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Impact Of Connective Tissue Matrix Products and Critical Size Defects on Gut Microbiota and Fracture Healing in Mice 结缔组织基质产品和临界尺寸缺陷对小鼠肠道微生物群和骨折愈合的影响
Pub Date : 2024-01-11 DOI: 10.18060/27940
Alexander Harris, Ashlyn Morris, Will Varner, Reginald S Parker, Murad K. Nazzal, Amy Creecy, Sonali J. Karnik, Rachel J. Blosser, Elizabeth Scott, Hannah S. Wang, Tyler J. Margetts, Marko Dragisic, Upasana Ganguly, Jill C. Fehrenbacher, Fletcher A. White, Jessica Hathaway-Schrader, Melissa A. Kacena
Abstract: Approximately 6.2 million people in the USA alone suffer from some form of fracture annually. Depending on the intensity of trauma and complexity of the fractures, some fractures will not heal without medical intervention. It is imperative to develop novel therapies that target fracture healing. Connective Tissue Matrix (CTM) Biomedical is a company that develops human placenta, amnion, chorion, and other umbilical derived allograft products which may provide a solution to the problem of impaired fracture healing. CTM products contain structural proteins, cytokines, and growth factors that may have regenerative and anti-inflammatory properties. Although these products are already used clinically for fracture and wound healing in humans, no pre-clinical studies exist verifying their efficacy or mechanism of action. Commensal microbiota is a collection of microorganisms such as bacteria, fungi, and viruses.  Disruption of the gut microbiota, known as gut dysbiosis, can lead to a variety of disorders in other tissues. In fact, new studies indicate that alterations in the gut microbiota can affect bone health. This is likely due to impaired nutrient uptake and an increase in inflammation from bacterial byproducts that are not favorable to a healthy gut ecosystem. More recent studies indicate that the microbiota is also implicated in fracture healing. Our study aims to investigate if CTM products have a positive effect on fracture healing by affecting the gut microbiota composition and bacteriome. To test this, critical sized defects (CSD) were induced in mice and treated with various CTM implants or saline control. Fecal samples were taken on the day of surgery and weekly thereafter. Bacterial DNA was subsequently extracted from these samples and analyzed using PCR. We anticipate seeing changes in load and composition of gut bacteria following CSD surgery.
摘要: 仅在美国,每年就有约 620 万人遭受某种形式的骨折。根据创伤的严重程度和骨折的复杂性,有些骨折在没有医疗干预的情况下不会愈合。开发针对骨折愈合的新型疗法势在必行。Connective Tissue Matrix (CTM) Biomedical 是一家开发人类胎盘、羊膜、绒毛膜和其他脐带衍生异体移植产品的公司,可为骨折愈合障碍问题提供解决方案。CTM 产品含有结构蛋白、细胞因子和生长因子,可能具有再生和抗炎特性。虽然这些产品已在临床上用于人类骨折和伤口愈合,但目前还没有临床前研究验证其功效或作用机制。共生微生物群是细菌、真菌和病毒等微生物的集合。 肠道微生物群的破坏,即所谓的肠道菌群失调,可导致其他组织的各种疾病。事实上,新的研究表明,肠道微生物群的改变会影响骨骼健康。这可能是由于营养吸收受损,以及不利于健康肠道生态系统的细菌副产品导致炎症增加。最近的研究表明,微生物群也与骨折愈合有关。我们的研究旨在探讨 CTM 产品是否会通过影响肠道微生物群的组成和细菌群而对骨折愈合产生积极影响。为了验证这一点,我们在小鼠体内诱发了临界大小缺损(CSD),并用不同的 CTM 植入物或生理盐水对照组进行治疗。在手术当天采集粪便样本,之后每周采集一次。随后从这些样本中提取细菌 DNA,并使用 PCR 进行分析。我们预计在 CSD 手术后,肠道细菌的数量和组成会发生变化。
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引用次数: 0
Analysis of the Binding Partners of Clusterin in their Role in Increased Intraocular Pressure in Glaucoma 分析群集素的结合伙伴在青光眼眼压升高中的作用
Pub Date : 2024-01-11 DOI: 10.18060/27859
Clay Hepp, Anoop Magesh, Avinash Soundararajan, P. Pattabiraman
Background and Objective:Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma (POAG). Clusterin (CLU) is a secretory chaperone protein found in trabecular meshwork tissue that is implicated with POAG risk. In this study, we aimed at understanding the role of CLU and its binding partners in IOP homeostasis and POAG pathology. Methods:Normal trabecular meshwork (NTM) cell lines were used. Half of the NTM cell lines were transfected with adenovirus empty (AdMT) while the other half of the NTM cell lines were transfected with adenovirus clusterin with histidine tag (AdCLUHIS). AdCLUHIS allows for the overexpression of CLU HIS in the NTM cells. After 72 hours of transfection, the media and cell lysate were collected. As CLU is a secretory chaperone protein, the media was analyzed. Immunoprecipitation (IP) was conducted to isolate CLU HIS and all the proteins bound to it. Western blot analysis was conducted to confirmed IP worked successfully. Once it was confirmed that CLU HIS with all its binding partners was isolated successfully using IP, the media samples were sent to proteomics to determine all the specific proteins that are bound directly to CLU. Results:Western blot analysis confirmed that the overexpression of CLU HIS was successfully accomplished through adenovirus transfection. In addition, Western blot analysis confirmed that IP worked successfully. At the current moment, results of proteomics are still being developed, so the specific binding partners of CLU are still unknown at the time. Conclusions and Potential Impact:Our preliminary study suggests that CLU can be overexpressed via adenovirus and analyzed via IP. Understanding this allows for the purification of the protein and its attached binding partners. Identifying these binding partners can be novel targets for improving aqueous humor outflow through trabecular meshwork to decrease IOP and decrease one’s risk for POAG.
