons, respectively. Overall mortality rate has increased specifically among male from 5.1 to 10.9 per 100,000 persons during the same period. Hispanic, non-Hispanic American Indian/Alaska Native and non-Hispanic Asian or Pacific Islander still have the highest mortality rate compared to other race/ethnicity with 11.3, 12.9 and 9.4 per 100,000 persons), respectively. From 2015 to 2016, incidence and mortality rates have decreased among all races and gender. Conclusions: Hispanic, non-Hispanic American-Indian/Alaska native and non-Hispanic Asian or pacific Islander are at greater risk of developing and dying from this cancer. Additionally, males are more likely to acquire and die from this cancer. Prevention programs should focus on these populations in order to reduce the burden of this cancer. Further studies are necessary to examine the alarming increase in overall incidence and mortality rates of this cancer. Citation Format: Michael Rutalira Koko, Glodi Mutamba. Incidence and mortality rate of liver and intrahepatic bile duct cancer in the United States, 2000-2016 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2347.
AB0381 THE UTILITY OF HYDROXYCHLOROQUINE (HCQ) THERAPY FOR TWO YEARS AS A SPARING CORTICOSTEROID AGENCY IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Authors: K. Inoue, K. Misaki, N. Dobashi, M. Miyazaki, Y. Mako, T. Yusuke, Y. Imaizumi
Journal: Annals of the Rheumatic Diseases (2020)

Background: Prednisolone (PSL) and HCQ are key drugs in the therapy of SLE. However, since PSL induce many harmful adverse events, PSL is preferred to be reduced especially in the maintenance therapy. The efficacy of HCQ for reducing the dose of PSL has not been revealed yet. So, we focused on the cessation of PSL under the treatment of HCQ with conventional SLE therapy. Objectives: The aim of this study is to evaluate the efficacy and the safety of HCQ as co-treatment in the standard therapy of SLE. Methods: SLE patients (n=30) under the maintenance therapy were enrolled in this study. Dose of PSL, titer of anti-DNA antibody, WBC count, serum complement and SLE disease activity index (SLEDAI) were examined retrospectively at 0 and 12 months after administration of HCQ. Results: Baseline patient-characteristics are as follows (mean±S.E); the age of patients was 54.4±3.2 years old, 21 patients (70%) were female, the disease duration was 108.5±25.2 months, SLEDAI was 4.0±0.9, the dose of PSL was 10.3±1.7 mg/day, the titer of anti-DNA antibody was 7.3±1.8 IU/ml, C3 was 85±4.3 mg/dl and C4 was 18±1.6 mg/dl. The mean dose of PSL was reduced with statistically significance (pre-administration of HCQ:10.3±1.7 mg/day, 24 months after administration of HCQ:2.2±0.3 mg/day, p&lt;0.0001 ). Furthermore, in this observation period, 6 patients could achieve the cessation of PSL. SLEDAI was also significantly reduced (4.0±0.9 vs 1.0±0.3, p&lt;0.01 ). There was no statistical significance between before treatment by HCQ and after treatment in the titer of anti-DNA antibody (7.3±1.8 vs 2.8±1.6 IU/ml, p=0.06 ), WBC count (6208±4.9 vs 5096±3.3 /μl, p=0.06 ) and serum complement level (C3 85±4.3 mg/dl vs 89±4.0 mg/dl, p=0.52 , C4 18±1.6 mg/dl vs 19±1.4 mg/dl, p=0.45 ). Relapse of SLE was clarified in only one patient. As for adverse events (AEs), Severe bacterial infection (n=4), herpes zoster (n=1) and patellar tendon rupture (n=1) were revealed. All cases of the AEs were fully recovered. Conclusion: Our study suggested that co-treatment with HCQ on standard SLE therapy could be enable to prevent the flare of SLE and reduce the dose of PSL with statistical significance. In some cases, we could achieve the cessation of PSL treatment. References: None. Disclosure of Interests: None declared
Abstract 3907: Invasive properties of GSCs with known <i>IDH1</i> status into human cerebral organoids
Authors: Maxime Munyeshyaka, Sanjay Singh, Joy Gumin, Jing Yang, Daniel Ledbetter, Frederick Lang
Journal: Cancer Research (2020)

Abstract Glioblastomas (GBM) are malignant Grade IV tumors whose prognosis for patients remains dismal, with median survival of 14.6 months after the standard therapy. GBMs have a high proliferative index and are highly invasive to normal brain tissue. GBMs characteristically exhibit areas of necrosis and recruitment of abnormal blood vessels. The most common form of GBMs are primary GBMs (~95%), with no prior clinical history and have poor clinical outcome. Secondary GBMs arise from lower-grade gliomas and are associated with IDH1 mutation (R132H/C/G/S). Methylation profiling identified a subtype of GBMs called glioma-CpG island methylator phenotype (G-CIMP+ve) GBMs, and this subtype yields significant survival benefit compared to non-G-CIMP+ve GBMs and is mostly associated with IDH1 mutant GBMs. GBM biology is traditionally