Podcasts about bmp7

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.07.515236v1?rss=1 Authors: Ramachandran, D., Kotikalapudi, N., Maridas, D. E., Gulko, A., Tsai, L. T., Rosen, V., Banks, A. S. Abstract: Growth differentiation factor 3 (Gdf3) is a relatively understudied member of the Tgf{beta} superfamily. GDF3 is highly expressed in stem cell populations and restricts cellular differentiation. Gdf3 expression levels decrease after development only to rise in states of obesity and inflammation. However, the function of GDF3 in adult mammalian biology is contentious. To understand the impact of GDF3 on cellular signaling we explored the cellular responses to either recombinant GDF3 or an inducible genetically-encoded Gdf3 in C2C12 myoblasts. In addition, we employ fluorescent reporters to simultaneously assay both BMP receptor signaling through a SMAD1/5/8 DNA-binding BMP-responsive element and TGF{beta} receptor signaling through a SMAD3 DNA-binding element. We find that GDF3 is capable of dose-dependent inhibition of multiple BMP proteins including BMP2, BMP7, BMP9, BMP10, and BMP15. We also find that GDF3 produces a bona fide activin-like ligand signaling through the TGFBR2 receptor. Expression profiling with RNA-seq reveals that BMP2-regulated genes are attenuated by the addition of GDF3. Together these results clarify the dual biological roles of Gdf3 in cultured myoblasts. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

FDA 批准首个用于治疗晚期尿路上皮癌的FGFR激酶抑制剂Nature Medicine 免疫检查点抑制剂PD-L1联合CTLA-4单抗治疗高危尿路上皮癌前沿医学 多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗CKD厄达替尼（erdafitinib）我们的节目曾在《消化科星期三 Episode 3》中介绍过培米加替尼，治疗成纤维细胞生长因子受体编码基因（FGFR）基因融合或重排的局部晚期胆管癌，胆管癌中约有20%的患者存在这种基因突变。研究人员发现FGFR突变在尿路上皮癌中也很常见，并且可能与对免疫干预的敏感性降低相关。厄达替尼（erdafitinib）是一种FGFR1-4的酪氨酸激酶抑制剂，2019年4月，FDA已经批准厄达替尼（erdafitinib）用于治疗局部晚期或转移性尿路上皮癌。《BLC2001研究：厄达替尼治疗局部晚期或转移性尿路上皮细胞癌的2期临床研究》New England Journal of Medicine，2019年8月 (1) 在这项开放标签的2期研究中，纳入了FGFR基因突变的、局部晚期和不可切除或转移性尿路上皮细胞癌的患者99人，所有患者既往均接受过化疗，并在化疗12个月内发生疾病进展。最初将患者随机分组，随后根据中期分析，将连续用药方案的起始剂量设定为8mg/d，并可在药效学指导下，将剂量增加至9mg/d。经过平均5个周期的厄达替尼治疗后，缓解率为40%（3%完全缓解，37%部分缓解）。在既往接受过免疫治疗患者中，缓解率为59%。中位无进展生存期为5.5个月，中位总生存期为13.8个月。结论：在既往接受过治疗的、有FGFR基因突变的、且患局部晚期和不可切除或转移性的尿路上皮细胞癌的患者中，厄达替尼治疗后肿瘤客观缓解率达40%。膀胱尿路上皮癌膀胱癌是最常见的泌尿系统恶性肿瘤，其中尿路上皮癌（也称移行细胞癌）是主要的组织学类型，占所有膀胱癌的90%。膀胱尿路上皮癌可表现为非肌肉浸润癌、肌肉浸润癌和转移癌，病变的程度可以反映自然病程，并决定了治疗和预后。膀胱癌通常表现为肉眼血尿或镜下血尿，刺激性或梗阻性排尿困难也可以 是首发症状。非肌肉浸润性膀胱癌的治疗对于非肌肉浸润性膀胱癌的患者，采用经尿道膀胱肿瘤切除术（TURBT），并联合膀胱内辅助治疗等保守治疗方式有可能保留膀胱功能。膀胱内辅助治疗主要包括卡介苗（牛结合分支杆菌的减毒活疫苗）和丝裂霉素C、表柔比星、吉西他滨等化疗药物。《系统回顾：膀胱治疗非肌肉浸润性膀胱癌的疗效》European Urology，2020年9月 (2)研究的目的是评价在卡介苗治疗后，保留膀胱功能的患者的疾病完全缓解率和无复发率。研究系统地回顾了42项研究，包括24种治疗方案、2254名患者。包含原位癌在内的肿瘤治疗中位完全缓解率，6个月时为26%，12个月时为17%，24个月时为8%。相比，乳头状癌的平均无进展率，6个月时为67%，12个月时为44%，24个月时为10%。特别是在卡介苗无效的、接受草分枝杆菌细胞壁-核酸复合物的患者中，6个月和12个月的完全缓解率分别为45%和27%；6、12、24个月中位不带病生存率分别为43%、35%和18%。总的中位无进展率为91%，原位癌的研究中为95%，乳头状癌的研究中为89%。膀胱内给药的不良反应少，且轻微。结论：卡介苗治疗后的、保留膀胱疗法，在非肌肉浸润性膀胱癌患者中取得了适度的疗效。《NIMBUS研究：卡介苗标准剂量和数量灌注治疗重度非肌肉浸润性膀胱癌的3期临床研究》European Urology，2020年11月 (3)膀胱内灌注卡介苗治疗是一种被广泛接受的预防非肌肉浸润性膀胱癌复发的策略，但是具有显著的毒性。研究的目的是评估了降低标准剂量卡介苗灌注的次数是否可以达到同样的疗效。研究纳入了345名非肌肉浸润性膀胱癌的患者，分别接受标准治疗（诱导6周，在第3、6和12个月时各治疗3周，共15次灌注），或低频率治疗（第1、2和6周诱导，在第3、6和12个月时各治疗2周，共9次灌注）。中位随访12个月后，标准治疗组复发率12%，低频率治疗组复发率27%。安全性分析达到了预先定义的、无效停止标准。结论：在预防膀胱癌复发方面，标准治疗方案更好，目前研究已经停止对参与者的招募。《国家质量指标项目：提高非肌肉浸润性膀胱癌经尿道膀胱肿瘤切除术的质量和有效性》European Urology，2020年8月 (4)非肌肉浸润性膀胱癌的临床预后部分取决于初始干预。为了改善和标准化癌症治疗，苏格兰实施了一项针对膀胱癌的国家质量指标项目。研究中纳入了2689例患者，标准干预包括：（1）使用膀胱图；（2）经尿道膀胱肿瘤切除术后单次膀胱内灌注丝裂霉素C一次；（3）逼尿肌活检；（4）高危膀胱癌患者中，早期行二次手术。研究中，67%患者接受了术后一次膀胱灌注；复发率、残余癌比例和继发肿瘤的比例分别为13%、33%和2.9%。术后一次膀胱灌注复发率降低相关；逼尿肌活检则癌症残留的可能性减半。结论：在苏格兰实施国家质量指标计划似乎有助于向患者提供高质量的经尿道膀胱肿瘤切除术，且降低了术后的复发率、肿瘤分期更准确。《DaBlaCa-13研究：短期强化化疗与标准辅助膀胱内灌注治疗非肌肉浸润性膀胱癌》European Urology，2020年8月 (5)膀胱灌注治疗非肌肉浸润性膀胱癌可减少复发。术前灌注化疗副作用更少，甚至一些患者在治疗后都无需接受肿瘤切除术了。研究旨在比较术前丝裂霉素C短期强化化疗治疗复发性非肌肉浸润性膀胱癌的效果。研究纳入120例患者，短期强化化疗组，膀胱灌注化疗每周3次，共2周；对照组先行经尿道膀胱肿瘤切除术，术后6周每周进行一次膀胱灌注辅助治疗。在短期强化化疗组中，有33名参与者（57%）出现了肿瘤完全缓解，且不良事件少。结论：术前短期强化化疗使一半以上的患者避免肿瘤切除术，但长期疗效仍需随访观察。肌肉浸润性膀胱癌的治疗对于肌肉浸润性膀胱癌，需行根治性膀胱切除术+尿流改道术，以及辅助化疗、免疫治疗。化疗方案中的MVAC方案（甲氨蝶呤、长春碱、多柔比星、顺铂）被认为是一线化疗方案，临床实践中多在这个方案上增减。目前已有几个免疫检查点抑制剂被获批用于膀胱尿路上皮癌的治疗：阿替利珠单抗（atezolizumab），帕博利珠单抗（pembrolizumab），纳武利尤单抗（nivolumab），阿伟鲁单抗（avelumab），德瓦鲁单抗（durvalumab）。《回顾性综述：FGFR3的水平变化与膀胱癌对铂化疗的敏感性有关》European Urology，2020年8月(6)大约15%的膀胱癌存在成纤维细胞生长因子受体3 （FGFR3）基因突变。研究人员回顾性的比较和综述三个队列的患者：（1）新辅助化疗治疗肌肉侵袭性膀胱癌患者的数据；（2）一线铂类化疗治疗转移性尿路上皮癌患者的数据；（3）来自癌症基因组图谱中的肌肉侵袭性膀胱癌患者的数据。队列一：72例新辅助化疗的肌肉侵袭性膀胱炎癌患者中有13%具有FGFR3突变，均没有达到病理完全缓解，且无复发生存期短。队列三：来自癌症基因组图谱中的肌肉侵袭性膀胱癌的患者，接受辅助化疗、且伴有FGFR3突变的无复发生存期也更短。相反，在未接受化疗的患者中，FGFR3突变与无复发生存期更长、总生存率更高。队列二：转移性尿路上皮癌的患者中，FGFR3突变虽然药物反应低，但不影响无进展生存率和总生存率。结论：肌肉浸润性膀胱癌中，FGFR3突变可能与围手术期铂类药物化疗反应差、易复发有关。《IMvigor130研究：化疗联合阿替利珠单抗治疗转移性尿路上皮癌的3期临床研究》Lancet，2020年5月 (7)这个多中心、3期、随机研究的目的是，比较阿替利珠单抗与安慰剂加铂类化疗在一线转移性尿路上皮癌的疗效。研究纳入未经治疗的、≥18岁的、局部晚期或转移性尿路上皮细胞癌患者共1213人。随机接受阿替利珠单抗+铂类化疗，或阿替利珠单抗单药治疗，或安慰剂+铂类化疗，随访11.8个月。中位无进展生存期，在阿替利珠单抗联合化疗组为8·2个月，在安慰剂联合化疗组为6.3个月（p = 0·007）。中位生存期，在阿替利珠单抗联合化疗组为16·0个月，安慰剂联合化疗组为13·4个月（p = 0·027）。阿替利珠单抗单药治疗组中位总生存期为15·7个月，与安慰剂联合化疗组无差异。结论：阿替利珠单抗联合铂类化疗延长了转移性尿路上皮癌患者的无进展生存，研究支持使用阿替利珠单抗联合铂类化疗作为转移性尿路上皮癌的潜在的、一线治疗选择。《JAVELIN Bladder200研究：PD-L1单抗阿伟鲁单抗维持治疗局部晚期、或转移性尿路上皮癌》New England Journal of Medicine，2020年9月 (8)这项3期临床试验中，研究人员纳入无法手术的局部晚期、或转移性尿路上皮癌患者共700人，在接受一线化疗后，随机给予阿伟鲁单抗维持治疗、或仅给予支持治疗。