tbuckley/cabot-search huggingface dataset:
Large X-Linked Palindromes Undergo Arm-to-Arm Gene Conversion across Mus Lineages
Authors: Callie M Swanepoel, Emma R Gerlinger, Jacob L Mueller
Journal: Molecular Biology and Evolution (2020)

Large (>10 kb), nearly identical (>99% nucleotide identity), palindromic sequences are enriched on mammalian sex chromosomes. Primate Y-palindromes undergo high rates of arm-to-arm gene conversion, a proposed mechanism for maintaining their sequence integrity in the absence of X-Y recombination. It is unclear whether X-palindromes, which can freely recombine in females, undergo arm-to-arm gene conversion and, if so, at what rate. We generated high-quality sequence assemblies of Mus molossinus and M. spretus X-palindromic regions and compared them with orthologous M. musculus X-palindromes. Our evolutionary sequence comparisons find evidence of X-palindrome arm-to-arm gene conversion at rates comparable to autosomal allelic gene conversion rates in mice. Mus X-palindromes also carry more derived than ancestral variants between species, suggesting that their sequence is rapidly diverging. We speculate that in addition to maintaining genes' sequence integrity via sequence homogenization, palindrome arm-to-arm gene conversion may also facilitate rapid sequence divergence.
Combination therapy of meloxicam, a selective COX-2 inhibitor, and interferon alfa in metastatic renal cell carcinoma: A phase II study on efficacy and toxicity
Authors: N. Shinohara, T. Harabayashi, A. Sazawa, K. Nonomura, Y. Watarai, A. Kumagai, M. Murakumo, K. Kanagawa, S. Sakashita
Journal: Journal of Clinical Oncology (2007)

5105 Background: Cyclooxygenase (COX)-2 plays a major role in the development of cancer through numerous mechanisms. We have previously confirmed that COX-2 is expressed in a renal cell carcinoma (RCC) and it has an important role in tumorigenesis and angiogenesis (Int J Cancer 2004). Some preclinical studies suggest that a selective COX-2 inhibitor may augment the antitumor effects of immunotherapeutic agents. We conducted a phase II trial of the combination of meloxicam, a selective COX-2 inhibitor, and interferon (IFN)-alfa 2a in metastatic RCC in order to test the hypothesis that meloxicam enhances the response to the immunotherapy. Methods: Eligible patients had metastatic RCC, no prior systemic therapy, performance status 0–2, measurable disease. Patients received IFN 3–5 MIU 3x/week and meloxicam 10 mg/daily orally. This was a single-stage trial. Primary end points were RECIST response rates and toxicity. Results: Twenty-one patients were enrolled. Patients characteristics included: median age 63 years (49–75), male/female: 16/5, PS 0/1/2: 11/6/4, prior nephrectomy: 16 (76%). MSKCC prognostic categories were good: intermediate: poor (24%: 48%: 29%). A median follow-up was 8 months (range 3–29+) and 18 of 21 (86%) patients are still alive. Toxicities were mostly grade 1 or 2 (fever, fatigue, anorexia, depression), except 1 patient with grade 3 liver dysfunction. Among 20 patients evaluable for response, complete response (CR) was observed in 3 patients (15%) and partial response (PR) in 5 (25%), yielding an overall response rate of 40% (95% CI: 17–63). An additional 5 patients (25%) had stable disease. Five of 6 patients classified as poor risk by MSKCC prognostic classification obtained a CR or PR, as did 3 of 14 patients as good or intermediate risk (p=0.038). Median time to progression for 20 patients was 6 months (1–29+). Conclusions: The overall response rate of 40% for the combination of meloxicam and IFN-alfa in metastatic RCC is greater than that of IFN-alfa alone reported previously, suggesting that meloxicam can enhance the response to immunotherapy. Further investigation with this combination is warranted. No significant financial relationships to disclose.
Abstract P419: Association Between Bundle Branch Block and Coronary Artery Status: Insights From The LIFE Heart Study
Authors: Jelena Kornej, Falco Kosich, Sylvia Henger, Joachim Thiery, Holger Thiele, Markus Scholz
Journal: Circulation (2020)

