tbuckley/cabot-search huggingface dataset:
Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells
Authors: Drew Neavin, Quan Nguyen, Maciej S. Daniszewski, Helena H. Liang, Han Sheng Chiu, Yong Kiat Wee, Anne Senabouth, Samuel W. Lukowski, Duncan E. Crombie, Grace E. Lidgerwood, Damián Hernández, James C. Vickers, Anthony L. Cook, Nathan J. Palpant, Alice Pébay, Alex W. Hewitt, Joseph E. Powell
Journal: Genome biology (2021)

Abstract Background The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) has provided a foundation for in vitro human disease modelling, drug development and population genetics studies. Gene expression plays a critical role in complex disease risk and therapeutic response. However, while the genetic background of reprogrammed cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of individual cells which would provide significant resolution. By integrating single cell RNA-sequencing (scRNA-seq) and population genetics, we apply a framework in which to evaluate cell type-specific effects of genetic variation on gene expression. Results Here, we perform scRNA-seq on 64,018 fibroblasts from 79 donors and map expression quantitative trait loci (eQTLs) at the level of individual cell types. We demonstrate that the majority of eQTLs detected in fibroblasts are specific to an individual cell subtype. To address if the allelic effects on gene expression are maintained following cell reprogramming, we generate scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type-specific eQTLs in iPSCs and show that the eQTLs in fibroblasts almost entirely disappear during reprogramming. Conclusions This work provides an atlas of how genetic variation influences gene expression across cell subtypes and provides evidence for patterns of genetic architecture that lead to cell type-specific eQTL effects.
Targeting choroidal vascular dysfunction via inhibition of circRNA-FoxO1 for prevention and management of myopic pathology
Authors: Dan Li, Chang Liu, Ya-Nan Sun, Chuan-Yan Zhu, Shan-Shan Xu, Kun Shan, Shu-Jie Zhang, Biao Yan, Yi Lu
Journal: Molecular Therapy (2021)

Myopia has become a global public health problem due to high prevalence. Although the etiological factors of myopia have been gradually recognized, the underlying mechanism remains largely elusive. Choroidal vascular dysfunction is recognized as a critical vision-threatening complication in myopia. Circular RNAs (circRNAs) are shown as the critical regulators in many biological processes and human diseases. In this study, we investigated the role of circRNAs in choroidal vascular dysfunction in myopia. The level of circFoxO1 was significantly upregulated in myopic choroid. circFoxO1 silencing suppressed choroidal endothelial cell viability, proliferation, migration, and tube formation in vitro and alleviated choroidal vascular dysfunction in vivo and ex vivo. circFoxO1 silencing retarded the progression of myopia as shown by reduced extracellular matrix remodeling and improved refractive error and axial elongation. Mechanistically, circFoxO1 acted as the sponge of miR-145 to sequester and inhibit miR-145 activity, thereby inducing VEGFA or ANGPT2 expression. miR-145 could mimic the effects of circFoxO1 silencing on choroidal endothelial phenotypes. Collectively, intervention of choroidal vascular dysfunction via regulating circFoxO1 level is a potential strategy for the prevention and management of myopia.
Immune checkpoint inhibitor–associated myocarditis: manifestations and mechanisms
Authors: Javid Moslehi, Andrew H. Lichtman, Arlene H. Sharpe, Lorenzo Galluzzi, Richard N. Kitsis
Journal: Journal of Clinical Investigation (2021)

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.
Diagnosing groin lumps
Authors: Willie Hamilton, John Pascoe, Joseph John, Tom Coats, Sophia Davies
Journal: BMJ (2021)

### What you need to know

Groin lumps are a common presentation in primary care in both sexes. Hernias are possibly the commonest cause of a groin lump. A prospective study (54 patients) found that a strangulated hernia was misdiagnosed by general practitioners in a third of patients (17) and by admitting surgeons in 15% of patients (8).1 Timely referral is critical in patients with complications or a suspected malignancy. This article outlines the presenting features of the different causes of groin lumps to aid primary care physicians in diagnosis and appropriate referral.

Figure 1 shows how the groin is traversed obliquely by the inguinal canal. The groin contains one or two deep inguinal lymph nodes, and about 11 (range 3-18) superficial inguinal lymph nodes, as per imaging studies. Inguinal lymph nodes are often palpable in healthy people.2 Their largest dimension ranges from 2.1 mm to 13.6 mm. They drain the penis, scrotum, vulva, perineum, inferior abdominal wall, and buttocks, as well as the lower leg.



Fig 1 
Anatomy of the groin



Groin lumps can broadly be divided as occurring due to infection, malignancy, or a surgical condition. Few published data exist on the incidence of the various causes of groin lumps.