阿伟鲁单抗维持治疗能显著延长了患者的总生存期。阿伟鲁单抗组和对照组的，1年总生存率分别为71.3%和58.4%，中位总生存期分别为21.4个月和14.3个月（死亡风险比 0.69，P = 0.001）。阿伟鲁单抗也显著延长了PD-L1阳性的患者的总生存率，两组分别为79.1%和60.4%（风险比 0.56，P < 0.001）。在总体人群中，阿伟鲁单抗组的中位无进展生存期为3.7个月，对照组为2.0个月（疾病进展或死亡的风险比为0.62）；在PD-L1阳性的人群中，阿伟鲁单抗组的中位无进展生存期为5.7个月，对照组为2.1个月（风险比 0.56）。结论：一线化疗+阿伟鲁单抗维持治疗，能进一步延长了患者的总生存期。《随机对照研究：卡博替尼和纳武利尤单抗联合或不联合伊匹木单抗治疗转移性尿路上皮癌的1期临床研究》Journal of Clinical Oncology，2020年10月 (9)卡博替尼（cabozantinib）是一种酪氨酸激酶受体抑制剂 ，纳武利尤单抗（nivolumab）是一种PD-1单抗，伊匹木单抗（ipilimumab）是一种CTLA-4单抗。研究的目的是评估了卡博替尼联合纳武利尤单抗的CaboNivo方案，以及CaboNivo联合伊匹木单抗的CaboNivoIpi方案在转移性尿路上皮癌和其他泌尿生殖系统恶性肿瘤患者中的安全性和有效性，共入组54人。平均随访时间为44.6个月，转移性尿路上皮癌的客观缓解率为38.5%，平均缓解持续时间尚未达到，中位无进展生存期达12.8个月，中位总生存期为25.4个月。CaboNivo和CaboNivoIpi治疗组中，严重不良事件发生率分别为75%和87%，主要包括疲劳、腹泻、高血压、肝炎、结肠炎。II期临床研究推荐剂量为卡博替尼40 mg/d、纳武利尤单抗3 mg/kg，伊匹木单抗1 mg/kg。结论：CaboNivo方案（卡博替尼+纳武利尤单抗）和CaboNivoIpi（卡博替尼+纳武利尤单抗+伊匹木单抗）方案均显示了良好的耐受性和持久的疗效，多项II期和III期临床研究正在进行中。《随机对照临床研究：新辅助PD-L1加CTLA-4阻滞治疗顺铂化疗无法耐受的、可手术切除的、高危、尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (10)这是首个抗PD-L1单抗（德瓦鲁单抗，durvalumab）联合抗CTLA-4单抗（曲美木单抗，tremelimumab）。研究纳入在顺铂化疗无法耐受的、具有高危特征的、尿路上皮癌患者共28人（高危特征为肿块大、组织学变异、淋巴血管侵犯、肾盂积水和/或高度上尿路疾病）。在完成手术的患者中，病理完全缓解为37.5%，58%的患者达到无残余侵袭性占位。21%的患者出现免疫相关不良事件，包括无症状实验室异常、肝炎和结肠炎结论：研究提供了抗PD-L1单抗联合抗CTLA-4单抗新辅助治疗的初步安全性、有效性和生物标志物数据，这对于局限性尿路上皮癌患者，特别是具有高危特征且目前没有建立标准护理新辅助治疗的顺铂不合格患者，值得进一步发展。《NABUCCO研究：术前CTLA-4联合PD-1抑制剂治疗局部晚期尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (11)伊匹木单抗（ipilimumab）是一种CTLA-4单抗，纳武利尤单抗（nivolumab）是一种PD-1单抗，在NABUCCO研究中，纳入了24名III期、尿路上皮癌患者，术前接受两次伊匹木单抗联合纳武利尤单抗治疗后，然后在12周内接受手术切除。研究中46%的患者达到病理学完全缓解，58%达到无残余侵袭性占位。与单独使用PD-1/PD-L1抑制剂的研究相比，伊匹木单抗联合纳武利尤单抗的疗效与基线时CD8+ T细胞活性无关。3-4级免疫相关不良事件发生率分别为55%和41%。结论：在局部晚期尿路上皮癌患者中，CTLA-4联合PD-1阻断可能提供一个有效的术前治疗策略，而不用考虑先前的CD8+ T细胞的活性。纳米颗粒作为抗纤维化基因载体治疗CKD《基础研究：多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗慢性肾脏病》J American Society of Nephrology，2020年8月 (12)预防或逆转促纤维化的细胞的基因表型是治疗慢性肾脏病的一个方向，来自南开大学的研究人员开发了一种纳米颗粒，作为抗纤维化的基因的载体，为损伤组织和常驻细胞提供抗纤维化治疗，以限制促纤维化表型的表现。研究人员将表达骨形态发生蛋白7（BMP7）或肝细胞生长因子（HGF）-NK1（HGF/NK1）的质粒DNA包裹在有一层透明质酸壳的聚糖纳米颗粒内，安全地将含有质粒DNA的多功能纳米粒导入肾脏，用于抗纤维化因子的局部和持续表达。在小鼠模型中，静脉注射后，这些纳米颗粒约有10-45%的基因被肾脏摄取，减轻了纤维化的发展，并挽救了肾功能。BMP7基因逆转了纤维化进展、促进肾小管再生；HGF/NK1基因减少胶原纤维沉积。结论：纳米颗粒作为BMP7基因和HGF-NK1基因的载体，提供了今后靶向基因治疗慢性肾脏病的基础。参考文献1.Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine. 2019;381(4):338-48.2.Li R, Sundi D, Zhang J, Kim Y, Sylvester RJ, Spiess PE, et al. Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non-muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guerin. Eur Urol. 2020;78(3):387-99.3.Grimm MO, van der Heijden AG, Colombel M, Muilwijk T, Martinez-Pineiro L, Babjuk MM, et al. Treatment of High-grade Non-muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial "NIMBUS". Eur Urol. 2020;78(5):690-8.4.Mariappan P, Johnston A, Padovani L, Clark E, Trail M, Hamid S, et al. Enhanced Quality and Effectiveness of Transurethral Resection of Bladder Tumour in Non-muscle-invasive Bladder Cancer: A Multicentre Real-world Experience from Scotland's Quality Performance Indicators Programme. Eur Urol. 2020.5.Lindgren MS, Bue P, Azawi N, Blichert-Refsgaard L, Sundelin MO, Dyrskjøt L, et al. The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial. Eur Urol. 2020.6.Teo MY, Mota JM, Whiting KA, Li HA, Funt SA, Lee CH, et al. Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma. Eur Urol. 2020.7.Galsky MD, Arija JÁ A, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-57.8.Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-30.9.Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol. 2020;38(31):3672-84.10.Gao J, Navai N, Alhalabi O, Siefker-Radtke A, Campbell MT, Tidwell RS, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020.11.van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020.12.Midgley AC, Wei Y, Zhu D, Gao F, Yan H, Khalique A, et al. Multifunctional Natural Polymer Nanoparticles as Antifibrotic Gene Carriers for CKD Therapy. J Am Soc Nephrol. 2020.

This month on Episode 5 of the Discover CircRes podcast, host Cindy St. Hilaire highlights five featured articles from the September 27 and October 11, 2019 issues of Circulation Research and talks with Sarvesh Chelvanambi and Matthias Clauss  about their article HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction: Implications for Statin Treatment in HIV Patients.   Article highlights:   Stamatelopoulos, et al. Reactive Vasodilation in AL Amyloidosis   Cao, et al. Miro2-Mediated Cardiac Mitochondrial Communication   Georgakis, et al. Circulating MCP-1 Levels and Incident Stroke   Sun, et al. Body Mass Index and DNA Methylation   Tan, et al. Yy1 Suppresses DCM Through Bmp7 and Ctgf Transcript Cindy St. H:                       Hi. Welcome to Discover CircRes, the monthly podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, and I'm an assistant professor at the University of Pittsburgh. My goal as host of this podcast is to share with you highlights from recent articles published in the September 27th and October 11th issues of Circulation Research.                                            We'll also have an in-depth conversation with Drs Matthias Clauss and Sarvesh Chelvanambi, who are the lead authors in one of the exciting discoveries from our October 11th issue.                                            