Background: Pro-fibrotic changes create a substrate for initiation and perpetuation of arrhythmias. PR interval prolongation ( pPR ) reflects the electrophysiological conduction disturbances in atria, while bundle branch block ( BBB ) mirrors impaired conduction in ventricles. Both pPR and BBB might be caused by fibrosis leading to remodeling processes, which can be recognized using ECG. Coronary artery disease ( CAD ) may impair blood circulation and facilitate cardiomyocytes’ death with their consequent replacement by fibrotic cells. Aims: To analyze the association between BBB and coronary artery status in the LIFE-Heart Study. We hypothesized that fibrotic patterns in ECG measured as BBB and pPR are associated with CAD. Methods: We analyzed patients with available demographic, echocardiographic, ECG and coronary catheterization data recruited at the Heart Center Leipzig between 2006 and 2014. CAD was defined as stenosis ≥50%, coronary artery sclerosis (CAS) - as plaque obstruction &lt;50%, pPR interval as PR≥200 ms, BBB as QRS ≥120 ms. Results: In total, 1.750 patients (median age 65 (IQR 55-71) years, females 36%) were included. There were 376 (22%) patients with CAS and 669 (38%) with CAD, pPR and BBB were documented in 181 (10.3%) and 176 (10.1%) patients, respectively. There was a significant association between pPR and BBB (OR 2.70, 95%CI 1.78-4.03, p&lt;0.001). CAD extent and origin were not associated with pPR and BBB. However, after adjustment for age and gender, CAS (OR 1.51, p=0.021) was associated with BBB. On multivariable analysis, beside age (OR 1.05, 95%CI 1.03-1.08, p&lt;0.001), males (OR 1.72, 95%CI 1.12-2.64, p=0.013), and EF (OR 0.95, 95%CI 0.93-0.96, p&lt;0.001), both CAS (OR 1.61, 95%CI 1.08-2.39, p=0.019), and pPR (OR 2.07, 95%CI 1.30-3.32, p=0.002) remained robustly associated with BBB. Conclusion: The prevalence of BBB and pPR was similar in LIFE-Heart Study. Patients with CAS have more often BBB than patients with CAD or normal coronary vessels. Neither CAD extent, nor origin were associated with BBB.
Abstract P359: Assessment of Household Salt Types, Iodine Intake, and Iodine Status in 2019-2020 NHANES
Authors: Abby G Ershow, Jaime Gahche, Nancy Potischman, Judith Spungen, Pamela Pehrsson
Journal: Circulation (2020)

Background: Iodine is an essential nutrient required for normal thyroid function in all age groups as well as healthy fetal, infant, and child development and growth. Because iodine levels in most foods are low, iodine usually must be provided through dietary supplements or fortified foods (such as salt). In recent NHANES cycles, sub-optimal iodine status has been observed in some U.S. populations, most notably pregnant women. Recent health campaigns have emphasized consuming less sodium and have focused on the primary source of the excess sodium in the U.S. diet: commercially prepared foods, most of which are made with non-iodized salt. Also, recent secular trends towards less home cooking and more use of non-iodized table salts may be contributing to relatively low usage of iodized salt, which was estimated in 2014 to comprise only half of retail salt sales. Therefore, for individuals who also limit their home use of salt in food preparation or at the table, an unintended consequence may be a decline in iodine intake. Population-level data thus are needed on the relative contributions of various foods to iodine intake in relation to iodine status markers, to characterize population groups at risk and develop guidance on appropriate dietary and supplementation strategies. Objective: Describe new measures of iodine intake and iodine status added into NHANES 2019-20, which is a nationally representative survey of the U.S. population. Methods: Iodine intake is being assessed through a questionnaire about household salt types (such as iodized salt or sea salt) and measured iodine content of household iodized salt, as well as individual 24-hour dietary recalls and use of iodine containing dietary supplements. This will be the first time NHANES will estimate dietary iodine intake using a newly developed USDA Special Interest Database on Iodine Content of Foods. Biomarkers include a thyroid panel (including thyroglobulin), inhibitors of iodine uptake in the thyroid (e.g., perchlorates), and urinary iodine concentration. Conclusions: The upcoming NHANES cycle will yield novel data on U.S. population coverage of household iodized salt, as well as individual thyroid and iodine status in relation to dietary iodine intake. Groups at risk from increased physiologic need or dietary preferences that limit iodine sources will be identified. A key tool in undertaking this work will be a new food composition database on the iodine content of U.S. foods. Clarification of key sources of iodine in the U.S. diet will be important in developing dietary guidance.
Bowen disease of the nail apparatus with <scp>HPV</scp> 16 positivity and resolution with human papillomavirus vaccination
Authors: Y.J. Jeon, D.W. Koo, J.S. Lee
Journal: British Journal of Dermatology (2020)