### Infective lymphadenopathy

Leg cellulitis or ulcers–These are commonly associated with enlarged inguinal lymph nodes and are probably the most common cause of abnormal lymphadenopathy in the inguinal region.

Herpes simplex— More than 30 000 people in the UK received a diagnosis of genital herpes in 2018, with …
Covid-19 and aerosol transmission: up in the air
Authors: Richard Turner
Journal: BMJ (2021)

The BMJ ’s article about aerosol transmission in covid-19 rightly draws attention to an important subject, but the title—“Risk of aerosol transmission to staff outside of intensive care is likely to be higher than predicted”—is misleading.1 The risk of aerosol transmission is probably substantial in covid-19, and infection control policies should reflect this. But the quoted study does not help us quantify this risk outside of intensive care units.

The study of Hamilton and colleagues, to which the article refers, reports two …
Paraganglioma From Vaginal Wall Revealed by 131I-MIBG Scan
Authors: Kun Zheng, Shikun Zhu, Libo Chen, Fang Li, Hongli Jing
Journal: Clinical Nuclear Medicine (2021)

Vaginal paraganglioma is very rare. Most patients first presented irregular heavy menses and abnormal vaginal bleeding. The accurate diagnosis can only be made pathologically. Here we report a case of paraganglioma arising from vaginal wall in a 44-year-old woman who only presented catecholamine-related symptoms. The lesion had negative 99mTc-HYNIC-TOC (hydrazinonicotinyl-Tyr3-octreotide) activity but positive on 131I MIBG scan. Paraganglioma was highly suspected, which was confirmed by pathological and immunohistochemical findings after surgical resection of the lesion.
Maintaining homeostatic control of periodontal epithelial tissue
Authors: Ana M. Chang, Nutthapong Kantrong, Richard P. Darveau
Journal: Periodontology 2000 (2021)

Abstract Years of coevolution with resident microbes has made them an essential component of health. Yet, little is known about oral commensal bacteria’s contribution to and role in the maintenance of oral health and homeostasis. Commensal bacteria are speculated to play a host protective role in the maintenance of health. In this review, we describe and provide examples of the coordinate regulation that occurs between oral commensal bacteria and the host innate immune response to modulate and maintain oral homeostasis.
The cytotoxic effects of benzo[a]pyrene, benzo[a]pyrene-7,8-dihydrodiol, and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide on hormone-insensitive prostate carcinoma cell line PC3
Authors: Onyinye Nwagbara, Selina Darling-Reed, Ronald Thomas, Cynthia Harris, Richard Gragg
Journal: Cancer Research (2007)

117  Polycyclic aromatic hydrocarbons (PAHs) are considered as potential human carcinogens. In the present study we determined cell viability, DNA damage, and cell cycle alteration on human prostate carcinoma cell line after exposure to B[a]P, BDP, and BPDE. In this study, we used a established prostate carcinoma cell line PC3 to evaluate the cytotoxicity of B[a]P and its selected metabolites. We observed that the effect on cell viability on PC-3 was dose-dependent as determined by MTT assay. After 48 hours treatment, it was observed that at higher concentration of 50 μM (B[a]P), 20 μM (BDP), and 10 μM (BPDE) the percent viable cells are 40 %, 35%, and 30% respectively for all three compounds. The study shows that B[a]P, BDP, and BPDE induced DNA strand breaks and cell cycle arrest in prostate carcinoma cell lines in a dose-dependent manner after 48 hours treatment. DNA damage was determined by the Comet assay and while cell cycle distribution was determined by flow cytometry. At concentrations of 50 μM, 20 μM, 10 μM for B[a]P, B[a]P-7,8-dihydrodiol and BPDE respectively, the effects on DNA strand breaks was calculated and determined based on the average olive tail moment score of 21, 25, 32 respectively. For the effect in cell cycle alteration as determined by flow cytometry, there was a G1 arrest and a possible S arrest/delay at higher concentrations of each compound. The percent scores which are representation of cells at each cycle phase were 71.07(%) for 50 B[a]P, 69.53(%) for 20 BDP, and 68.29(%) for BPDE.  Taken together, our results seem to suggest that B[a]P and its selected metabolites (BDP, and BPDE) induced simultaneous multifaceted responses in prostate carcinoma cell line PC-3 such as cell death, DNA strand breaks, and modulation of cell cycle arrest/delay that could be an induction of DNA damage on human prostate carcinoma cell line. Cell death or DNA strand breaks thus may provide the basis for developing biomakers for use in the field of ecotoxicology to monitor non-lethal levels of xenobiotic induced cellular stress and toxicity.
Patterns of progression in patients treated with nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214.
Authors: Nizar M. Tannir, Robert J. Motzer, Laurence Albiges, Elizabeth R. Plimack, Saby George, Thomas Powles, Frede Donskov, Brian I. Rini, Viktor Grünwald, Hans J. Hammers, Toni K. Choueiri, Howard Gurney, Scott S. Tykodi, Camillo Porta, Mauricio Burotto, Yoshihiko Tomita, Chung-Wei Lee, Chad Tang, David F. McDermott, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