The first article I want to share with you is titled, Reactive Vasodilation Predicts Mortality in Primary Systemic Light Chain Amyloidosis. The first authors are Drs Kimon Stamatelopoulos, Georgios Georgiopoulos, and the corresponding author is Dr Efstathios Kastritis. And the studies were conducted at the National Kapodistrian University of Athens School of Medicine in Athens, Greece.                                            So we hear about amyloids a lot in things like Alzheimer's, but amyloids are really just aggregates of protein that fold into shapes. And the nature of these shapes allows these individual protein molecules to bind and form many copies that form these fibers that are rather sticky. And the fibers then aggregate into larger and larger globules. And light chain amyloidosis is the most common type of amyloidosis. It's a rare but deadly disease, and it's caused by antibody-producing cells that are aberrantly churning out parts of antibodies called light chains. And it's these light chains that will aggregate and form sticky fibers.                                            So these fibers aggregate and form amyloid deposits, and these deposits build up and damage the organs and the tissue in which they're accumulating. And because it's dependent on where the aggregates are accumulating, AL amyloidosis can present with a wide variety of symptoms. However, symptoms of heart dysfunction and low blood pressure correlate with poor prognosis.                                            And because vascular dysfunction can contribute to hypotension or low blood pressure, this group decided to examine the vascular health of patients by conducting a measurement called flow-mediated vasodilation. And so this is a measurement where the diameter of the brachial artery, which is located in your arm, is measured before and then after a brief period of lower arm ischemia. And they formed a cohort of 115 newly diagnosed AL patients and another cohort of 115 matched controls. This study found that in AL patients, flow-mediated vasodilation was higher than in aged, sex, and cardiovascular risk factor-matched controls. The mean follow-up time for this study was 54 months, and in that time, the authors went on to find that high values of FMD in the amyloidosis patients was strongly predictive of mortality. In fact, high FMD values were more predictive of death than some measures of cardiovascular health. These results suggest that flow-mediated vasodilation may be a superior means of identifying AL patients most at risk and for assessing potential benefits of therapeutic interventions.                                            The next article I'd like to highlight is titled, Miro2 Regulates Inter-Mitochondrial Communication in the Heart and Protects Against TAC-Induced Cardiac Dysfunction. The first author is Yangpo Cao, and the corresponding author is Ming Zheng. And the work was conducted at Peking University, Beijing, China, Key Laboratory of Molecular Cardiovascular Science at the Ministry of Education, also in Beijing, China.                                            Beating heart cells have very high energy requirements, and thus they need lots of fully functioning mitochondria. And as we all know from our good old high school biology days, mitochondria are the powerhouse of the cell. Mitochondrial health and performance is directly dependent on the ability of individual mitochondria to be able to communicate with each other. In many cells, this mitochondrial communication occurs via the fusion of mitochondria into a giant network. However, in cardiomyocytes, the mitochondrial movement is much more constrained. In cardiomyocytes, mitochondria communicate by briefly connecting with neighboring mitochondria, which is often called kissing, mitochondrial kissing, or by nanotunneling, which is when the mitochondria create a sustained connection by means of long nanometer-sized tubular protrusions called nanotubes. And it's thought that the proper health of the cell is dependent on proper mitochondrial communication.                                            Miro2 is a Rho GTPase on the outer mitochondrial membrane and it harbors a calcium sensing domain. Miro2 can interact with transport proteins to promote mitochondrial transport along microtubules in a calcium-dependent manner. This group wanted to investigate whether Miro2 regulates cardiac inter- mitochondrial communication. To do this, they used transverse aortic constriction or TAC or they used an Ang II infusion model to induce hypertrophy in murine hearts. Using these two models, they found Miro2 expression was decreased via Parkin-mediated ubiquitination, and they also found that inter-mitochondrial communication was disrupted.                                            By contrast, transgenic mice over-expressing Miro2 were more resistant to hypertrophy, and they were able to do this by maintaining proper cardiac function than their wild type counterparts. Together these results reveal a novel role for Miro2 in mitochondrial communication and show that maintaining such communication may mitigate effects of hypertrophy.                                            