investigated by utilizing patient-derived tumor cells (e.g GBM stem-like cells “GSCs”) in vitro and in vivo as orthotopic xenografts in immunocompromised mouse models. However, these systems lack normal human neural tissue, and therefore the contribution of the normal human neural microenvironment is unable to be studied using these systems. This shortcoming can be addressed by utilizing human cerebral organoids (COs). Cerebral organoids are derived from induced pluripotent stem cells and can serve as in vitro model systems to recapitulate the human brain microenvironment where multiple neural cell types are represented. A recent study showed that GSCs invade and proliferate in human cerebral organoids, and these tumors phenocopy parental tumors. Here, we hypothesized that the invasiveness of GSCs within COs is dictated by IDH1 status, where IDH1 wild-type are more aggressive than IDH1 mutant GSCs. To test our hypothesis, we utilized 45 day-old COs and three GSCs lines (2 IDH1 wild-type and 1 IDH1 mutant) for in vitro invasion and proliferation assays. These GSCs stably express either green or red fluorescent proteins and can be used as surrogates to identify GSCs within COs. Upon co-incubation for various time points, these GSC bearing COs were fixed, embedded, sectioned, and imaged with a confocal microscope. Our preliminary results show that GSCs with wild-type IDH1 appear to be more aggressive within COs. With further research studies, the use of COs will elucidate the contribution of the normal brain microenvironment to the growth and invasiveness of GBMs. Citation Format: Maxime Munyeshyaka, Sanjay Singh, Joy Gumin, Jing Yang, Daniel Ledbetter, Frederick Lang. Invasive properties of GSCs with known IDH1 status into human cerebral organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3907.
Association of Maternal Prepregnancy Weight and Gestational Weight Gain With Children’s Allergic Diseases
Authors: Yiting Chen, Jianzhen Zhu, Jiajun Lyu, Yuanqing Xia, Yong Ying, Yabin Hu, Jiajie Qu, Shilu Tong, Shenghui Li
Journal: JAMA Network Open (2020)

Information on the association between maternal prepregnancy body weight, gestational weight change, and childhood allergies is not consistent. Little is known on whether there is a combined association with comprehensive childhood allergies.To examine the association of maternal prepregnancy body mass index and gestational weight gain (GWG) with the risk of childhood allergic diseases including asthma and/or wheezing, allergic rhinitis, eczema, and food and/or drug allergy.This cross-sectional study was conducted from April 12 to June 1, 2019, using the Shanghai Children Allergy Study (SCAS), a large, population-based survey. A multistage and multistrata sampling approach was applied to conduct the survey in 13 districts across Shanghai, China, with an enrollment of 15 145 mother-child pairs.Reported maternal weight before pregnancy and at the time of delivery were requested in the survey; GWG was examined in absolute terms and with reference to the Institute of Medicine guideline.The ascertainment of allergic diseases was based on the International Study of Asthma and Allergies in Childhood questionnaire.Among 15 145 children aged 3 to 14 years (7911 [52.2%] boys) within the SCAS, 8877 children (58.6%) were screened for allergic diseases. Multivariable log-binomial regression models suggested that excessive GWG was associated with risks of 19% for asthma/wheezing, 11% for allergic rhinitis, and 10% for eczema in the children. Gestational weight gain extremely above the Institute of Medicine guideline in women who were overweight/obese before pregnancy was associated with the highest risk of childhood asthma/wheezing (adjusted prevalence ratio, 1.42; 95% CI, 1.16-1.74; P = .001), allergic rhinitis (adjusted prevalence ratio, 1.32; 95% CI, 1.12-1.56; P = .001), and eczema (adjusted prevalence ratio, 1.24; 95% CI, 1.08-1.41; P = .002). Gestational weight gain below the Institute of Medicine guideline was associated with an attenuated risk of 13% for childhood asthma/wheezing, 11% for allergic rhinitis, 14% for eczema, and 15% food/drug allergy when mothers were of prepregnancy normal weight; similar associations were observed in underweight mothers, but there was no association in overweight mothers. Generally, the associations were similar in the stratified analysis according to children's age group. Moreover, the results were similar in the allergen test subgroup.The findings of this study suggest that excessive GWG may be a risk factor for childhood allergic diseases. Further studies on the long-term effects of the intrauterine environment on children's health may take maternal weight management during pregnancy into consideration since GWG could be a controllable and modifiable risk factor.