313 Background: First-line NIVO+IPI demonstrates superior survival and response benefits in intent-to-treat (ITT) patients (pts) with aRCC after long-term follow-up in the phase 3 CheckMate 214 trial. Data are scarce on tumor relapse and patterns of disease progression with immuno-oncology agents in this setting. This exploratory analysis of CheckMate 214 characterizes patterns of progression with NIVO+IPI vs SUN with 4 years minimum follow-up. Methods: Pts with clear cell aRCC were randomized to NIVO+IPI Q3W×4 followed by NIVO monotherapy Q2W, or SUN QD×4 weeks (6-week cycle). Patterns of progression were characterized in ITT pts and analyzed post hoc using descriptive statistics. Progression patterns were defined by ≥ 20% target lesion growth (T), unequivocal progression of nontarget lesions (NT), and new lesion(s) (NL). Response and progression were assessed per independent radiology review committee via RECIST v1.1. Results: Radiographic progression (RP) was documented in 299/550 (54.4%) ITT pts with NIVO+IPI vs 289/546 (52.9%) with SUN. Among ITT pts with a confirmed response (objective response = 215/550 [39.1%, NIVO+IPI] vs 177/546 [32.4%, SUN]), 71/215 (33.0%) vs 84/177 (47.5%) pts experienced post-response RP with NIVO+IPI vs SUN; 8/59 (13.6%) vs 3/14 (21.4%) progressed after complete response, and 63/156 (40.4%) vs 81/163 (49.7%) progressed after partial response, respectively. The pattern of RP differed between arms (Table). With NIVO+IPI, 106/299 (35.5%) RPs resulted from NL only vs 74/289 (25.6%) with SUN, and this differential was more pronounced in pts with an initial confirmed response (36/71 [50.7%] vs 23/84 [27.4%]). Most NL-only RPs in initial responders occurred in a single organ (34/36 [94.4%] for NIVO+IPI; 20/23 [87.0%] for SUN) with the most common being lymph nodes (11/34 [32.4%]), brain (8/34 [23.5%]), and lung (5/34 [14.7%]) with NIVO+IPI, and lymph nodes (7/20 [35.0%]), brain (4/20 [20.0%]) and adrenal gland (3/20 [15.0%]) with SUN. Additional progression details, baseline characteristics, and key efficacy outcomes in progressors will be reported. Conclusions: Differential patterns of tumor relapse and disease progression were observed after long-term follow up of patients treated with NIVO+IPI vs SUN in CheckMate 214. NL-only progression occurred more often with NIVO+IPI vs SUN, in particular in the subset of pts who progressed post-response. These patterns may have therapeutic implications. Clinical trial information: NCT02231749 . [Table: see text]
COVID-19 Vaccine–Related Local FDG Uptake
Authors: Mohan Doss, Shazia K. Nakhoda, Yi Li, Jian Q. Yu
Journal: Clinical Nuclear Medicine (2021)

We present a case of increased FDG uptake in the lymph nodes after COVID-19 vaccine administration. Restaging PET/CT scan of a 70-year-old woman with a history of multiple relapsed Hodgkin lymphoma showed muscle activity in the left upper arm laterally, which is in the deep musculature of the left deltoid muscle. There was also increased activity in several normal-sized left axillary nodes as well. On further review of the patient's history, she had received her second shot of the Pfizer-BioNTech COVID-19 vaccine approximately 2 days before the restaging PET/CT scan.
A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML
Authors: Bo-Rui Chen, Anagha Deshpande, Karina Barbosa, Maria Kleppe, Xue Lei, Narayana Yeddula, Pablo Sánchez Vela, Alexandre Rosa Campos, Robert J. Wechsler-Reya, Anindya Bagchi, Soheil Meshinchi, Connie Eaves, Irmela Jeremias, Torsten Haferlach, David A. Frank, Ze’ev Ronai, Sumit Chanda, Scott A. Armstrong, Peter D. Adams, Ross L. Levine, Aniruddha J. Deshpande
Journal: Blood (2021)
PLANETTE: A modular phase IIa multicenter open-label study evaluating the ATR inhibitor ceralasertib (AZD6738) in ATM mutant advanced solid tumors.
Authors: Wassim Abida, Elkhan Sanay, Natalia Lukashchuk, Andrew Pierce, Wessel de Graaf, Alan Lau, Vidalba Rocher Ros, Nisha Kurian, Graeme Parr, Bienvenu LoembE, Emma Dean, Rahul Raj Aggarwal
Journal: Journal of Clinical Oncology (2021)