The next paper I want to highlight is titled, Circulating Monocyte Chemoattractant Protein-1 or MCP-1 and the Risk of Stroke: A Meta-Analysis of Population-Based Studies Involving 17,180 individuals. That is a huge study. The first author is Marios Georgakis, and the corresponding author is Martin Dichgans. And they are from the University of Munich in Munich, Germany.                                            A major component of atherosclerosis is chronic inflammation and inhibiting the activity of proinflammatory cytokines has been identified as a potential therapeutic strategy to help slow the disease progression. One such cytokine under study is monocyte chemoattractant protein-1 or MCP-1, and animal studies have shown that blocking MCP-1 limits, or boosting MCP-1, accelerates atherosclerosis. However, large scale observational studies of MCP-1 in humans are lacking. To address this gap in knowledge, this group performed a meta-analysis of previously unpublished data from six population cohorts, which totaled over 17,000 individuals.                                            These individuals were followed for an average of 16 years, which when you think about it, this is an absolutely huge study. So in looking at this cohort of patients, the team identified a significant association between high baseline MCP-1 levels and the likelihood of suffering a future ischemic stroke. Interestingly, this effect was not seen with hemorrhagic stroke, which is typically not associated with atherosclerosis. These findings not only support the previous animal studies, but also support a recent study in humans in which a genetic predisposition for high levels of MCP-1 was associated with an increased risk of coronary artery disease and stroke. This study also suggests that future studies should explore the potential of lowering MCP-1 levels as a possible prevention strategy. Perhaps there could be another CANTOS-like trial where we use something to block MCP-1 signaling. Maybe that would have much broader effects. I guess we'll have to wait and see what the data says.                                            The next paper I want to highlight is titled, Body Mass Index Drives Changes in DNA Methylation, a Longitudinal Study. The first authors are Dianjianyi Sun, Tao Zhong and Shaoyong Su, and the corresponding authors are Shengxu Li and Wei Chen. And they're from the Children's Minnesota Research Institute, Children's Hospitals and Clinics of Minnesota in Minneapolis, Minnesota and The Peking University Health Science Center in Beijing, China, respectively.                                            So it's well appreciated that obesity is increasing worldwide. And obesity contributes to a whole host of cardiovascular morbidity, and ultimately contributes to mortality. It's also well known that environmental factors such as the food we eat and the air we breathe, as well as genetic factors, can influence a person's risk of obesity. And recently there have been studies that suggest that perhaps epigenetic factors also contribute to obesity. And just to remind you what epigenetics is, DNA is the genetic code, and mutations can happen on DNA that can alter either gene expression or maybe protein folding or whether a protein is made at all. But epigenetic factors are not as permanent as DNA mutations.                                            Epigenetic factors are alterable modifications that can happen to DNA itself or that can happen to the proteins on which the DNA is wrapped around. And epigenome-wide association studies have shown that DNA methylation at certain loci is linked to an increase in body mass index, or BMI. However, it's unknown whether these methylations are a cause or consequence of obesity.                                            So to get to the bottom of this, this group performed a large-scale longitudinal study. They examined thousands of DNA methylation sites in 995 white individuals and 490 black individuals. And they also determined the subjects' BMIs. They did this at a baseline measurement and then approximately six years later, they collected the same data in the same patient cohort. What they found was that only a handful of methylation sites were shared between the two ethnicities. And in both groups, however, there was a similar unidirectional link between BMI and methylation. Very interestingly, baseline BMI could predict methylation at a number of genetic loci. However, the team found that none of those baseline methylation sites could predict future BMI. From this data, the authors are able to conclude that it's obesity driving the methylation at certain genetic loci as opposed to certain genetic loci driving obesity, which I think is just extremely interesting. Really nice study.                                            The last article I want to highlight for you is a paper titled, Yin Yang 1 Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis Through Regulation of Bmp7 and Ctgf. The first author is Chia Yee Tan, and the corresponding author is Jianming Jiang, and they're from the National University of Singapore.                                            