Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to a heterogeneous drug response, bringing about significant challenges in comprehending drug mechanisms. Our study applied data-independent acquisition-based mass spectrometry to multidimensional proteome profiling of PROTAC (DIA-MPP) to uncover the efficacy and sensitivity of the PROTAC compound. We profiled the signal transducer and activator of transcription 3 (STAT3) PROTAC degrader in six leukemia and lymphoma cell lines under multiple conditions, demonstrating the pharmacodynamic properties and downstream biological responses. Through comparison between sensitive and insensitive cell lines, we revealed that STAT1 can be regarded as a biomarker for STAT3 PROTAC degrader, which was validated in cells, patient-derived organoids, and mouse models. These results set an example for a comprehensive description of the multidimensional PROTAC pharmacodynamic response and PROTAC drug sensitivity biomarker exploration.

Acute promyelocytic leukemia (APL) with typically PML::RARA fusion gene caused by t (15;17) (q22; q12) was distinguished from other types of acute myeloid leukemia. In a subset of patients with APL, t (15;17) (q22;q21) and PML::RARA fusion cannot be detected. In this report, we identified the coexistence of STAT3::RARA and RARA::STAT5b fusions for the first time in a variant APL patient lacking t (15;17)(q22;q21)/PML::RARA fusion. Then, this patient was resistant to all-trans retinoic acid combined arsenic trioxide chemotherapy. Accurate detection of RARA gene partners is crucial for variant APL, and effective therapeutic regime is urgently needed.

STAT3 belongs to a family of seven transcription factors. It plays an important role in activating the transcription of various genes involved in a variety of cellular processes. High levels of STAT3 are detected in several types of cancer. Hence, STAT3 inhibition is considered a promising therapeutic anti-cancer strategy. However, since STAT3 inhibitors bind to the shallow SH2 domain of the protein, it is expected that hydration water molecules play significant role in ligand-binding complicating the discovery of potent binders. To remedy this issue, we herein propose to extract pharmacophores from molecular dynamics (MD) frames of a potent co-crystallized ligand complexed within STAT3 SH2 domain. Subsequently, we employ genetic function algorithm coupled with machine learning (GFA-ML) to explore the optimal combination of MD-derived pharmacophores that can account for the variations in bioactivity among a list of inhibitors. To enhance the dataset, the training and testing lists were augmented nearly a 100-fold by considering multiple conformers of the ligands. A single significant pharmacophore emerged after 188 ns of MD simulation to represent STAT3-ligand binding. Screening the National Cancer Institute (NCI) database with this model identified one low micromolar inhibitor most likely binds to the SH2 domain of STAT3 and inhibits this pathway.

Vaccines against SARS-CoV-2 are the most effective measure against the COVID-19 pandemic. The safety profile of mRNA vaccines in patients with rare diseases has not been assessed systematically in the clinical trials, as these patients were typically excluded. This report describes the occurrence of agranulocytosis within days following the first dose of an mRNA-1273 vaccination against COVID-19 in a previously healthy older adult. The patient was diagnosed with a suspected STAT3 wild-type T-cell large granular lymphocytic leukaemia (T-LGL). Neutropenia was successfully treated with IVIG, glucocorticoids, and G-CSF. In vitro experiments aimed at elucidating the pathways potentially causing the mRNA vaccine-associated neutropenia indicated that the mRNA, but not the adenoviral Ad26.COV2.S vector vaccine, triggered strong IL-6/STAT3 activation in vitro, resulting in excessive T-cell activation and neutrophil degranulation in the patient but not in controls. mRNA-1273 activated TLR-3 suggesting TLR mediated IL-6/STAT3 pathway activation. To complete the primary series of COVID-19 immunization, we used a single dose of Ad26.COV2.S vector vaccine without reoccurrence of neutropenia. The T-LGL clone remained stable during the follow-up of more than 12 months without ongoing therapy. Our data suggest that switching the immunization platform may be a reasonable approach in subjects with rare associated hematologic side effects due to excess STAT3-mediated stimulation following mRNA vaccination. Using in vitro testing before re-administration of a (COVID) vaccine also has relevance for other rare immune events after (mRNA) vaccination.