TPS189 Background: Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are kinases that orchestrate cellular responses to DNA damage. ATM is primarily activated by DNA double strand breaks, and ATR is recruited to regions of single stranded DNA that arise due to collapsed or stalled replication forks. Although ATM and ATR are activated by distinct pathways, their downstream targets and effects partially overlap to activate cell cycle checkpoints and DNA damage repair. Ceralasertib is a potent, oral, selective inhibitor of ATR. Pre-clinical studies have consistently demonstrated synthetic lethality of ATR inhibitors, including ceralasertib, in ATM-deficient models across multiple tumor types (Kwok et al 2017, Min et al 2017, Lloyd et al 2020, Hustedt et al 2019). Early clinical evidence of efficacy is from a phase I study of ceralasertib in combination with olaparib in relapsed, refractory cancer (NCT02576444). Amongst 5 participants with a range of solid tumors harboring deleterious ATM mutations, there was 1 complete response, 3 stable diseases (1 with minor response 20-30%) and 1 patient with disease progression. Two participants had clinical benefit ongoing for more than 12 months (Eder et al 2019). ATM deficiency may be detected through genomic testing for loss-of-function alterations in the gene, or through immunohistochemical methods to detect loss of protein expression. Genomic alterations in ATM occur across multiple solid tumor types, including approximately 4% of advanced prostate cancers. Methods: PLANETTE (clinicaltrials.gov identifier (NCT 04564027) is a modular phase 2a multicenter open-label study investigating DNA-damage response agents in patients with advanced cancers that harbor molecular alterations. Module 1 will study the ATR inhibitor ceralasertib in tumors with deleterious or suspected deleterious mutations in ATM. Patients will be identified at cancer centers which routinely perform molecular profiling to detect ATM mutations. Central confirmation of ATM mutation by NGS and ATM IHC testing will be conducted retrospectively. Cohort A will enroll ~25 patients with advanced solid tumors (except NSCLC and prostate cancer), cohort B will include ~27 patients with metastatic CRPC who have previously progressed on a novel hormonal agent. The primary endpoints are investigator assessed ORR in Cohort A and composite response that includes radiographic, PSA, and CTC response per PCWG criteria in Cohort B. Secondary endpoints include duration of response, and progression free survival. Pharmacodynamic and other biomarkers will be explored. Enrolment is planned to start in November 2020. Clinical trial information: 04564027.
Covid-19: 237m vaccine doses to be distributed worldwide over next three months
Authors: Abi Rimmer
Journal: BMJ (2021)

Covid-19: 237m vaccine doses to be distributed worldwide over next three months Abi RimmerThe Covax Facility (Covax) has announced where 237 million doses of the Oxford AstraZeneca covid-19 vaccine will be delivered during the first round of its worldwide allocation.It said that the doses were being manufactured by AstraZeneca and by Serum Institute of India (SII AZ) and would be delivered between February and May. 1 Covax publishes first round of allocations.Gavi. 2 March
Diagnosis and Treatment of Irritable Bowel Syndrome
Authors: Michael Camilleri
Journal: JAMA (2021)