Dilated cardiomyopathy or DCM is characterized by left ventricle enlargement and associated contractile dysfunction and fibrosis. Patients with DCM are at risk of arrhythmia and also of sudden death. And there's actually a huge number of genetic variants that have been linked to DCM, but the most common one or the most well-studied are mutations that affect the nuclear lamin gene or LMNA. So LMNA knockout mice are used to study the role of this gene in DCM, and these animals exhibit not only cardiac defects but also systemic defects. And those systemic defects include things like shorter lifespan, growth retardation, muscular dystrophy, neuropathy, and lipodystrophy.                                            Recently, LMNA-related dilated cardiomyopathy was linked to the deregulation of cardiac cell cycle. Meaning there was issues in how these cardiac cells are proliferating. So in this study, Tan and colleagues showed that boosting expression of a protein involved in cell cycle regulation, this protein is called Yin Yang 1, so boosting this gene's expression actually reversed the dilated cardiomyopathy symptoms in mice with heart-specific LMNA deficiency. Compared with untreated mice, mice receiving Yy1 via an adenoviral vector exhibited improved cardiac function and also reduced fibrosis after four weeks. The team then went on to show that Yy1 treatment prompted suppression of the extracellular matrix factor, Ctgf, and the upregulation of the growth factor, Bmp7.                                            Now, neither of these factors alone could rescue the symptoms of LMNA lacking mice. However, when both of these factors were manipulated together, they mimicked Yy1 treatment. These results highlight that Yin Yang 1 and its downstream targets Bmp7 and Ctgf are key players and potential therapeutic targets that can be harnessed for tackling LMNA-driven dilated cardiomyopathy.                                            Okay, so now we're going to have our interview with Drs Matthias Clauss and Sarvesh Chelvanambi. And they are from Indiana University School of Medicine in Indianapolis, Indiana. And their title of their paper is, HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction: Implications for Statin Treatment in HIV Patients. So thank you both very much for joining me. Sarvesh C:                         Thank you so much, Cindy. Matthias C:                       Thanks for having us here. Cindy St. H:                       Could you both introduce yourselves and tell us a little bit about your background? Sarvesh C:                         My name is Sarvesh Chelvanambi. I grew up in Chennai, India. I did my undergraduate degree at Miami University in Oxford, Ohio. I got a Bachelor of Arts in Zoology with a minor in Finance. I then went to the Pennsylvania State University where I got my Masters in Biotechnology before coming over to Indiana University in 2014 to do my PhD work. And then I joined the lab of Dr Matthias Clauss, and in 2016, I got an American Heart Association predoctoral fellowship to study this project specifically. Cindy St. H:                       Wow! Congratulations. That's wonderful. Sarvesh C:                         Thank you so much. Cindy St. H:                       And now you completed the circle by publishing your AHA grant in Circulation Research. Sarvesh C:                         Exactly. Cindy St. H:                       And Matthias, how about you? Matthias C:                       I'm a Research Professor at IU School of Medicine, and my research interests focus in understanding how stressors connected with endothelium in this way contribute to vascular disease. These stressors include cigarette smoke and viral infections. Regarding viral agents, we are studying both acute infections and chronic infections and that is HIV. This HIV interest started actually 12 years ago in collaboration with Dr Samir Gupta who is also of course on this paper. We started off with a simple question, why are there so many cardiovascular events in patients, in HIV patients, with interrupted antiretroviral therapy? Cindy St. H:                       So it's not just the fact that they're HIV positive, it's that they were on therapy and then went off it? Matthias C:                       Yes. And this was part of this SMART study and this study was then actually halted because of the safety issues. Cindy St. H:                       So you're starting with the idea that patients with HIV who go off this antiviral therapy are more prone or get more cardiovascular events. So what did you start with, with this particular study? Matthias C:                       Well, our overarching idea was that the HIV virus could also do damage in the era of the combined antiretroviral therapy. And we started up with two questions, one was, is there an HIV protein which is persistent? And the other question, how is this HIV protein, if there's any one which is persistent, performing this? And this may be then leading over to your specific way to address these questions. Sarvesh C:                         That's kind of where we are starting with this project. Because back in 2016, the START trial came out saying, "We need to change the way we treat HIV patients," because initially the previous regimen of our drugs had a lot of metabolic side effects, but the current regimen of integrase inhibitors is actually really good and has very low metabolic effects. So there was a New England Journal Of Medicine paper that said, "Well, if a patient walks into the clinic, they're diagnosed as being HIV positive, put them on antiretroviral therapy right away."                                            