Azacitidine

小汇说血液肿瘤：认识这群“不安分”的血液细胞 想象一下，你身体里有一支默默守护你的“军队”，它们时刻巡逻，抵御外敌入侵，维持着你的生命活力。这支“军队”就是你的血液细胞，包括红细胞（运输氧气）、白细胞（免疫防御）和血小板（止血）。然而，当这支“军队”中出现了一些“叛变者”，它们不再听从指挥，反而疯狂扩张，扰乱整个“军队”的秩序，甚至反过来攻击自己的身体，这就是我们今天要聊的血液肿瘤。 听起来是不是有点可怕？ 别担心，小汇这就带你拨开迷雾，认识这群“不安分”的血液细胞！ 一、什么是血液肿瘤？ 简单来说，血液肿瘤，就是血液系统中出现了异常增生的细胞，这些细胞如同脱缰的野马，失去了正常的生长调控，疯狂增殖，在各年龄段人群中均可发生，同时呈现两头高发的趋势。 血液肿瘤和实体肿瘤的区别：肺癌、胃癌等实体肿瘤在器官上长“肿块”，而血液肿瘤的癌细胞会“弥漫”在血液或骨髓中，也可能在淋巴结等处形成肿块。 二、常见的血液肿瘤类型？ 血液肿瘤主要分为以下几大类： 白血病： 也被称为“血癌”，是最为人们所熟知的血液肿瘤之一。它的发病机制是骨髓中的造血干细胞发生恶变，产生大量异常的白血病细胞，抑制了正常血细胞的生成，导致患者出现贫血、感染、出血等一系列症状。根据病情进展速度，又可分为急性白血病和慢性白血病。 淋巴瘤： 淋巴系统是人体重要的免疫防线，当淋巴细胞发生恶性增殖时，就形成了淋巴瘤，以无痛性淋巴结肿大为常见症状。根据病理类型，可分为霍奇金淋巴瘤和非霍奇金淋巴瘤两大类。前者治疗效果较好，后者类型复杂，需个体化治疗。 多发性骨髓瘤：骨髓中的浆细胞（产生抗体）恶性增殖时，就形成了多发性骨髓瘤，会引发骨痛、肾功能损伤等，常见于中老年人。 三、血液肿瘤有哪些症状？ 血液肿瘤的症状多种多样，取决于肿瘤的类型、分期和受累器官。如出现以下症状，建议及时就医检查： 贫血表现：脸色苍白、头晕乏力（红细胞不足）。 异常出血：牙龈出血、皮肤瘀斑（血小板减少）。 反复感染：发烧、口腔溃疡难愈合（白细胞功能异常）。 淋巴结肿大：颈部、腋下无痛性肿块（可能是淋巴瘤）。 骨痛/骨折：尤其是夜间疼痛（骨髓瘤的典型表现）。 四、哪些原因会导致血液肿瘤？ 血液肿瘤的病因复杂，目前尚未完全明确，可能与以下因素有关： 遗传因素： 某些遗传性疾病可能增加患血液肿瘤的风险。 化学因素： 长期接触苯、甲醛等化学物质可能诱发血液肿瘤。 放射因素： 接受过量电离辐射可能增加患血液肿瘤的风险。 病毒感染： 某些病毒感染，如EB病毒、HTLV-1病毒等，可能与淋巴瘤的发生有关。 免疫因素： 免疫功能低下或免疫系统紊乱可能增加患血液肿瘤的风险。 五、如何诊断？ 血液肿瘤的诊断需要进行一系列的检查，以明确肿瘤的类型、分期及预后。常见的诊断方式有血常规、骨髓穿刺、活检、影像学检查、 基因检测等。 六、血液肿瘤的治疗与希望 随着医学技术的不断进步，血液肿瘤的治疗方法也日益丰富。常见的治疗方式有： 化疗： 利用化学药物杀灭肿瘤细胞，是血液肿瘤治疗的常用方法，但可能误伤正常细胞。 靶向治疗： 利用靶向药物针对肿瘤细胞的特定靶点进行攻击，具有疗效好、副作用小的优点。 免疫治疗： 利用免疫系统自身的力量杀灭肿瘤细胞，是近年来备受关注的新型治疗方法。 造血干细胞移植： 将患者自身（自体移植）或健康供者（异基因移植）的造血干细胞移植到患者体内，重建正常的造血功能，是治疗部分急性白血病、多发性骨髓瘤、原发性中枢神经系统淋巴瘤、重型β-地中海贫血、部分非霍奇金淋巴瘤等疾病的重要治疗选项。 七、预防与早筛建议 血液肿瘤≠绝症 随着医学进步，许多血液肿瘤已成为“慢性病”（如慢性粒细胞白血病患者可长期生存），淋巴瘤的治愈率也大幅提高。早发现、规范治疗是关键，无需过度恐慌！ 高风险人群：长期接触苯类化学物（如油漆工）、有血液肿瘤家族史、接受过放化疗者需定期体检。 重视血常规异常：体检报告中的“箭头”↑↓可能是早期信号，需进一步检查。 避免接触致癌物：戒烟、减少染发剂使用、新房注意甲醛污染。 