Funding sources: no external funding. Conflicts of interest: none to declare. A 15‐year‐old woman presented with a 4‐year history of enlarging, tender, verrucous plaque involving the nailfolds of the thumbs (a). Histopathological examination revealed moderate dysplasia of the squamous epithelium with perinuclear haloes, suggesting Bowen disease related to viral infection (c, d).1 HPV16 positivity appeared in the human papillomavirus (HPV) genotyping polymerase chain reaction test. She was treated with cryosurgery (three freeze–thaw cycles for 30 s, two sessions with a 1‐month interval) and HPV vaccine injection (Gardasil®) with no sign of recurrence for 6 months (b). Few cases of HPV‐associated Bowen disease of the nail apparatus have been reported.1,2 We report a case of HPV16+ Bowen disease on the periungual area with favourable outcome following cryosurgery and vaccination. ...
Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss
Authors: Behzad Najafian, Camilla Tøndel, Einar Svarstad, Marie-Claire Gubler, João-Paulo Oliveira, Michael Mauer
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Mutations in the gene encoding α -galactosidase A leads to globotriaosylceramide accumulation in various cell types; in podocytes, this accumulation progresses with age. In this study of 55 males with classic Fabry disease genotype and/or phenotype, the authors found an increasing fraction of podocyte cytoplasm occupied by globotriaosylceramide, which plateaued at around the age of 27 years. At the same time, podocyte volume continued to rise, apparently at the expense of increasing podocyte stress (indicated by increasing podocyte foot process width) and podocyte loss. These changes associated with increasing urinary protein excretion, a strong prognosticator of adverse renal outcomes, and with reduction in GFR, indicating a need for early intervention before critical podocyte loss. Background In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α -galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss. Methods In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases. Results Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion—a strong prognosticator of adverse renal outcomes in Fabry disease—as well as with decreasing GFR. Conclusions Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.
Abstract P268: Greater Cognitive Impairment Among Older Adults With Type 1 Diabetes as Compared to Non-diabetic Controls: Results From the Study of Longevity in Diabetes (SOLID)
Authors: Mary E Lacy, Paola Gilsanz, Chloe Eng, Michal S Beeri, Andrew J Karter, Rachel A Whitmer
Journal: Circulation (2020)