But even in this era when everybody is on ART and there's almost no viral replication, you still see the persistence of a lot of comorbidities. And especially those associated with vascular events, whether it's peripheral arterial disease, coronary arterial disease, and a lot of other vascular diseases in the lung, or the kidney or the brain. So that kind of is what set us up, is there an element in the blood of these patients that is contributing towards vascular dysfunction? Cindy St. H:                       And so the protein that you are talking about in this paper is a protein called Nef, and is that where you come in,  Sarvash? Sarvesh C:                         Yes, because the project before I joined the lab, that's kind of where it led off, saying that Nef can get to the endothelium and it's very good at killing endothelial cells, but the mechanism through which it transfers into endothelial cells and the signaling pathways that Nef hijacks to induce this apoptosis was not clearly elucidated. A lot of work is done in Nef in monocytes and macrophages because as an HIV protein, it was studied in CD40 cells and the whole immune system as a whole, but we were the first to leverage all of those findings within an endothelial context and answer the questions, so what does Nef do and how does it get there? Cindy St. H:                       All right, so tell us a little bit what does it do and how does it get there? Sarvesh C:                         So we started doing some experiments with starting with HIV patient blood. So we took two fragments, we took the PBMC fraction, that Dr Clauss was talking about, which we knew had Nef within many of those cells. We also took the extracellular vesicle fraction, and we chose to look at this because there's a lot of literature out there saying that this fraction could not only disseminate particles throughout the body but also help signal through that. So in both of these fractions we added to the endothelial cells, we found increased apoptosis in HIV patients when compared to HIV negative patients.                                            And we were excited, but then we went and asked which of these patients had HIV Nef positivity in their blood, and then using that information when we stratified our apoptosis results, we made the surprising observation that the HIV positive, Nef positive patients were more prone to endothelial cell apoptosis. And this sparked a lot of conversation, so how do we target this and what is the signaling pathway it gets into? And that is kind of what led to most of the work in this paper, where you're showing that the transfer is mediated by extracellular, because this is such a nice tool, for HIV I guess, to spread itself into literally every cell type. Because while the HIV virus can only infect very few cell types, extracellular vesicles can be taken up by anything.                                            And the second observation we made was within endothelial cells, we found the signaling pathways that Nef was able to hijack to induce cell death. And that became the focus of this paper. Cindy St. H:                       That was one thing I wanted you to clarify, because I think what a really interesting aspect of this study is that it's the immune cells that are infected. The endothelial cells themselves are healthy and really they're getting this damage from the vesicles. That is,…wow! I don't know. It's just a really, really neat study. So can you tell us a little bit about the techniques you used in this paper? Sarvesh C:                         Yes, so we did a lot of assays to evaluate endothelial cell stress. So we started by looking at apoptosis, and a lot of those studies were done by looking at caspase-3 activity, which is a classic marker for cell death. We also did a lot of microscopy work where we took out extracellular vesicles out of those vesicles on the endothelial cells to show the uptake of Nef protein and thereby hammer that extracellular vesicles are indeed a mechanism of transfer for this protein in particular.                                            