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Safety switch optimization enhances antibody-mediated elimination of CAR T cells. 安全开关优化增强了抗体介导的 CAR T 细胞清除能力。
Pub Date : 2022-10-11 eCollection Date: 2022-01-01 DOI: 10.3389/fmmed.2022.1026474
Tamer B Shabaneh, Howell F Moffett, Sylvia M Stull, Thomas Derezes, Leah J Tait, Spencer Park, Stan R Riddell, Marc J Lajoie

Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal growth factor receptor (EGFRt) is a promising safety switch that has been used in multiple clinical constructs and can be targeted by cetuximab, a clinically available monoclonal antibody. However, this approach requires high and persistent cell surface expression of EGFRt to ensure that antibody-mediated depletion of engineered cells is rapid and complete. Here we show that incorporating a short juxtamembrane sequence into the EGFRt polypeptide enhances its expression on the surface of T cells and their susceptibility to antibody-dependent cellular cytotoxicity (ADCC). Incorporating this optimized variant (EGFRopt) into bicistronic and tricistronic CAR designs results in more rapid in vivo elimination of CAR T cells and robust termination of their effector activity compared to EGFRt. These studies establish EGFRopt as a superior safety switch for the development of next-generation cell-based therapeutics.

激活条件安全开关有可能逆转因施用工程细胞疗法(包括嵌合抗原受体(CAR)T细胞)而产生的严重毒性。源自人类表皮生长因子受体(EGFRt)的功能惰性、非免疫原性细胞表面标记物是一种很有前景的安全开关,已被用于多种临床构建物中,并可被西妥昔单抗(一种临床可用的单克隆抗体)靶向。然而,这种方法需要 EGFRt 在细胞表面高水平持续表达,以确保抗体介导的工程细胞耗竭迅速而彻底。在这里,我们展示了在表皮生长因子受体t多肽中加入短并膜序列可增强其在T细胞表面的表达以及对抗体依赖性细胞毒性(ADCC)的敏感性。与 EGFRt 相比,将这种优化变体(EGFRopt)纳入双组分和三组分 CAR 设计会更快地在体内消除 CAR T 细胞,并强力终止它们的效应活性。 这些研究确立了 EGFRopt 作为开发下一代细胞疗法的卓越安全开关的地位。
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引用次数: 0
Keratoacanthomas Induced by Cat Scratches in an Elderly Woman 老年妇女猫抓致角膜棘瘤1例
Pub Date : 2021-03-06 DOI: 10.26420/AUSTINJCLINCASEREP.2021.1197
Alawami Az, Elberg Jj, Tannous Zs
Background: Keratoacanthomas (KAs) are relatively common self-limited squamous proliferations. It is a matter of debate, whether they are a variant of squamous cell carcinoma or benign neoplasms. The exact etiology is uncertain, but is believed to be multifactorial, and is reportedly associated with trauma. This report describes an elderly woman with multiple keratoacanthomas developing at sites scratched by a pet cat. Methods: A case of a 92-year-old woman with Alzheimer’s disease, presented with multiple rapidly growing, bizarre looking lesions on the left leg. The lesions appeared several weeks after being scratched by a cat. Results: Tissue cultures for bacteria, fungi and atypical mycobacteria were negative. Histopathologic examination was consistent with keratoacanthoma. Conclusion: The development of Keratoacanthomas (KAs) have been associated with actinic damage, genetic susceptibility, carcinogens, immunosuppression and viruses. It also seems that keratoacanthoma has predilection for sites with previous trauma. Our case is a further evidence that trauma and keratoacanthoma are closely related.