背景与目的:眼压升高是原发性开角型青光眼(POAG)的一个危险因素。簇蛋白(CLU)是一种存在于小梁网组织中的分泌性伴侣蛋白,与 POAG 风险有关。本研究旨在了解 CLU 及其结合伙伴在眼压平衡和 POAG 病理中的作用。方法:使用正常小梁网(NTM)细胞系。一半的NTM细胞系转染空腺病毒(AdMT),另一半的NTM细胞系转染带有组氨酸标签的腺病毒集簇素(AdCLUHIS)。AdCLUHIS 可以在 NTM 细胞中过表达 CLU HIS。转染 72 小时后,收集培养基和细胞裂解液。由于 CLU 是一种分泌型伴侣蛋白,因此要对培养基进行分析。进行免疫沉淀(IP)以分离 CLU HIS 及其结合的所有蛋白质。进行 Western 印迹分析以确认 IP 成功发挥作用。在确认使用 IP 成功分离出 CLU HIS 及其所有结合伙伴后,培养基样本被送往蛋白质组学研究,以确定直接与 CLU 结合的所有特定蛋白质。结果:Western 印迹分析证实,通过腺病毒转染,CLU HIS 成功实现了过表达。此外,Western 印迹分析也证实了 IP 的成功。目前,蛋白质组学的研究成果仍在开发中,因此CLU的特定结合伙伴尚不清楚。结论和潜在影响:我们的初步研究表明,CLU 可以通过腺病毒过表达,并通过 IP 进行分析。了解了这一点,就可以纯化该蛋白及其附着的结合伙伴。确定这些结合伙伴可以成为改善通过小梁网流出的房水的新靶点,从而降低眼压并减少罹患 POAG 的风险。
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引用次数: 0
Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Promote Muscle Regeneration in a Diabetic Mouse Model of Critical Limb Threatening Ischemia 诱导多能干细胞衍生的间充质基质细胞促进糖尿病小鼠危重肢体缺血模型中的肌肉再生
Pub Date : 2024-01-11 DOI: 10.18060/27790
Ali Sualeh, Theresa Doiron, C. Gil, Jennifer Stashevsky, Olivia Jimez, Stone Chen, Nancy Zhang, Humraaz S. Samra, Steven J. Miller, Michael P. Murphy
Critical limb threatening ischemia (CLTI), the end stage of peripheral arterial disease (PAD), is diagnosed in 500,000 patients each year, often results in amputation, and has a ~50% 5-year mortality rate. Diabetic CLTI patients experience especially high morbidity and mortality, and no effective non-surgical therapy exists for this population. Our Phase II MOBILE trial demonstrated that autologous bone marrow nucleated cells were unable to prevent amputations in diabetic patients; however, data from a Phase I trial shows that allogeneic bone marrow-derived mesenchymal stromal cells (BMD-MSC) stimulated angiogenesis in ischemic muscle, including diabetics. While allogeneic MSC may be an effective cell preparation to treat diabetic CLTI, passaging-related cell senescence prevents generation of sufficient cell numbers for therapeutic use. The development of induced pluripotent stem cell (iPSC)-derived MSC overcomes cell senescence issues and offers the possibility of genetic modifications to enhance cell function. The current study was designed to determine potential mechanisms by which iPSC-MSC stimulate muscle regeneration in a rodent CLTI model. The CLTI mouse model was created by ligation/excision of the femoral artery in male polygenic diabetic TallyHo mice. Mice with intramuscular administration of iPSC-MSC displayed positive indicators of muscle regeneration compared to vehicle control mice. Real-time PCR performed with gastrocnemius muscle obtained 7- or 30-days post iPSC-MSC injection showed an increase in mRNA expression for MyH3, MyoD1, Mrc1, FoxP3, and VEGF-A vs. vehicle treated muscle, indicating promotion of muscle regeneration, M2-biased macrophage expression, T regulatory cell (Treg) expansion, and vascular proliferation. Downregulation of the NADPHoxidase subunit p47phox indicated a decrease in oxidative stress in the treated mice. The results are consistent with iPSC-MSC  promotion of muscle regeneration via a Treg mediated stimulation of the M1-M2 macrophage phenotypic shift. Thus, human iPSC-MSC could be an effective treatment to stimulate muscle regeneration and ameliorate CLTI in diabetic patients.