Introduction: Studies have shown poorer cognitive function in children and adolescents with type 1 diabetes (T1D) as compared to non-diabetic peers. However, little is known about cognitive function in older adults with T1D. Hypothesis: We hypothesized that older adults with T1D and type 2 diabetes (T2D) would have greater cognitive impairment than age, sex, race/ethnicity, and education-matched controls without diabetes. Methods: We compared baseline cognitive impairment among older adults (aged ≥60) from the Study of Longevity in Diabetes (SOLID) with T1D (n=771), T2D (=234) and no diabetes (n=253). Cognitive tests assessed three cognitive domains identified via factor analysis (language, executive function, episodic memory). All cognitive test scores were standardized and cognitive impairment was defined as 1.5 SD below the mean. In logistic regression models adjusted for age, sex, education, and race/ethnicity, we examined the association between diabetes status (T1D, T2D or no diabetes) and cognition on each cognitive domain and on global cognition (average of scores on the 3 domains). Results: In adjusted regression models, compared to older adults without diabetes, those with T1D were more likely to have impaired cognitive function on the language (OR=2.13, 95% CI: 1.08, 4.17) and executive function domains (OR=2.66, 95% CI: 1.36, 5.22). No significant differences in global cognitive impairment or impairment on the episodic memory domain were observed for T1D and no significant differences on any domain were observed for T2D. Conclusions: Our findings suggest that older adults with T1D have greater cognitive impairment than their peers without diabetes; findings were specific to the language and executive function domains, with episodic memory being unaffected. No increase in cognitive impairment was observed for older adults with T2D. Additional research is needed to understand the causes and potentially modifiable factors associated with impaired cognition among older adults with T1D.
A functional scaffold to promote the migration and neuronal differentiation of neural stem/progenitor cells for spinal cord injury repair
Authors: Weiyuan Liu, Bai Xu, Weiwei Xue, Bin Yang, Yongheng Fan, Bing Chen, Zhifeng Xiao, Xiaoyu Xue, Zheng Sun, Muya Shu, Qi Zhang, Ya Shi, Yannan Zhao, Jianwu Dai
Journal: Biomaterials (2020)
ターゲッティングプログラム死1+脂肪T細胞による,加齢および食事誘発肥満マウスにおける脂肪炎症およびインスリン抵抗性の改善
Authors: Shirakawa Kohsuke, Yan Xiaoxiang, Shinmura Ken, Endo Jin, Tamaki Kayoko, Katsumata Yoshinori, Yamamoto Tsunehisa, Anzai Atsushi, Matsuhashi Tomohiro, Fukuda Keiichi, Sano Motoaki
Journal: Circulation (2015)
Covid-19: hoarding and misuse of protective gear is jeopardising the response, WHO warns
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Nearly 90 million face masks are required every month to protect health staff as they tackle covid-19, the World Health Organization has estimated, as it warned that current supplies were “rapidly depleting.”

The ability of countries to respond to the outbreak is being compromised by the “severe and increasing disruption to the global supply of personal protective equipment—caused by rising demand, hoarding, and misuse,” said WHO’s director general, Tedros Adhanom Ghebreyesus.

Speaking at the daily press briefing on 3 March, he warned that stopping the covid-19 outbreak would not be possible without protecting …
Editor's Note: Regulation of HMGA1 Expression by MicroRNA-296 Affects Prostate Cancer Growth and Invasion
Authors: Jian-Jun Wei, Xinyu Wu, Yi Peng, Guizhi Shi, Basturk Olca, Ximing Yang, Garrett Daniels, Iman Osman, Jiangyong Ouyang, Eva Hernando, Angel Pellicer, Johng S. Rhim, Jonathan Melamed, Peng Lee
Journal: Clinical Cancer Research (2020)

The editors are publishing this note to alert readers to a concern about [this article][1] ([1][2]). In Fig. 1C, similarities exist in two sets of the HMGA1 (mRNA) beta actin blots: DU145 cells treated with Block-it and with anti-Let-7, and DU145 cells treated with anti-296 and PC3 cells treated
Employing a blood based gene expression signature to detect early stage breast cancer
Authors: D. Tobin, T. Lindahl, N. Hagen, K. Bårdsen, M. Jensen, P. Sharma, A. Lönneborg, A. Børresen-Dale, J. Aarøe2, S. Sæbø, P. Skåne
Journal: Journal of Clinical Oncology (2007)