背景:角斑蝥瘤是一种相对常见的自限性鳞状细胞增生。它们是鳞状细胞癌的变体还是良性肿瘤,这是一个有争议的问题。确切的病因尚不确定,但据信是多因素的,据报道与创伤有关。本报告描述了一位患有多发性角化棘皮瘤的老年妇女在被宠物猫抓伤的部位发展。方法:一例92岁的阿尔茨海默病患者,其左腿出现多处快速生长、外观怪异的病变。病变出现在被猫抓伤几周后。结果:细菌、真菌和非典型分枝杆菌的组织培养均为阴性。组织病理学检查与角化棘皮瘤一致。结论:角斑蝥瘤的发生与光化损伤、遗传易感性、致癌物、免疫抑制和病毒有关。角化棘皮瘤似乎也更倾向于既往有创伤的部位。我们的病例进一步证明了创伤和角化棘皮瘤密切相关。
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引用次数: 0
Cardiac Tamponade - A Hypothyroidism Associated Emergency: A Report of 2 Cases 心脏填塞-甲状腺功能减退相关急症2例报告
Pub Date : 2021-03-01 DOI: 10.26420/AUSTINJCLINCASEREP.2021.1194
S. Tripathi, Sharma Jb, P Vijayvergia, S. Khichar, Garg Mk
Pericardial effusion in commonly seen in-patient with hypothyroidism but effusion large enough to cause cardiac tamponade is not a common presenting feature whereas myxedema coma is a commonly defined medical emergency in-patient with hypothyroidism. We report 2 cases of hypothyroid associated medical emergencies. First case is a young female with history of recurrent pericardial effusion presenting to the emergency department with cardiac tamponade and later on diagnosed as having hypothyroidism. The second patient is a known case of hypothyroidism non-compliant to thyroid supplement and presented with lethargy, fatigue, decreased talking and breathlessness who was later diagnosed as having myxedema coma and impending cardiac tamponade. Both the patient required percutaneous pericardiocentesis and improved with medical management.
甲状腺功能减退症常见住院患者的心包积液,但足以导致心脏填塞的积液不是常见的表现特征,而粘液水肿昏迷是甲状腺功能减退病常见的急诊住院患者。我们报告2例甲状腺功能减退相关的医疗紧急情况。第一个病例是一名年轻女性,有复发性心包积液史,因心脏压塞到急诊科就诊,后来被诊断为甲状腺功能减退。第二名患者是一例已知的甲状腺功能减退症,不符合甲状腺补充剂,表现为嗜睡、疲劳、说话减少和呼吸困难,后来被诊断为粘液水肿昏迷和即将发生的心脏压塞。两名患者都需要经皮心包穿刺,并通过医疗管理得到改善。
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引用次数: 0
A Rare Case of Extensive Spondylodiscitis 一例罕见的广泛性脊柱炎
Pub Date : 2021-02-01 DOI: 10.26420/AUSTINJCLINCASEREP.2021.1192
S. Nicolau, M. Moniz, J. Jardim, M. Grego
A 71-year-old man with a history of diabetes mellitus was admitted to our hospital with a 2-week history of fever and low back pain. Physical examination showed fever (38.1°C), painful palpation of the lower lumbar vertebrae and right lower limb paresis. Blood examination revealed an increased white blood cell count (16700x109/L) and C- reactive protein (22,39 mg/dL). Magnetic resonance imaging showed extensive spondylodiscitis, with osteomyelitis of the L5, S1 and S2 vertebral bodies, discitis, large epidural empyema, paraspinal and epidural abscesses. Patient was submitted to surgical treatment and was started on empirical antimicrobial therapy. Blood and intraoperative cultures were negative. Brucellosis and tuberculosis testing was negative. A 10- week course of antimicrobial therapy was performed with progressive decline of acute-phase reactants, reduction in pain and improvement of the neurological deficit. At 1-year follow up with light residual lower back pain and no neurological deficit.