Now, one of the interesting experiments that we actually ended up doing, which was not a part of this paper really, was we wanted to see if chemotaxis was being affected by this. So we took an endothelial monolayer and separated T-cells that are expressing Nef using a Transwell membrane. And I had this huge problem where I couldn't read for a week because instead of using the 4-micron filters that allow T-cells to transfer, I was using 0.4 micron filters that T-cells cannot transfer through. But I still went about it and did my whole experiment because I didn't make that realization until a week later, because when I looked at the bottom of these chambers, there were no T-cells at all. But when I looked at the endothelial cells, I observed cytoplasmic transfer and Nef transfer, and we had a couple of conversations going, why is this happening? Did the T-cells all die or did they disappear?                                            And that's when we went back and looked in literature and found that Nef is very good at making virion particles. And those are the similar pathways that extracellular vesicle trafficking comes from. And so that was a huge shift in the way this project was designed and where we then started looking into the modes of transfer, the protein and the subsequent apoptosis that that transfer can cause. Cindy St. H:                       I love this story. So essentially your mistaken filter created this paper and this finding of the vesicles affecting the endothelial cells. Matthias C:                       Yeah, that's a typical finding for practitioner Chelvanambi, because he has this gift to turn negative things into positive things. So we have a lot of fun, and this mistake was really the beginning of a great study. Cindy St. H:                       That's wonderful. Really beautiful images, as well. So a little bit digging into, I guess, the next step. So first off, how were the endothelial cells getting damaged? They're getting damaged from these extracellular vesicles, but then what's Nef doing in the endothelial cell? What's happening there? Sarvesh C:                         So that was a very big question because if you look at it, Nef is a very small protein with almost no known enzymatic function. And yet it is able to interact with a lot of host proteins, which I guess makes it a very good viral protein. So when I went back and looked at literature, there were a host of studies in the 90s to show that Nef interacts with this kinase and that small GTPases, and there was a giant list for us to go after. And we were kind of left a bit fuddled, because we were like, which signaling pathway do we start with? Cindy St. H:                       Right. It's almost like there's too many. Sarvesh C:                         Exactly. And so what we ended up doing was we started looking into one of the various mutants of Nef that we had access to. And one of these mutants was a mutant that was incapable of PAK2 activation, and we showed that that doesn't have a lot of these stress damages. So we asked, "What is directly upstream of PAK2?" And that is where Rac1 came into the picture. And the small GTPase Rac1 is a nice candidate because it is also a master of many, many trades. Cindy St. H:                       I love this because it's such an interesting multidisciplinary approach to addressing the question, why are patients with HIV getting more cardiovascular events? What do you think evolutionarily is going on? Why would this be beneficial? Why would damaging the endothelium be beneficial? What are your thoughts on that? Sarvesh C:                         Personally, I think this is a side effect because HIV is never meant to exist in the era of ART. One of the analogies I always like to use is from Harry Potter, where HIV is Voldemort, which is the big bad villain. And what we have done is a really good job of banishing Voldemort. But what we have failed to do as a field is target its Death Eater, Nef. And I think with what we are suggesting, this paper with additional statins and other strategies that focus this, we can get to that point where we not only block HIV expansion but also the expansion of its minions, Nef. Cindy St. H:                       I love this analogy. I think you should redo your graphical abstract in a Harry Potter theme. Matthias C:                       Yeah, but I like your question. But also in this regard, I think it may be an example of a novel mechanism, how viral infections work in a different way than just infecting cells. And there's evidence from lots of viruses that they make toxic proteins, and why they are doing this, we don't know. But we noticed that the systemic effect of Nef may have some advantage for the infectious agent, because it makes T-cells more sticky, it makes them stick and transmigrate through the endothelium, and that is also shown in our paper. Cindy St. H:                       You have evidence that perhaps statins would be beneficial to give to these HIV patients on ART therapy. Can you tell us a little bit about that and how that would work? Sarvesh C:                         So based on what we did on our mouse studies that was a part of this paper, even after there is endothelial dysfunction, treatment with statins was able to restore endothelial function. Currently, there is a study going on called The Reprieve Trial where they're giving a statin called pitavastatin to HIV patients. The interesting part here is that these are HIV patients who don't have dyslipidemia. And