危重肢体缺血(CLTI)是外周动脉疾病(PAD)的终末阶段,每年有 50 万患者被确诊,通常会导致截肢,5 年死亡率约为 50%。糖尿病 CLTI 患者的发病率和死亡率尤其高,但目前还没有针对这一人群的有效非手术疗法。我们的 MOBILE II 期试验表明,自体骨髓有核细胞无法防止糖尿病患者截肢;但 I 期试验的数据显示,异体骨髓间充质干细胞(BMD-MSC)可刺激缺血肌肉(包括糖尿病患者)的血管生成。虽然异体间充质干细胞可能是治疗糖尿病 CLTI 的有效细胞制备方法,但与传代相关的细胞衰老阻碍了产生足够数量的细胞用于治疗。诱导多能干细胞(iPSC)衍生间充质干细胞的开发克服了细胞衰老问题,并提供了基因修饰以增强细胞功能的可能性。目前的研究旨在确定iPSC-间充质干细胞在啮齿动物CLTI模型中刺激肌肉再生的潜在机制。CLTI小鼠模型是通过结扎/切除雄性多基因糖尿病TallyHo小鼠的股动脉而建立的。与药物对照小鼠相比,肌肉注射 iPSC-间充质干细胞的小鼠显示出肌肉再生的积极指标。对注射 iPSC-MSC 后 7 天或 30 天的腓肠肌进行的实时 PCR 显示,与药物处理的肌肉相比,MyH3、MyoD1、Mrc1、FoxP3 和 VEGF-A 的 mRNA 表达量增加,这表明肌肉再生、M2 偏巨噬细胞表达、T 调节细胞(Treg)扩增和血管增殖得到了促进。NADPH 氧化酶亚基 p47phox 的下调表明,经处理的小鼠氧化应激减少。这些结果与 iPSC-间充质干细胞通过 Treg 介导的 M1-M2 巨噬细胞表型转变刺激促进肌肉再生是一致的。因此,人iPSC-间充质干细胞可作为刺激糖尿病患者肌肉再生和改善CLTI的有效治疗方法。
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引用次数: 0
Detection of Bowel and Mesenteric Injuries Using Deep Learning Computer Vision Models 利用深度学习计算机视觉模型检测肠道和肠系膜损伤
Pub Date : 2024-01-11 DOI: 10.18060/27726
Neal Mahajan, S. Steenburg, Peter Gunderman, John Burns, Arya Iranmanesh
Background/Objective:While only seen in 1-5% of patients who undergo a CT (computed tomography) scan, blunt bowel and mesenteric injuries (BMI) are associated with significantly increased morbidity and mortality. A significant cause of the increased morbidity of BMI is due to the difficulty of diagnosis from clinical and imaging information which leads to delay in diagnosis. Accurate and timely diagnosis is vital to reduce the morbidity of BMI. Methods:For this project, our primary objective is to create a binary prediction model that determines if a patient has BMI based on their abdominal CT scans. Due to the importance of the early and definitive diagnosis of BMI in trauma patients, an extension of this project will seek to introduce explainability into the model to highlight which features on the CT scan caused the model to make its prediction. The patients with BMI were sourced from a trauma registry that recorded trauma cases from IU Health with relevant diagnosis codes. The images from our search will be reduced to the relevant slices for diagnosis of BMI and then used to train an ML model to makea yes/no prediction from the image. Once the model is trained, testing data will be evaluated on the model and the gradient vectors from the model during inference will be used to create a heatmap with GRAD-CAM that illustrates what portions of the image were relevant for the decision made by the algorithm. Future Directions:Using the collected abdominal CTs, we can train our machine learning pipeline to detect BMI. Based on the performance of the model, we will determine if we need to collect more data. Then, we can evaluate the explainability of the model using GRAD-CAM and compareperformance of the ML model to the performance of expert and trainee radiologists.
背景/目的:在接受 CT(计算机断层扫描)扫描的患者中,钝性肠道和肠系膜损伤(BMI)仅占 1-5%,但其发病率和死亡率却显著增加。钝性肠道和肠系膜损伤发病率增加的一个重要原因是临床和影像学信息难以诊断,导致诊断延误。准确及时的诊断对于降低 BMI 发病率至关重要。方法:在本项目中,我们的主要目标是创建一个二元预测模型,根据患者的腹部 CT 扫描结果来确定其是否患有 BMI。由于早期明确诊断创伤患者 BMI 的重要性,本项目的一个延伸部分将寻求在模型中引入可解释性,以突出 CT 扫描上的哪些特征导致模型做出预测。有 BMI 的患者来自创伤登记处,该登记处记录了来自 IU Health 并带有相关诊断代码的创伤病例。我们将把搜索到的图像缩减为用于诊断 BMI 的相关切片,然后用于训练 ML 模型,以便根据图像做出是/否预测。模型训练完成后,将对模型的测试数据进行评估,推理过程中模型的梯度向量将用于使用 GRAD-CAM 创建热图,说明图像的哪些部分与算法做出的决定相关。未来方向:利用收集到的腹部 CT,我们可以训练机器学习管道来检测 BMI。根据模型的性能,我们将确定是否需要收集更多数据。然后,我们可以使用 GRAD-CAM 评估模型的可解释性,并将 ML 模型的性能与放射科专家和实习医生的性能进行比较。
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引用次数: 0
Long-Term Outcomes in Stage II/III Thymic Epithelial Tumor Patients Treated with Post- Operative Radiotherapy 接受术后放疗的 II/III 期胸腺上皮肿瘤患者的长期疗效
Pub Date : 2024-01-11 DOI: 10.18060/27867
Nikhitha Lavu, Aneesha Anand, Patrick J. Loehrer, Kenneth A. Kesler
Thymic epithelial tumors (TETs) are rare malignancies that originate in the anterior mediastinum. Unlike other tumors of the chest, TETs recur most often in the pleura. The primary treatment of early stage TETs is surgical resection, with the role of adjuvant chemotherapy/radiotherapy controversial. Mixed results have been reported as to whether postoperative radiotherapy (PORT) decreases tumor recurrence or time to recurrence, but PORT can cause short-term and long-term toxicity. Therefore, assessing the benefit of PORT is important. For the present retrospective study, we created a database of stage II/III TET patients seen at Simon Cancer Center from 2000-2023 to examine long-term outcomes. Of the 214 stage II/III TET patients that underwent surgery in the database, 67 patients treated with PORT were isolated. Subsequently, 67 patients who did not receive PORT were matched to the PORT population based on similarities in histology, surgical margins, and chemotherapy received. Local vs. distant tumor recurrence, long-term complications, and overall survival were then compared. The PORT population had the following histologic distribution: 3 Type A, 3 Type AB, 47 Type B1/B2/B3, and 14 carcinoma; for the non-PORT population: 8 Type A, 13 Type AB, 36 Type B1/B2/B3, and 10 carcinoma. There were 16 stage IIA, 6 stage IIB, and 45 stage III patients in the PORT population, and 17 stage IIA, 9 stage IIB, and 41 stage III patients in the non-PORT population. The PORT population had 57 recurrences, whereas the non-PORT population had 20 recurrences (p=1.02 x 10-9). The PORT population had 5 deaths and 50 instances of long-term complications, while the non-PORT population had 3 deaths and 25 instances of long-term complications. Overall, these data do not support the routine usage of PORT in resected Stage II/III TET. Further analysis in larger data sets are warranted.