一位有糖尿病病史的71岁男性因发烧和腰痛两周而入院。体格检查显示发热(38.1°C),下腰椎触诊疼痛,右下肢轻瘫。血液检查显示白细胞计数(16700x109/L)和C反应蛋白(22,39mg/dL)增加。磁共振成像显示广泛的椎间盘炎,伴有L5、S1和S2椎体骨髓炎、椎间盘炎、硬膜外大脓胸、椎管旁和硬膜外脓肿。患者接受手术治疗,并开始接受经验性抗菌治疗。血液和术中培养均为阴性。布鲁氏菌病和结核病检测均为阴性。进行为期10周的抗菌治疗,急性期反应物逐渐减少,疼痛减轻,神经功能缺损得到改善。随访1年,轻度残余下背痛,无神经功能缺损。
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引用次数: 0
Anagrelide Treatment and Congestive Heart Failure in the COVID-19 Era: A Case Report 新冠肺炎时代阿那格列特治疗与充血性心力衰竭1例
Pub Date : 2021-01-01 DOI: 10.37421/2165-7920.2021.11.1444
Corsini Anna, Fiorini Giulia, Zuffa Elisa, Borghi Claudio, Galie’ Nazzareno
Background: This case report emphasises the importance of differential diagnosis in dilated cardiomyopathy and the frequent misdiagnosis of congestive heart failure in the COVID-19 era. Case presentation: A patient with Polycythaemia Vera (PV) and no history of cardiac disease developed dyspnoea and radiological signs of pulmonary congestion. He was then treated as a suspected COVID-19 patient. However, echocardiogram showed biventricular dysfunction and severely reduced Left Ventricular Ejection Fraction (LVEF) (22%) without regional wall motion abnormalities. We hypothesised drug-related cardiotoxicity. Conclusion: Particular attention should be paid to patient admitted to Emergency Department (ED) with respiratory symptoms and clinical signs of congestion in order to correctly differentiate COVID-19 related respiratory disease from cardiogenic dyspnoea. Cardiotoxicity should always be ruled out in dilated-hypokinetic cardiomyopathy.
背景:本病例报告强调了COVID-19时代扩张型心肌病鉴别诊断的重要性以及充血性心力衰竭的频繁误诊。病例介绍:一名无心脏病史的真性红细胞增多症患者出现呼吸困难和肺充血的影像学征象。随后,他被作为疑似COVID-19患者接受治疗。然而,超声心动图显示双室功能障碍,左室射血分数(LVEF)严重降低(22%),无局部壁运动异常。我们假设与药物相关的心脏毒性。结论:急诊收治有呼吸系统症状和充血临床体征的患者应给予特别重视,以正确区分COVID-19相关呼吸系统疾病和心源性呼吸困难。扩张型低运动心肌病应始终排除心脏毒性。
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引用次数: 1
A Rare Case of Infective Endocarditis Complicated with a Cardiac Abscess Causing Heart Block 感染性心内膜炎合并心脓肿致心脏传导阻滞1例
Pub Date : 2021-01-01 DOI: 10.37421/2165-7920.2021.11.1456
Veshesh Patel, Collin Tacy, B. Ramírez, Alfredo Lindo, M. Suárez
Individuals that have undergone cardiac surgery or heart valve replacement are at increased risk for developing Infective Endocarditis (IE). IE has numerous signs and symptoms as well as complications. However, an interesting and unique presentation of IE can be in an individual showing a complete heart block on EKG. A heart block from an IE will typically present with a cardiac abscess on Transesophageal Echocardiogram (TEE) and coronary Computed Tomography Angiography (CTA). This individual, with a past medical history of transcatheter aortic valve replacement in 2011, was found to have Enterococcus faecalis bacteremia and endocarditis. Soon after discovery of the infection, CTA of the coronaries showed a 7.6 × 4.6 × 2.5 cm loculated pericardial collection consistent of a cardiac abscess. Despite the initiation of antibiotic therapy, this gentleman with bacterial endocarditis had an increased risk of immediate mortality, due to the complete heart block and additional complications. High clinical suspicion and early intervention are warranted for cases of infective endocarditis.