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Objective: To improve the awareness of hyper-IgE syndrome (HIES) characterized by disseminated infection. Methods: We retrospectively analyzed a patient with HIES characterized by Talaromyces marneffei and Staphylococcus aureus mixed disseminated infection in Shenzhen People\'s Hospital. The clinical manifestations, results of laboratory tests/genetic examinations, therapeutic strategies and prognosis were summarized. The keywords \"hyper-lgE syndrome\" were used to search and review the literature in Wanfang databases and Pubmed database. Results: In February 2021, an 18-year-old male patient was admitted to our hospital with backache for over 3 weeks and fever for 4 days. Physical examination revealed deciduous teeth in the oral cavity, bilateral renal pain on percussion, and interphalangeal joint hyperextension. Laboratory studies demonstrated increased blood eosinophils and serum level of total IgE. Bacterial culture from bronchoscopic secretions, bronchial mucosa, and necrotic tissue from the left upper arm showed Talaromyces marneffei. Bacterial culture from alveolar lavage fluid, left upper arm necrotic tissue, puncture fluid of right retroauricular abscess and renal drainage fluid suggested methicillin-sensitive Staphylococcus aureus. The chest and abdominal CT revealed diffuse patchy and nodular lesions in bilateral lungs, cavitary lesions in the upper lobe of the left lung, multiple enlarged lymph nodes in the mediastinum, and infectious lesions within both kidneys and perirenal space. Furthermore, the patients was identified with STAT3 mutations by whole exome sequencing, which confirmed the diagnosis of HIES. Nineteen literature articles were retrieved, involving 27 adult patients with a median age of diagnosis of 23 years. The most common manifestations included: skin infection (16/27), eczema (15/27), elevated IgE (26/27) and eosinophils (17/27), as well as positive STAT3 mutation (11/27). Conclusion: Clinicians should be alert to the possibility of hyper-IgE syndrome in patients with severe or disseminated intracellular bacterial infections.
目的： 提高对以播散性感染为特征的高IgE综合征（HIES）的认识。 方法： 回顾性分析深圳市人民医院1例以马尔尼菲篮状菌和金黄色葡萄球菌播散性感染为表现的HIES，总结其临床表现、实验室检查、基因检测、治疗过程及预后。以“高IgE综合征”和“Hyper-IgE syndrome”为关键词分别在万方数据库和Pubmed数据库检索并复习相关文献。 结果： 患者男性，18岁，因“腰痛3周余，发热4 d”入院。体格检查示口腔有乳牙滞留，双肾区叩击痛、手指关节过展。血嗜酸性粒细胞、血总IgE明显升高。痰培养、支气管黏膜/左上臂坏死组织培养提示马尔尼菲篮状菌；肺泡灌洗液、左上臂坏死组织及右侧耳后脓肿穿刺液、肾脏引流液培养提示甲氧西林敏感金黄色葡萄球菌。CT提示双肺弥漫斑片及结节样影，左肺上叶空洞性病变，纵隔多发肿大淋巴结，双肾及肾周内感染性病变。全外显子测序提示患者存在STAT3突变，确诊HIES。检索到中英文文献19篇，涉及27例成人患者，确诊中位年龄23岁。常见皮肤感染（16/27）、湿疹（15/27）、IgE升高（26/27）、血嗜酸性粒细胞升高（17/27）和STAT3突变（11/27）。 结论： 对于严重或播散性感染应警惕高IgE综合征。.

Hyperimmunoglobulin E syndrome (HIES) is a rare immunologic disorder. Typical clinical features of HIES include recurrent bacterial pneumonia, lung cysts, characteristic facial features, and newborn dermatitis. The varied clinical presentation can lead to a delayed diagnosis. We herein present a sporadic case of HIES in a man who initially presented with a longstanding history of intractable skin abscesses.

A boy, aged 4 years and 6 months, had disease onset of fever, cough, pale complexion, and weakness, with hepatosplenomegaly, lymphadenectasis, and pancytopenia. He had been having repeated respiratory and digestive tract infections. Gene detection showed a pathogenic heterozygous mutation, c.C2147 > T(p.T716M), in the STAT3 gene. The boy was thus diagnosed with immune dysregulation syndrome. Anti-infective therapy and irregular corticosteroid therapy had an unsatisfactory effect in the early stage, but the symptoms improved after regular corticosteroid therapy. This article reported the case of immune dysregulation syndrome caused by STAT3 gene mutation and summarized the epidemiology, clinical features, diagnosis, and treatment of this disease, which can provide a reference for early diagnosis, treatment, and future studies of this disease.

Introduction: Hyperimmunoglobulin E syndromes (HIESs) are characterized by a high serum immunoglobulin E (IgE) level, eczematoid rashes, recurrent staphylococcal skin abscesses, and recurrent pneumonia and pneumatocele formation. Autosomal dominant HIES is the most common form of HIES and mainly occurs due to loss-of-function mutations in the Signal Transducer and Activator of Transcription 3 (STAT3) gene (STAT3 LOF). Case Presentation: We report the case of an 11-year-old Peruvian girl diagnosed with STAT3 LOF caused by p.R382W mutation. She presented with recurrent staphylococcal pneumonia and empyema caused by the rarely reported Achromobacter xylosoxidans, which led to severe destruction of the lung parenchyma, multiple lung surgeries, and the development of bronchopleural fistulas. A laparotomy was also performed, which showed evidence of sigmoid colon perforation. The patient received immunoglobulin replacement therapy (IRT) and antibiotic prophylaxis, and the frequency of her infections has decreased over the past 3 years. Conclusion: This is the first case of STAT3 LOF diagnosed by genomic sequencing in Peru. Patients with this mutation have recurrent pulmonary infections, and require multiple surgical procedures with frequent complications. A. xylosoxidans infection could be related to the prolonged stay in intensive care leading to high mortality; therefore, additional care must be taken when treating patients with this infection. In addition, colonic perforation is a rare complication in STAT3 LOF patients. IRT and antibiotic prophylaxis appear to decrease the frequency of infections and hospitalizations.