胸腺上皮肿瘤(TET)是一种罕见的恶性肿瘤,起源于前纵隔。与胸部其他肿瘤不同,TET 最常在胸膜复发。早期 TET 的主要治疗方法是手术切除,而辅助化疗/放疗的作用则存在争议。关于术后放疗(PORT)是否会降低肿瘤复发率或缩短复发时间,目前报道不一,但PORT会引起短期和长期毒性。因此,评估 PORT 的益处非常重要。在本回顾性研究中,我们建立了一个 2000-2023 年期间在西蒙癌症中心就诊的 II/III 期 TET 患者的数据库,以检查长期疗效。在数据库中接受手术的 214 例 II/III 期 TET 患者中,有 67 例患者接受了 PORT 治疗。随后,根据组织学、手术切缘和接受化疗的相似性,将 67 名未接受 PORT 治疗的患者与 PORT 患者进行配对。然后比较了局部与远处肿瘤复发、长期并发症和总生存率。PORT人群的组织学分布如下:3例A型、3例AB型、47例B1/B2/B3型和14例癌;非PORT人群:8例A型、13例AB型、36例B1/B2/B3型和10例癌。PORT 患者中有 16 名 IIA 期、6 名 IIB 期和 45 名 III 期患者,非 PORT 患者中有 17 名 IIA 期、9 名 IIB 期和 41 名 III 期患者。PORT人群有57例复发,而非PORT人群有20例复发(P=1.02 x 10-9)。PORT 患者中有 5 人死亡,50 人出现长期并发症,而非 PORT 患者中有 3 人死亡,25 人出现长期并发症。总体而言,这些数据并不支持在切除的 II/III 期 TET 中常规使用 PORT。有必要对更大的数据集进行进一步分析。
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引用次数: 0
Clinical Characteristics of Pre-pubescent Patients with Systemic Lupus Erythematosus (SLE) 青春期前系统性红斑狼疮患者的临床特征
Pub Date : 2024-01-11 DOI: 10.18060/27814
Ruth Zagales, Stacey E. Tarvin, Martha Rodriguez
Background:Systemic Lupus Erythematosus (SLE) is a chronic autoimmune condition that affects multiple organ systems, including cutaneous, renal, neurological, and hematological disorders. Pediatric SLE (pSLE) has a prevalence of 3.3-8.8 cases per 100,000 children. Children with SLE (cSLE) have higher disease severity than adults, but the evidence on cSLE is mostly from pubertal patients, and the reasons for the variation on presentation is unclear. There is limited data on prepubertal SLE, as SLE rarely affects pre-pubescent patients. This study aims to outline the clinical characteristics, disease activity and organ damage of pre-pubescent patients with SLE.Methods:A retrospective study was performed on prospectively collected multi-center data from 2005-2015. Patient data, including race, ethnicity, sex, age of presentation and diagnosis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and Systemic Lupus International Collaborating Clinics (SLICC) damage index was collected using REDcap.Results:This study included 43 pre-pubescent SLE patients, with an average age at diagnosis of 9.7 years and 10.7 years at the study's start. Organ systems with the highest prevalence rates were musculoskeletal (Arthritis – 69.77%) and cutaneous (Malar rash – 58.14%). The organ systems with the highest involvement frequency, according to the SLICC damage index, were skin (alopecia - 9.3%), ocular (retinal changes/optic atrophy/cataracts - 9.3%), gastrointestinal (pancreatic insufficiency – 4.65%), neuropsychiatric (cognitive impairment – 4.65%), and renal (reduced glomerular filtration rate – 4.65%). Throughout the study, all patients had SLEDAI scores ranging from no activity to high activity, with 55.8% having mild activity, 27.9% having moderate activity, and 14% having high activity.Conclusion:Similar to SLE studies on pediatric populations, our study found that cutaneous, gastrointestinal, and renal manifestations were common. However, we found a high prevalence of damage in prepubertal patients, in particular ocular and cognitive impairment. This highlights the need to prioritize ocular exams and cognitive assessments in patients with prepubertal SLE.