接受过心脏手术或心脏瓣膜置换术的个体发生感染性心内膜炎(IE)的风险增加。IE有许多体征和症状以及并发症。然而,一个有趣而独特的IE表现可能是在心电图上显示完全的心脏传导阻滞。IE引起的心脏传导阻滞通常在经食管超声心动图(TEE)和冠状动脉ct血管造影(CTA)上表现为心脏脓肿。该患者于2011年有经导管主动脉瓣置换术病史,发现有粪肠球菌菌血症和心内膜炎。发现感染后不久,冠状动脉CTA显示7.6 × 4.6 × 2.5 cm的定位性心包积液,符合心脏脓肿。尽管开始了抗生素治疗,这位细菌性心内膜炎的先生由于完全的心脏传导阻滞和其他并发症,立即死亡的风险增加了。对于感染性心内膜炎的病例,应保持高度的临床怀疑和早期干预。
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引用次数: 0
Jordanian Girl with Juvenile Granulose Cell Tumor Presented as Precocious Puberty: A Case Report 以性早熟为表现的约旦女孩少年颗粒细胞瘤1例报告
Pub Date : 2021-01-01 DOI: 10.37421/2165-7920.2021.11.1463
F. F. Ayyash, Abdalrazzaq Ahmmad Alyassen, Samer Sukre Karadsheh, Ibrahim Mohammad Sawalha, Alia MusaAl-Khlaifat, Alaeddin Ali Saleh, Omar Ashokaibi, Mustafa Al-haji
Objective: Our objective is to explain precocious puberty, type, etiology, investigation, how to differentiate between central and peripheral precocious puberty, and focus on one of the rarest causes of precocious puberty. Case report: In our case of precocious puberty, a two-year-old female presented with bilateral breast enlargement, vaginal secretion, pubic hair, and abdominal swelling. An abdominal and pelvic CT shows a very large ovarian mass. Asalpino-oophorectomy was carried out with regression of symptoms and signs and improvement in laboratory exams. The biopsy showed Juvenile Granulosa Cell Tumors (JGCT). Discussion: Due to an increase in the levels of estradiol and no increase in the gonadotropins (LH, FSH), advanced bone age and height age are compatible with the chronic age of 2 years old, so we think about peripheral precocious puberty. Due to abdominal swelling and patient age (small age), we suspect malignancy, so we did a CT scan and sonography of the pelvis. Conclusion: Every patient with signs and symptoms of precocious puberty must do all the investigation that leads to diagnosis, especially when there is a red flag like in our patient (very small age).
目的:我们的目的是解释性早熟,类型,病因,调查,如何区分中枢性和外周性早熟,并重点关注性早熟的一种罕见的原因。病例报告:在我们的性早熟病例中,一名两岁的女性表现为双侧乳房增大,阴道分泌物,阴毛和腹部肿胀。腹部及盆腔CT显示卵巢有一个很大的肿块。在症状和体征消退和实验室检查改善的情况下进行了卵巢切除术。活检显示幼年颗粒细胞瘤(JGCT)。讨论:由于雌二醇水平升高而促性腺激素(LH, FSH)未升高,骨龄和身高年龄超前与2岁的慢性年龄相适应,因此我们认为是外周性性早熟。由于腹部肿胀和患者年龄(小),我们怀疑是恶性肿瘤,因此我们对骨盆进行了CT扫描和超声检查。结论:每一个有性早熟体征和症状的患者都必须做所有的调查来诊断,特别是当有一个危险信号时,就像我们的病人(很小的年龄)。
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引用次数: 0
Effort Rupture of the Oesophagus (Boerhaave's Syndrome) 食道破裂(布尔哈夫综合征)
Pub Date : 2021-01-01 DOI: 10.37421/2165-7920.2021.11.1470
J. Callaghan
Boerhaave's Syndrome is a rare condition that develops when the distal oesophagus ruptures, resulting in a high risk of morbidity and fatality. Oesophageal perforations are rare, with an incidence of 3.1 per 1,000,000 per year. Patients with a normal underlying oesophagus are more likely to develop Boerhaave's syndrome. A portion of patients with Boerhaave's syndrome, however, have underlying eosinophilic esophagitis, medication-induced esophagitis, Barrett's disease, or infectious ulcers. A longitudinal oesophageal perforation occurs when a sudden increase in intra-oesophageal pressure is paired with negative intrathoracic pressure, as in severe straining or vomiting, and less frequently in childbirth, seizure, continuous coughing or laughing, or weightlifting.