<h3>Importance</h3> The prevalence of irritable bowel syndrome (IBS) in the United States is between 7% and 16%, most common in women and young people, with annual direct costs estimated at more than $1 billion dollars in the United States. Traditionally, the diagnosis of IBS has been based on the positive identification of symptoms that correlate with several different syndromes associated with disorders such as IBS diarrhea, IBS constipation, functional diarrhea, functional constipation, chronic functional abdominal pain, or bloating. Several peripheral and central mechanisms initiate gastrointestinal motor and sensory dysfunctions leading to IBS symptoms. Those dysfunctions may require evaluation in patients whose symptoms do not respond to first-line treatments. <h3>Observations</h3> Validation studies of consensus symptom-based criteria have identified deficiencies that favor a simpler identification of the predominant symptoms of abdominal pain, bowel dysfunction, and bloating and exclusion of alarm symptoms such as unintentional weight loss, rectal bleeding, or recent change in bowel function. Symptom-based diagnosis of IBS is enhanced with additional history for symptoms of somatoform and psychological disorders and alarm symptoms, physical examination including digital rectal examination, and screening tests to exclude organic disease (by measuring hemoglobin and C-reactive protein concentrations). The initial treatment plan should include patient education, reassurance, and first-line treatments such as fiber and osmotic laxatives for constipation, opioids for diarrhea, antispasmodics for pain and for management of associated psychological disorders. For patients who do not respond to those IBS treatments, testing for specific functional disorders may be required in a minority of patients with IBS. These disorders include rectal evacuation disorder, abnormal colonic transit, and bile acid diarrhea. Their identification is followed by individualized treatment, such as pelvic floor retraining for rectal evacuation disorders, sequestrants for bile acid diarrhea, and secretory agents for constipation, although there is only limited evidence that this individualized management approach is effective. <h3>Conclusions and Relevance</h3> Advances in the identification of specific dysfunctions as causes of individual symptoms in the “IBS spectrum” leads to the potential to enhance the diagnosis and management of symptoms for the majority of patients for whom first-line therapies of IBS and management of comorbid psychological disorders are insufficient.
원저 : HBeAg 음성 만성 B형 간질환에서 Lamivudine의 치료 효과
Authors: Jeong， In du, Neunghwa Park, 김병철, 박지현, Kwang Won Seo, 김대현, 주광로, Do Ha Kim
Journal: Clinical and Molecular Hepatology (2003)

목적: HBeAg 음성 만성 B형 간질환 환자에서 라미부딘 치료 효과, 내성 발생률, 치료 종료 후 재발률 및 각각의 예측 인자를 알아보고자 하였다. 대상과 방법: HBeAg 음성, anti-HBe 양성이나 HBV DNA가 양성인 HBeAg 음성 만성 B형 간질환으로 진단 받은 환자 중에서 혈청 ALT치가 상승되어 있는 59명을 대상으로 라미부딘을 1일 100 mg씩 6개월(평균 14개월)이상 투여하였다. 평균 연령은 42.1세였고 남녀 비는 52:7이였다. 치료 전 혈청 ALT평균치는 368 IU/L, HBV DNA평균치는 494 pg/mL였다. 치료 전, 치료 개시 후 및 종료 후 1-2개월 간격으로 간기능 검사, HBeAg, anti- HBe, HBV DNA를 측정하였다. 치료 반응군은 반응이 일어난 시점을 기준으로 1-2개월 간격으로 2번 이상 반응이 유지되는 것을 확인한 후 투약을 중지하고 재발 유무를 추적 관찰하였다. 결과: 라미부딘 투여 후 59명 중 56명(94.9%)에서 혈청 HBV DNA가 음전되었으며 누적 음전율은 1개월 후 27%, 2개월 후 71%, 3개월 후 90%, 5개월 후 95%였다. 혈청 ALT치는 52명(88.1%)에서 정상으로 회복되었으며 대부분 6개월 내에 이루어졌다. 혈청 ALT치의 누적 정상화율은 2개월 후 30%, 3개월 후 47%, 6개월 후 78%, 10개월 후 86%였다. 혈청 HBV DNA가 음전되고 혈청 ALT치가 정상으로 유지된 치료 반응은 52예(88.1%)에서 일어났으며, 누적 치료반응률은 2개월 후 10%, 4개월 후 49%, 6개월 후 66%, 10개월 후 80%, 18개월 후 88%였다. 라미부딘 총 투여 기간이 유일한 치료 반응 예측 인자였다(p=0.000). 변이형의 출현은 5예(8.5%)에서 일어났고 누적 발생률은 10개월 후 8%, 16개월 후 13%였다. Breakthrough발생 예측 인자와 관련된 유의한 인자는 없었다. 치료 반응군중 투여 중지한 34명 중 17명(50%)에서 재발하였으며(평균 추적기간: 6개월, 범위: 1-22개월) 대부분 투여중지 6개월 내에 재발하였다. 누적 재발률은 3개월 후 24%, 6개월 후 47%, 10개월 후 66%였다. 재발과 관련된 예측 인자는 치료 반응 후 추가적인 라미부딘 투여만이 유의한 인자였다(p=0.019). 특히 12개월 이상 유지한 7명 모두에서 재발하지 않았다. 결론: 라미부딘은 HBeAg 음성 만성 B형 간질환에서 높은 치료효과와 낮은 breakthrough을 보였으며 라미부딘 투여 기간만이 유일한 치료 반응 예측 인자이었다. 그러나 치료 종료 후 많은 예에서 재발하였으며 치료 반응 후 추가적인 라미부딘 투여 기간만이 유일한 재발 예측 인자였으며 재발을 막기 위해서는 장기간의 추가적인 라미부딘 투여가 필요할 것으로 사료된다.