背景:系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病,影响多个器官系统,包括皮肤、肾脏、神经和血液系统疾病。小儿系统性红斑狼疮(pSLE)的发病率为每 10 万名儿童中有 3.3-8.8 例。儿童系统性红斑狼疮(cSLE)患者的病情严重程度高于成人,但有关 cSLE 的证据大多来自青春期患者,其表现差异的原因尚不清楚。有关青春期前系统性红斑狼疮的数据很有限,因为系统性红斑狼疮很少影响青春期前的患者。本研究旨在概述青春期前系统性红斑狼疮患者的临床特征、疾病活动性和器官损害。结果:该研究共纳入43名青春期前系统性红斑狼疮患者,诊断时的平均年龄为9.7岁,研究开始时的平均年龄为10.7岁。发病率最高的器官系统是肌肉骨骼系统(关节炎-69.77%)和皮肤系统(皮疹-58.14%)。根据 SLICC 损伤指数,受累频率最高的器官系统是皮肤(脱发 - 9.3%)、眼部(视网膜病变/视神经萎缩/白内障 - 9.3%)、胃肠道(胰腺功能不全 - 4.65%)、神经精神(认知障碍 - 4.65%)和肾脏(肾小球滤过率降低 - 4.65%)。在整个研究过程中,所有患者的SLEDAI评分从无活动到高活动不等,其中55.8%的患者有轻度活动,27.9%的患者有中度活动,14%的患者有高度活动。然而,我们发现青春期前患者的损害发生率很高,尤其是眼部和认知障碍。这凸显了对青春期前系统性红斑狼疮患者优先进行眼部检查和认知评估的必要性。
{"title":"Clinical Characteristics of Pre-pubescent Patients with Systemic Lupus Erythematosus (SLE)","authors":"Ruth Zagales, Stacey E. Tarvin, Martha Rodriguez","doi":"10.18060/27814","DOIUrl":"https://doi.org/10.18060/27814","url":null,"abstract":"Background:\u0000Systemic Lupus Erythematosus (SLE) is a chronic autoimmune condition that affects multiple organ systems, including cutaneous, renal, neurological, and hematological disorders. Pediatric SLE (pSLE) has a prevalence of 3.3-8.8 cases per 100,000 children. Children with SLE (cSLE) have higher disease severity than adults, but the evidence on cSLE is mostly from pubertal patients, and the reasons for the variation on presentation is unclear. There is limited data on prepubertal SLE, as SLE rarely affects pre-pubescent patients. This study aims to outline the clinical characteristics, disease activity and organ damage of pre-pubescent patients with SLE.\u0000Methods:\u0000A retrospective study was performed on prospectively collected multi-center data from 2005-2015. Patient data, including race, ethnicity, sex, age of presentation and diagnosis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and Systemic Lupus International Collaborating Clinics (SLICC) damage index was collected using REDcap.\u0000Results:\u0000This study included 43 pre-pubescent SLE patients, with an average age at diagnosis of 9.7 years and 10.7 years at the study's start. Organ systems with the highest prevalence rates were musculoskeletal (Arthritis – 69.77%) and cutaneous (Malar rash – 58.14%). The organ systems with the highest involvement frequency, according to the SLICC damage index, were skin (alopecia - 9.3%), ocular (retinal changes/optic atrophy/cataracts - 9.3%), gastrointestinal (pancreatic insufficiency – 4.65%), neuropsychiatric (cognitive impairment – 4.65%), and renal (reduced glomerular filtration rate – 4.65%). Throughout the study, all patients had SLEDAI scores ranging from no activity to high activity, with 55.8% having mild activity, 27.9% having moderate activity, and 14% having high activity.\u0000Conclusion:\u0000Similar to SLE studies on pediatric populations, our study found that cutaneous, gastrointestinal, and renal manifestations were common. However, we found a high prevalence of damage in prepubertal patients, in particular ocular and cognitive impairment. This highlights the need to prioritize ocular exams and cognitive assessments in patients with prepubertal SLE.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":"12 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ethanol Induces Blood Brain Barrier Dysfunction in Healthy and Familial Alzheimer’s Blood Brain Barrier Models 乙醇诱导健康和家族性阿尔茨海默氏症血脑屏障模型的血脑屏障功能障碍
Pub Date : 2024-01-11 DOI: 10.18060/27823
Abby M. Wetzel, Kameron T. Bell, J. Hughes, Scott G. Canfield
Background/Objective: The blood brain barrier (BBB) is a highly selective semipermeable membrane between the blood and brain. Active efflux transporters such as PGP, MRP-1, and BCRP and localized tight junction proteins ensure barrier integrity. Interestingly, both alcohol consumption and Alzheimer’s disease (AD) suppress barrier functions independently. Furthermore, alcohol use can lead to or worsened neurodegenerative disorders, including AD. In this study, human stem-cell derived healthy and AD BBB models with near in vivo properties are used to investigate the effects of alcohol on critical BBB properties such as barrier tightness and efflux transporter activity. Methods: Induced pluripotent stem cells (iPSCs) from healthy (IMR90) and Familial Alzheimer’s (APP, PSEN1, PSEN2) cell lines were differentiated into brain microvascular endothelial cells (BMECs).  BMECs were treated with varying ethanol concentrations (5, 25, 50, and 100 mM) for one hour. Following ethanol treatment several barrier properties were assessed: trans-endothelial electrical resistance (TEER), sodium fluorescein permeability, tight junction localization, and efflux transporter activity. Results: Moderate to severe ethanol concentrations (25 mM and 50 mM) reduced TEER and delocalized tight junctions in healthy and AD-derived BMECs, indicating a disruption in barrier integrity. AD-derived BMEC cell lines also show an increased susceptibility to ethanol-induced barrier dysregulation at lower concentrations of ethanol (5 mM). Interestingly, our preliminary data shows that ethanol exposure seems to reduce BCRP efflux transporter activity in APP and PSEN1 AD cell lines. Conclusion and Scientific Impact and Implications: This study is novel in elucidating the enhanced disruption of BBB properties in familial AD-derived BMEC cell lines following ethanol exposure and provides insight into the potential harm of alcohol consumption in the development and/or exacerbation of BBB dysfunction in Alzheimer’s disease. Further studies will also unveil the possibility of ethanol-induced reduction of BCRP efflux transporter activity in APP and PSEN1 AD.