布尔哈夫综合征是一种罕见的疾病,当远端食道破裂时发生,导致高发病率和死亡率。食道穿孔是罕见的,发生率为3.1 / 100万每年。食管底层正常的患者更容易患上布尔哈夫综合征。然而,部分Boerhaave综合征患者存在潜在的嗜酸性粒细胞性食管炎、药物性食管炎、Barrett病或感染性溃疡。纵向食道穿孔发生在食道内压力突然增加同时胸内压力为负时,如严重紧张或呕吐时,在分娩、癫痫发作、持续咳嗽或笑或举重时较少发生。
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引用次数: 0
Fat Embolism in Common Carotid Artery after Temporal Lipofilling in Post-Cancer Reconstruction: A Case Report and Review of the Literature 癌后重建颞部充脂后颈总动脉脂肪栓塞一例报告及文献复习
Pub Date : 2021-01-01 DOI: 10.37421/2165-7920.2021.11.1462
A. Aydin, M. GomesDavid, S. Cortese, F. Marchal, G. Dolivet
Background: Lipofilling is a common aesthetic and reconstructive procedure. Embolism is a possible complication of every filler, which can be lethal. We describe the case of a 56 years old man who had a fat embolism in the common carotid artery with fatal issue. Case presentation: Our patient initially had a left oropharynx cancer, treated by surgery and adjuvant radiotherapy. Many flaps and graft procedure has been tried to treat an ankyloglossia sequelae, and the effective procedure was a forearm free flap. Lipofilling was performed for a temporal defect after a temporal myocutaneous flap. A common carotid embolism was the source of a severe unilateral stroke, leading patient to the death 15 days after initial surgery. Discussion and conclusion: Reverse-flow mechanism explains the artery tropism of fat embolism in the face, contrary to veinous tropism for fat embolism in the body. Pressure of injection, needle (in contrast to blunt end cannula) and large syringe use are the factors of fat embolism in lipofilling procedure. Volume is not a significative factor.
背景:脂肪填充是一种常见的美容和重建手术。栓塞是每一种填充物的可能并发症,这可能是致命的。我们描述的情况下,56岁的男子谁有脂肪栓塞在颈总动脉与致命的问题。病例介绍:我们的病人最初患有左口咽癌,通过手术和辅助放疗治疗。许多皮瓣和移植物的程序已经尝试治疗强直性咬合后遗症,有效的程序是前臂游离皮瓣。在颞部肌皮瓣后,对颞部缺损进行脂肪填充。颈动脉栓塞是严重单侧中风的原因,导致患者在初次手术后15天死亡。讨论与结论:逆向血流机制解释了面部脂肪栓塞的动脉偏向性,与体内脂肪栓塞的静脉偏向性相反。注射压力、针头(与钝端插管相比)和使用大注射器是脂质填充术中脂肪栓塞的因素。数量不是一个重要的因素。
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引用次数: 0
Langerhans Cell Histiocytosis with Multisystem Involvement in a Young Woman: A Case Report and Literature Review 年轻女性朗格汉斯细胞组织细胞增多症伴多系统累及:1例报告及文献复习
Pub Date : 2021-01-01 DOI: 10.37421/2165-7920.2021.11.1452
Sheniz Yuzeir, Hinko Varbanov, T. Yordanova, I. Micheva
Langerhans Cell Histiocytosis (LCH), also known as Histiocytosis X (HX), is a group of hyperplastic cellular diseases of unknown causes. LCH could affect bones, lungs, central nervous system, liver, thymus, skin, and also lymph nodes. The diagnosis of LCH is difficult to enforce and rarely found in adults, with just about 5 cases per million per year. The present study reports the case of a young woman with LCH with multisystem involvement, including that of the bone, orbit, pulmonary system and central nervous system. The patient received chemotherapy for 6 months and exhibited rapid improvement in the involved systems. The last PET/CT showed metabolic activity in the right iliac bone. One year after completion of the therapy, the patient returned to the hospital showing deteriorating health. The clinical case is interesting not only because of the registered clinical, morphological, and imaging data of histiocytosis but also because of the unclear prognostic and diagnostic importance of this phenomenon.
朗格汉斯细胞组织细胞增生症(LCH)又称X型组织细胞增生症(HX),是一组病因不明的增生性细胞疾病。LCH会影响骨骼、肺部、中枢神经系统、肝脏、胸腺、皮肤和淋巴结。LCH的诊断很难执行,在成年人中很少发现,每年每百万人中只有大约5例。本研究报告一例年轻女性LCH多系统受累,包括骨、眼眶、肺系统和中枢神经系统。患者接受化疗6个月,受累系统改善迅速。最后一次PET/CT显示右髂骨代谢活动。治疗结束一年后,患者返回医院,显示健康状况恶化。这个临床病例很有趣,不仅因为组织细胞增多症的临床、形态学和影像学资料,还因为这种现象的预后和诊断重要性尚不明确。
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引用次数: 0
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Journal of clinical case reports
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