the long-term goal is that statin treatment can help prevent the development of cardiovascular events. We're eagerly awaiting the results of this trial. Cindy St. H:                       Well done. Well thank you so much for speaking with me today. It was a pleasure to speak with you, Dr Chelvanambi and Dr Clauss. And congratulations again on this beautiful project, this beautiful story. And really, the implications for helping patients with HIV is really profound. HIV used to always be in the news and now that we have the ART therapy it's not talked about as much, but these patients are still in danger and I think your study is really doing a lot to highlight that and maybe even help them. So thank you very much and congratulations. Matthias C:                       Thank you. Sarvesh C:                         Thank you so much for the opportunity. Cindy St. H:                       So that's it for highlights from the September 27th and October 11th issues of Circulation Research. Thank you so much for listening. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams.                                            I'm your host, Dr Sidney St. Hilaire, and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

Dr Karol talks to ecancertv at ASH 2015 about genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukaemia. Osteonecrosis or avascular necrosis is a treatment-limiting toxicity associated with chemotherapy, Dr Karol explains. So identifying who may be most at risk of experiencing this side effect would be very useful. Dr Karol discusses preliminary results of a genome-wide association study involving 1,186 children, with an initial discovery group of 82 children with and 287 without osteonecrosis. It was found that children who developed osteonecrosis were more likely to have genetic variants near a gene important to bone development (BMP7) and a gene important to fat levels in the blood (PROX1) than those who did not develop the bone disease.

Dr Stock talks to ecancertv at ASH 2015 on a study that looked at genetic risk factors for the development of osteonecrosis in children aged 10 years or younger who were being treated for acute lymphoblastic leukaemia. The study, presented by Dr Seth Karol of St Jude Children's Research Hospital in Tampa, USA, showed that children who developed osteonecrosis were more likely to have genetic variants near a gene important to bone development (BMP7) and a gene important to fat levels in the blood (PROX1) than those who did not develop the bone disease.

The forebrain is generated by distinct sets of precursor cells that express specific transcription factors as well as secreted signaling factors in a time- and region-dependent manner. The distribution of these factors is similar in the avian and mammalian forebrains. In this work I aimed to examine the molecular mechanisms regulating telencephalic patterning. Therefore, I first compared the expression pattern of homeobox transcription factors, known to play crucial roles in regionalization of the forebrain, such as Emx1 and Emx2. This analysis showed particularly intriguing domains in the developing telencephalon expressing either only Emx2, such as the dorso-ventricular ridge (DVR) and the cortical hem, both genes, such as the hippocampus and the pallium or none, such as the subpallium and the choroid plexus (ChP). Taken together with other expression patterns I could conclude that the DVR, the nature of which was debated for a long period of time, displays a dorsal nature and that the pallial/subpallial boundary is located between DVR and subpallium. Next, I aimed to examine the role of Emx1 and Emx2 in the specification of these distinct regions. Therefore, I used a misexpression approach targeting Emx1 and Emx2 into the anlage of the choroid plexus (ChP) where these transcription factors are normally not expressed. In this region normal development was disturbed. The normally non-neuronal, thin morphology of the ChP with a low rate of proliferation and the characteristic expression of Otx2 and Bmp7 was lost. Instead, the rate of proliferation and the thickness of the tissue were increased and rather displayed “hem-like” properties. Instead, the Otx2-positive region of the ChP was shifted beside the region of ectopic Emx1/2-expression and exhibited intermediate properties, with features of ChP-tissue like Otx2 and Bmp7-expression, but also features of the cortical hem with a higher rate of proliferation and increased thickness of tissue. Thus, Emx1 and Emx2 play a key role in instructing dorsal neuroepithelium to proliferate. The misexpression of these genes is sufficient to convert non-neuronal ChP-tissue into neuroepithelium. Ectopic expression of Emx1/2 in the dorsal pallium, its normal region of expression, also displayed alterations. Ectopic Emx-expression blocked the expression of the neurogenic transcription factor Pax6 and suppressed neuronal differentiation. This change of neuronal differentiation could be caused by reduction of Pax6. Taken together, Emx1 and Emx2 are two potent factors that can change regional identity, enhance proliferation and block neuronal differentiation.