背景/目的:血脑屏障(BBB)是血液和大脑之间的一层高选择性半透膜。PGP、MRP-1 和 BCRP 等活性外排转运体以及局部紧密连接蛋白确保了屏障的完整性。有趣的是,饮酒和阿尔茨海默病(AD)都会单独抑制屏障功能。此外,饮酒可导致或加重神经退行性疾病,包括阿尔茨海默病。在本研究中,使用了接近体内特性的人类干细胞衍生健康和阿兹海默症 BBB 模型,以研究酒精对 BBB 重要特性(如屏障紧密性和外流转运体活性)的影响。方法:将来自健康细胞系(IMR90)和家族性阿尔茨海默氏症细胞系(APP、PSEN1、PSEN2)的诱导多能干细胞(iPSCs)分化成脑微血管内皮细胞(BMECs)。 用不同浓度的乙醇(5、25、50 和 100 mM)处理 BMECs 一小时。乙醇处理后,对几种屏障特性进行了评估:跨内皮电阻(TEER)、荧光素钠通透性、紧密连接定位和外流转运体活性。结果显示中度到重度乙醇浓度(25 毫摩尔和 50 毫摩尔)降低了健康和 AD 衍生 BMEC 的 TEER 和紧密连接脱位,表明屏障完整性受到破坏。在较低的乙醇浓度(5 mM)下,AD 衍生的 BMEC 细胞系对乙醇诱导的屏障失调的敏感性也有所增加。有趣的是,我们的初步数据显示,乙醇暴露似乎降低了 APP 和 PSEN1 AD 细胞系中 BCRP 外排转运体的活性。结论及科学影响和意义:这项研究的新颖之处在于阐明了乙醇暴露后家族性 AD 衍生 BMEC 细胞系中 BBB 特性的强化破坏,并深入揭示了饮酒在阿尔茨海默病 BBB 功能障碍的发展和/或加剧过程中的潜在危害。进一步的研究还将揭示在 APP 和 PSEN1 AD 中乙醇诱导 BCRP 外排转运体活性降低的可能性。
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引用次数: 0
Assessment of Patient Referrals with Large Numbers of Non-pedunculated Colorectal Lesions 对转诊的大量非梗阻性结直肠病变患者进行评估
Pub Date : 2024-01-11 DOI: 10.18060/27740
William Cheng, Douglas Rex
Background: Large (≥20mm) non-pedunculated colorectal lesions are frequently referred to specialty centers for endoscopic resection. These lesions are technically challenging to resectand associated with substantially greater risk than smaller lesions. Patients with such polypsoften have synchronous lesions. We sought to identify evidence for whether synchronouslesions were sometimes the true basis for referral of large non-pedunculated colorectal polypsfrom community endoscopists to a tertiary center. Methods: We utilized a prospectively collected database of 1356 consecutive referred patients to an expert colonoscopist at our tertiary center between August 2019 and May 2023. We identified patients with ≥30 precancerous lesions resected from the colorectum during their first two colonoscopies at our center. Patients in the database with the same gender, within 3 yearsof age, and with the same location (proximal vs. distal colon) of the index large lesion referred for resection were identified as controls. Groups were compared for the size of index lesion,  number of polyps resected by both centers, and size of polyps resected. Results: Among 1356 patients, 49 (3.6%) had ≥30 precancerous lesions resected at our center. Compared to controls, the index lesion was smaller in patients with ≥30 lesions (mean 28.9mmvs 23.3mm). Among patients with ≥30 synchronous polyps, the referring physician resected 10.6% of all synchronous lesions, compared to 47.8% in the control group (p<0.0001). Inpatients with ≥30 lesions, 84% of all synchronous lesions were <10mm, 15% were 10-19mm, and only 1% were >20mm. Conclusion: Our results suggest a subset of patients with large non-pedunculated colorectal precancerous lesions referred to tertiary centers are referred because of the number of lesions present, rather than technical challenges associated with resection of individual lesions. The rationale for these referrals is uncertain. It may lie in the reimbursement system, which only compensates physicians for the first polypectomy.