Abstract 6473: Outcomes of advanced renal cell carcinoma with sarcomatoid features post-cytoreductive nephrectomy in clear cell and non-clear cell disease
Authors: Jacob J. Adashek, Alyssa Bilotta, Jad Chahoud, Jiannong Li, Philippe E. Spiess
Journal: Cancer Research (2020)

Abstract Background: Cytoreductive nephrectomy in the setting of treatment of advanced renal cell carcinoma with sarcomatoid features (sRCC) has been highly contested in terms of added benefit for survival. Patients with sRCC are known to have a poor prognosis and more aggressive tumor biology. Methods: Pts with clear cell RCC and non-clear cell RCC underwent cytoreductive nephrectomy in efforts to improve overall survival. Patients were stratified by presence or absence of histologic presence of sarcomatoid features within the tumor samples. Results: Of 167 patients who underwent cytoreductive nephrectomy, 127 had clear cell, of which 14 had sarcomatoid features and 40 had non-clear cell RCC of which 13 had sarcomatoid features. Median age in the cohort was 62 (range, 56.5-69). The cohort included 119 male (71.3%) and 48 (28.7%) female patients. There were 121 patients with &amp;gt;T3 disease, 24 (14.4%) with T2a/b disease, and 22 (13.2%) with T1a/b disease. In all patients with advanced RCC having sRCC had a significant impact on survival post-cytoreductive nephrectomy (30 vs. 8 mos; HR 2.88; p &amp;lt;0.0001). Additionally, good-risk patients had significantly longer OS compared to intermediate- or poor-risk patients (56 vs 30 vs 10 mos; HR 0.21; p = 0.00016). For patients with clear cell RCC, having sRCC present conferred a poorer significant survival (30 vs 9 mos; HR 2.82; p = 0.0035). Patients with non-clear cell sRCC also had significantly worse outcomes compared to those without sarcomatoid features (30 vs 6.5 mos; HR 3; p = 0.009). When sRCC patients were stratified by whether there was &amp;gt;10% or ≤10% present within the sample, there was no significant difference in overall survival (8 vs 8.5; p = 0.32). Conclusions: Sarcomatoid features within tumor histology confers significantly poor prognosis. Patients with sRCC regardless of clear cell vs non-clear cell histology have significantly shorter overall survival. Even among patients with 10% or less sarcomatoid features there was no overall survival benefit to cytoreductive nephrectomy. Based on our findings, there appears to be a limited to no role of cytoreductive nephrectomy, if sRCC is identified on pre-treatment biopsy. Citation Format: Jacob J. Adashek, Alyssa Bilotta, Jad Chahoud, Jiannong Li, Philippe E. Spiess. Outcomes of advanced renal cell carcinoma with sarcomatoid features post-cytoreductive nephrectomy in clear cell and non-clear cell disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6473.