21117 Background: Existing methods to detect breast cancer (BC) in asymptomatic patients have limitations, and there is a need to develop more accurate and convenient methods. We recently demonstrated the potential use of gene expression profiling in peripheral blood cells (PBC) for early detection of BC (1) and repeated this with a larger study using the Agilent platform with an accuracy of 75± 7%. Objective: 2 studies are presented that investigate: i) whether effective normalization of experimental conditions can improve diagnostic accuracy, ii) whether a blood based signature developed for BC can discriminate other forms of cancer, and iii) whether an expression signature developed using stage 0 patients can be used to predict BC in stage I disease, and vice versa. Material and Methods: Study I enrolled 60 females with BC and 60 healthy females. Study II enrolled 20 females with early stage BC (10 stage 0 and 10 stage I), 20 healthy females, and 8 females with colon cancer. Gene expression analysis was conducted using the ABI HGSM v2.0 with 32,878 oligo probes. Expression data were analyzed by PLSR for model building and results validated using cross-validation and test set validation. Results: Effective normalization of the data led to improved diagnostic performance. The signature developed using 20 BC and 20 non-BC samples classified 7/8 colon cancer patients as non-BC. The signature developed using stage 0 vs non-BC detected cancer in stage I patients, and the signature developed for stage 1 detected cancer in stage 0 patients. Conclusion: A blood-based gene expression signature can be developed for early stage breast cancer, which is specific and able to distinguish between other forms of malignancy such as colon cancer. The gene expression pattern is systemically affected in early stage BC patients in which there is typically no direct contact of blood cells with cancer cells. References: 1. Sharma P et al. (2005) Breast Cancer Res. 7 (5): R 634–44 2. Aaroe J et al (2006), poster no:125, 97th AACR Annual Meeting, Washington DC, USA Some RT-PCR analyses were performed by Marion Hirt IMGM Laboratories, Martinsried, Germany. [Table: see text]
Abstract 11122: Early Experience With Novel Real-Time and Extended Wear Continuous Cardiac Rhythm Monitor
Authors: Mehdi Razavi, Lori Crosson, Mike Hsu, Julie Campioni, Judith C Lenane
Journal: Circulation (2019)

Introduction: Delays in cardiac rhythm monitoring for select high-risk patients may lead to delay in patient diagnosis and potential life-saving intervention. Similarly, episodic and/or short durat...
Cysteine 202 of cyclophilin D is a site of multiple post-translational modifications and plays a role in cardioprotection
Authors: Georgios Amanakis, Junhui Sun, Maria M Fergusson, Shane McGinty, Chengyu Liu, Jeffery D Molkentin, Elizabeth Murphy
Journal: Cardiovascular Research (2020)

Abstract Aims Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. We investigated whether C202 regulates the opening of PTP. Methods and results We developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Infarct size is reduced in CypD-C202S Langendorff perfused hearts compared to wild type (WT). Cardiac mitochondria from CypD-C202S mice also have higher calcium retention capacity compared to WT. Therefore, we hypothesized that oxidation of C202 might target CypD to the PTP. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component F1F0-ATP-synthase. We previously found C202 to be S-nitrosylated in ischaemic preconditioning. Cysteine residues can also undergo S-acylation, and C202 matched an S-acylation motif. S-acylation of CypD-C202 was assessed using a resin-assisted capture (Acyl-RAC). WT hearts are abundantly S-acylated on CypD C202 under baseline conditions indicating that S-acylation on C202 per se does not lead to PTP opening. CypD C202S knock-in hearts are protected from ischaemia/reperfusion injury suggesting further that lack of CypD S-acylation at C202 is not detrimental (when C is mutated to S) and does not induce PTP opening. However, we find that ischaemia leads to de-acylation of C202 and that calcium overload in isolated mitochondria promotes de-acylation of CypD. Furthermore, a high bolus of calcium in WT cardiac mitochondria displaces CypD from its physiological binding partners and possibly renders it available for interaction with the PTP. Conclusions Taken together the data suggest that with ischaemia CypD is de-acylated at C202 allowing the free cysteine residue to undergo oxidation during the first minutes of reperfusion which in turn targets it to the PTP.