背景:大块(≥20 毫米)非梗阻性结直肠病变经常被转到专科中心进行内镜切除。与较小的病变相比,这些病变的切除在技术上具有挑战性,而且风险更大。此类息肉患者往往伴有同步病变。我们试图找出证据,证明同步病变有时是否是社区内镜医师将大的非梗阻性结直肠息肉转诊到三级中心的真正原因。方法:我们利用了一个前瞻性收集的数据库,其中包含了 2019 年 8 月至 2023 年 5 月期间连续转诊到我们三级中心的结肠镜专家处的 1356 例患者。我们确定了在本中心进行的前两次结肠镜检查中,从结肠直肠切除癌前病变≥30 处的患者。数据库中性别相同、年龄在 3 岁以内、大病灶切除位置相同(近端结肠与远端结肠)的患者被确定为对照组。比较两组患者的指标病灶大小、两个中心切除的息肉数量以及切除息肉的大小。结果:在1356名患者中,49人(3.6%)在本中心切除了≥30个癌前病变。与对照组相比,病灶≥30 个的患者的指标病灶较小(平均 28.9 毫米对 23.3 毫米)。在同步息肉≥30 个的患者中,转诊医生切除了所有同步病变的 10.6%,而对照组为 47.8%(p20mm)。结论我们的研究结果表明,在转诊至三级中心的大面积非梗阻性结直肠癌前病变患者中,有一部分人是因为病变的数量而被转诊,而不是因为切除单个病变所面临的技术挑战。这些转诊的原因尚不确定。这可能与报销制度有关,因为报销制度只对医生的首次息肉切除术进行补偿。
{"title":"Assessment of Patient Referrals with Large Numbers of Non-pedunculated Colorectal Lesions","authors":"William Cheng, Douglas Rex","doi":"10.18060/27740","DOIUrl":"https://doi.org/10.18060/27740","url":null,"abstract":"Background: Large (≥20mm) non-pedunculated colorectal lesions are frequently referred to specialty centers for endoscopic resection. These lesions are technically challenging to resectand associated with substantially greater risk than smaller lesions. Patients with such polypsoften have synchronous lesions. We sought to identify evidence for whether synchronouslesions were sometimes the true basis for referral of large non-pedunculated colorectal polypsfrom community endoscopists to a tertiary center. \u0000Methods: We utilized a prospectively collected database of 1356 consecutive referred patients to an expert colonoscopist at our tertiary center between August 2019 and May 2023. We identified patients with ≥30 precancerous lesions resected from the colorectum during their first two colonoscopies at our center. Patients in the database with the same gender, within 3 yearsof age, and with the same location (proximal vs. distal colon) of the index large lesion referred for resection were identified as controls. Groups were compared for the size of index lesion,  number of polyps resected by both centers, and size of polyps resected. \u0000Results: Among 1356 patients, 49 (3.6%) had ≥30 precancerous lesions resected at our center. Compared to controls, the index lesion was smaller in patients with ≥30 lesions (mean 28.9mmvs 23.3mm). Among patients with ≥30 synchronous polyps, the referring physician resected 10.6% of all synchronous lesions, compared to 47.8% in the control group (p<0.0001). Inpatients with ≥30 lesions, 84% of all synchronous lesions were <10mm, 15% were 10-19mm, and only 1% were >20mm. \u0000Conclusion: Our results suggest a subset of patients with large non-pedunculated colorectal precancerous lesions referred to tertiary centers are referred because of the number of lesions present, rather than technical challenges associated with resection of individual lesions. The rationale for these referrals is uncertain. It may lie in the reimbursement system, which only compensates physicians for the first polypectomy.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":"27 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139534357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring the Influence of tGLI-1 on Temozolomide Resistance in Glioblastomas: Unraveling Novel Therapeutic Targets 探索替莫唑胺对胶质母细胞瘤耐药性的影响:揭示新的治疗靶点
Pub Date : 2024-01-11 DOI: 10.18060/27907
Hannah Von Werder, Haddie DeHart, Richard Carpenter
Background/Objective:Temozolomide (TMZ) is a standard chemotherapy treatment for patients with glioblastoma (GBM), but its effectiveness is limited, with only 50% of patients initially responding and developing resistance over time. Glioma stem cells (GSCs) have been implicated in TMZ resistance, particularly the mesenchymal subtype. The truncated form of GLI1, known as tGLI1, is highly expressed in mesenchymal GSCs and has been associated with poor patient outcomes in GBM. However, the role of tGLI1 in TMZ resistance remains unknown. Methods:The GBM cell line, U87MG, was utilized for this study. The IC50 of TMZ was determined using a cell viability assay. After successful transfection with vector, GLI1, and tGLI1, the cells were treated with the IC50 of TMZ to assess changes in cell viability between the groups. Results:The IC50 of TMZ is 290.1 μM, as averaged between replicate assays. Thus far, the results showed that tGLI1-expressing cells exhibited significantly higher cell viability (average: 39.09%) compared to Vector (average: 26.78%) and GLI1 (average: 27.11%). However, the tGLI1 group displayed higher variability in cell viability results, as evidenced by a larger standard deviation (0.2758) and standard error (0.1592) compared to vector (SD: 0.0325, SE: 0.0188) and GLI1 (SD: 0.1354, SE: 0.0781). The One-Way ANOVA, followed by Tukey's Multiple Comparison Test, results showed no statistically significant differences in cell viability between the groups. Conclusion/Impact:The increased cell viability observed in tGLI1-expressing cells suggests a potential association between tGLI1 and TMZ resistance, warranting additional research to fully comprehend its impact on GBM treatment response. Further investigation and replication studies are needed to establish the robustness of these results. This knowledge may contribute to the development oftargeted therapies aimed at inhibiting tGLI1 or its downstream signaling pathways, potentiallyimproving the response to TMZ and patient outcomes.