Abstract 6152: Characterizing cancer stem cells in diffuse intrinsic pontine glioma
Authors: Sarah F. Ferris, Rachel K. Surowiec, Carlos Espinoza, Stefanie Galban
Journal: Cancer Research (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain cancer with a five-year survival rate of less than 1%. This is reflective of a 100% tumor reoccurrence emphasizing the need for efficacious therapies. Previous studies have identified Aldehyde dehydrogenase expression (ALDH) as a marker for stemness and an indicator of tumor aggression and therapeutic resistance in many malignancies including adult glioma. Understanding the role of cancer stem-cells in gliomagenesis of DIPG is critical for developing therapies targeting resistance and averting 200-400 pediatric deaths in the US per year. We identified a subpopulation of cells expressing the ALDH cancer stem-cell marker in patient-derived DIPG cell lines with high variability in ALDH expression among the cell lines likely indicating previous treatment and resistance. As expected, proliferation and neurosphere formation as well as neurosphere size were dramatically increased in ALDH+ CSC compared to ALDH- CSC supporting our hypothesis of a tumor initiating, aggressive subpopulation likely conferring therapeutic resistance. To evaluate tumor initiation properties of ALDH+ CSC subpopulation in vivo, implantation of SU-DIPG-7 luciferase expressing cells into the pons of immunocompromised mice (NSG) was performed after sorting for ALDH by FACS. Our results demonstrate tumor initiation and tumor growth in ALDH+ mice as assessed by Bioluminescence imaging (BLI) as well as histological analysis. Furthermore, survival of mice implanted with ALDH+ CSCs was significantly reduced compared to mice implanted with ALDH- cells indicating tumor initiating and ‘stem cell' properties of this subpopulation. In summary, we have identified and characterized ALDH+ cancer stem-cells in DIPG which are more aggressive than the non-cancer stem-cell population (ALDH-). These results highlight the need to develop therapies targeting this highly aggressive cancer stem-cell population. Future studies investigating the gene regulation response to treatment in these stem-cell subpopulations could provide valuable insight to co-targeted therapies to address treatment resistance in DIPG. Citation Format: Sarah F. Ferris, Rachel K. Surowiec, Carlos Espinoza, Stefanie Galban. Characterizing cancer stem cells in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6152.
Abstract 3754: PPP6C regulation of ERK signaling in melanoma
Authors: Eunice Cho, Hua Jane Lou, Benjamin E. Turk
Journal: Cancer Research (2020)

Abstract Melanoma, the deadliest form of skin cancer, is characterized by aberrant hyperactivation of the ERK mitogen-activated protein kinase signaling pathway. Inhibitors of BRAF and MEK1/2, both members of this pathway, have shown clinical efficacy and are used in combination to treat BRAFV600E melanoma, the most common melanoma genomic subtype. However, not all BRAFV600E melanomas respond to these inhibitors, and those that do respond eventually acquire resistance. To better understand mechanisms of drug susceptibility in BRAFV600E melanoma, we performed a loss-of-function screen to identify kinases and phosphatases that modulate sensitivity to two clinical MEK1/2 inhibitors. In this screen, we identified PPP6C, the catalytic subunit of protein phosphatase 6 (PP6), as a factor promoting sensitivity to MEK1/2 inhibition. PPP6C is a potential tumor suppressor mutated in 7-12% of melanomas, and has roles in cell cycle regulation and DNA damage repair. shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of PPP6C in BRAF mutant melanoma cells both lead to hyperactivation of MEK1/2 and ERK1/2, resulting in decreased sensitivity to pathway inhibitors. This finding was confirmed in a panel of BRAFV600E melanoma cell lines. Through in vitro biochemical and cell-based studies, we have established that PP6 directly dephosphorylates MEK1/2. As with complete loss of PPP6C, cells expressing most recurrent cancer-associated PPP6C mutants similarly have hyperactive ERK signaling. Our studies support a novel negative regulatory role for PPP6C in ERK signaling that contributes to its activity as a tumor suppressor and promotes pathway inhibitor sensitivity in BRAFV600E melanoma. Citation Format: Eunice Cho, Hua Jane Lou, Benjamin E. Turk. PPP6C regulation of ERK signaling in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3754.