背景/目的:替莫唑胺(TMZ)是胶质母细胞瘤(GBM)患者的标准化疗方法,但其疗效有限,只有50%的患者最初有反应,并随着时间的推移产生耐药性。胶质瘤干细胞(GSCs)与TMZ耐药性有关,尤其是间质亚型。GLI1的截短形式,即tGLI1,在间质GSCs中高度表达,与GBM患者的不良预后有关。然而,tGLI1在TMZ耐药性中的作用仍然未知。方法:本研究使用的是 GBM 细胞系 U87MG。TMZ的IC50用细胞活力测定法确定。在成功转染载体、GLI1和tGLI1后,用IC50的TMZ处理细胞,以评估各组间细胞活力的变化。结果:TMZ 的 IC50 为 290.1 μM,为重复实验的平均值。到目前为止,结果显示表达 tGLI1 的细胞与 Vector(平均:26.78%)和 GLI1(平均:27.11%)相比,细胞存活率明显更高(平均:39.09%)。然而,tGLI1 组细胞存活率结果的变异性更高,表现为标准偏差(0.2758)和标准误差(0.1592)大于载体组(SD:0.0325,SE:0.0188)和 GLI1 组(SD:0.1354,SE:0.0781)。单向方差分析和 Tukey's 多重比较检验的结果表明,各组之间的细胞存活率差异无统计学意义。结论/影响:在表达 tGLI1 的细胞中观察到的细胞活力增加表明,tGLI1 与 TMZ 抗性之间可能存在关联,因此有必要开展更多研究,以充分了解其对 GBM 治疗反应的影响。要确定这些结果的稳健性,还需要进一步的调查和重复研究。这些知识可能有助于开发旨在抑制 tGLI1 或其下游信号通路的靶向疗法,从而改善对 TMZ 的反应和患者的预后。
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引用次数: 0
Clinician Perspectives on Risks and Benefits of Sharing Cardiovascular Implanted Electronic Device (CIED) Data with Patients 临床医生对与患者共享心血管植入式电子设备 (CIED) 数据的风险和益处的看法
Pub Date : 2024-01-11 DOI: 10.18060/27805
Brandon Tran, Carly Daley, Stephanie Pruitt, Jonathan Shirazi, Tina Allmandinger, Tammy R Toscos, Michael Mirro
Background and Objective: Cardiovascular implantable electronic devices (CIEDs) are critical, life-saving devices that are essential for the clinical decision-making process due to the data they collect. Because not all patients have ready access to their device data, there may be a clinical care gap where the CIED data are not being used most effectively in the care of patients with CIEDs. However, sharing CIED data may risk harming clinician-patient relationships and necessitates further study into clinician’s perspectives on CIED data sharing. The objective of this study was to explore clinicians’ perspectives on sharing CIED data with their patients and explore the perceived benefits and concerns. Methods: Clinicians involved in CIED care in the United States were recruited for semi-structured phone interviews. Participants were asked questions regarding their experiences and perspectives in sharing CIED data, and were presented scenarios to assess how they would leverage the CIED data in particular situations. Responses from the participants were analyzed by one researcher using thematic analysis. Results: Of the 28 clinicians interviewed in this study, the majority were white (85.7%) and located in the midwestern United States (67.9%). Participants included cardiac device clinic nurses and electrophysiology nurses (28.6%), electrophysiologists (25%), electrophysiology advanced practice providers (APPs) (17.9%), cardiologists (14.3%), and cardiology APPs (14.3%). The following themes were identified: (1) Patient engagement with healthcare, (2) Patient selfadvocacy, (3) Patients cannot interpret CIED data, (4) One size does not fit all. Conclusion and Potential Impact: Clinicians perceived both potential benefits and harms from CIED data sharing. Clinicians noted that CIED data sharing has the potential to increase patient participation in their healthcare, but it also can cause increased patient anxiety due to insufficient patient education. This study demonstrated some of the ways CIED data sharing may affect clinical practice involving CIEDs and the challenge of sharing complex data elements with patients.
背景与目的:心血管植入式电子设备(CIED)是关键的救生设备,其收集的数据对临床决策过程至关重要。由于并非所有患者都能随时访问其设备数据,因此可能存在临床护理缺口,即 CIED 数据未能最有效地用于 CIED 患者的护理。然而,共享CIED数据可能会损害临床医生与患者之间的关系,因此有必要进一步研究临床医生对共享CIED数据的看法。本研究的目的是探讨临床医生对与患者共享CIED数据的看法,并探究其感知到的益处和顾虑。研究方法研究人员招募了美国参与 CIED 治疗的临床医生进行半结构化电话访谈。访问者被问及有关他们共享CIED数据的经验和观点的问题,并通过情景模拟来评估他们在特定情况下如何利用CIED数据。一名研究人员使用主题分析法对参与者的回答进行了分析。结果:在本研究采访的28名临床医生中,大多数为白人(85.7%),居住在美国中西部(67.9%)。参与者包括心脏设备诊所护士和电生理学护士(28.6%)、电生理学家(25%)、电生理学高级实践提供者(APPs)(17.9%)、心脏病学家(14.3%)和心脏病学 APPs(14.3%)。确定了以下主题:(1)患者参与医疗保健;(2)患者自我主张;(3)患者无法解释 CIED 数据;(4)一刀切。结论和潜在影响:临床医生认为CIED数据共享既有潜在的益处,也有潜在的害处。临床医生指出,CIED数据共享有可能提高患者对医疗保健的参与度,但也可能因患者教育不足而增加患者焦虑。本研究展示了CIED数据共享可能影响涉及CIED的临床实践的一些方式,以及与患者共享复杂数据元素所面临的挑战。
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引用次数: 0
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Proceedings of IMPRS
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