以科研之力，共克血液肿瘤挑战 汇宇制药始终致力于 血液肿瘤疾病的探索和治疗 在化疗及造血干细胞移植领域不断突破 已获批上市10余款血液肿瘤产品 汇涞®普乐沙福注射液 汇必定®克拉屈滨注射液 汇芙安®注射用盐酸美法仑 汇立泰®注射用塞替派 汇昕®注射用阿扎胞苷 汇祺®注射用盐酸苯达莫司汀 汇固®注射用硼替佐米 汇赛®注射用甲氨蝶呤 汇栖®注射用地西他滨 汇赛®甲氨蝶呤注射液 汇璘®注射用环磷酰胺等 以期为患者带来更多福祉 守护血液生命之河的健康 小汇说血液肿瘤：认识这群“不安分”的血液细胞 想象一下，你身体里有一支默默守护你的“军队”，它们时刻巡逻，抵御外敌入侵，维持着你的生命活力。这支“军队”就是你的血液细胞，包括红细胞（运输氧气）、白细胞（免疫防御）和血小板（止血）。然而，当这支“军队”中出现了一些“叛变者”，它们不再听从指挥，反而疯狂扩张，扰乱整个“军队”的秩序，甚至反过来攻击自己的身体，这就是我们今天要聊的血液肿瘤。 听起来是不是有点可怕？ 别担心，小汇这就带你拨开迷雾，认识这群“不安分”的血液细胞！ 一、什么是血液肿瘤？ 简单来说，血液肿瘤，就是血液系统中出现了异常增生的细胞，这些细胞如同脱缰的野马，失去了正常的生长调控，疯狂增殖，在各年龄段人群中均可发生，同时呈现两头高发的趋势。 血液肿瘤和实体肿瘤的区别：肺癌、胃癌等实体肿瘤在器官上长“肿块”，而血液肿瘤的癌细胞会“弥漫”在血液或骨髓中，也可能在淋巴结等处形成肿块。 二、常见的血液肿瘤类型？ 血液肿瘤主要分为以下几大类： 白血病： 也被称为“血癌”，是最为人们所熟知的血液肿瘤之一。它的发病机制是骨髓中的造血干细胞发生恶变，产生大量异常的白血病细胞，抑制了正常血细胞的生成，导致患者出现贫血、感染、出血等一系列症状。根据病情进展速度，又可分为急性白血病和慢性白血病。 淋巴瘤： 淋巴系统是人体重要的免疫防线，当淋巴细胞发生恶性增殖时，就形成了淋巴瘤，以无痛性淋巴结肿大为常见症状。根据病理类型，可分为霍奇金淋巴瘤和非霍奇金淋巴瘤两大类。前者治疗效果较好，后者类型复杂，需个体化治疗。 多发性骨髓瘤：骨髓中的浆细胞（产生抗体）恶性增殖时，就形成了多发性骨髓瘤，会引发骨痛、肾功能损伤等，常见于中老年人。 白血病： 也被称为“血癌”，是最为人们所熟知的血液肿瘤之一。它的发病机制是骨髓中的造血干细胞发生恶变，产生大量异常的白血病细胞，抑制了正常血细胞的生成，导致患者出现贫血、感染、出血等一系列症状。根据病情进展速度，又可分为急性白血病和慢性白血病。 淋巴瘤： 淋巴系统是人体重要的免疫防线，当淋巴细胞发生恶性增殖时，就形成了淋巴瘤，以无痛性淋巴结肿大为常见症状。根据病理类型，可分为霍奇金淋巴瘤和非霍奇金淋巴瘤两大类。前者治疗效果较好，后者类型复杂，需个体化治疗。 多发性骨髓瘤：骨髓中的浆细胞（产生抗体）恶性增殖时，就形成了多发性骨髓瘤，会引发骨痛、肾功能损伤等，常见于中老年人。 三、血液肿瘤有哪些症状？ 血液肿瘤的症状多种多样，取决于肿瘤的类型、分期和受累器官。如出现以下症状，建议及时就医检查： 贫血表现：脸色苍白、头晕乏力（红细胞不足）。 异常出血：牙龈出血、皮肤瘀斑（血小板减少）。 反复感染：发烧、口腔溃疡难愈合（白细胞功能异常）。 淋巴结肿大：颈部、腋下无痛性肿块（可能是淋巴瘤）。 骨痛/骨折：尤其是夜间疼痛（骨髓瘤的典型表现）。 贫血表现：脸色苍白、头晕乏力（红细胞不足）。 异常出血：牙龈出血、皮肤瘀斑（血小板减少）。 反复感染：发烧、口腔溃疡难愈合（白细胞功能异常）。 淋巴结肿大：颈部、腋下无痛性肿块（可能是淋巴瘤）。 骨痛/骨折：尤其是夜间疼痛（骨髓瘤的典型表现）。 四、哪些原因会导致血液肿瘤？ 血液肿瘤的病因复杂，目前尚未完全明确，可能与以下因素有关： 遗传因素： 某些遗传性疾病可能增加患血液肿瘤的风险。 化学因素： 长期接触苯、甲醛等化学物质可能诱发血液肿瘤。 放射因素： 接受过量电离辐射可能增加患血液肿瘤的风险。 病毒感染： 某些病毒感染，如EB病毒、HTLV-1病毒等，可能与淋巴瘤的发生有关。 免疫因素： 免疫功能低下或免疫系统紊乱可能增加患血液肿瘤的风险。 遗传因素： 某些遗传性疾病可能增加患血液肿瘤的风险。 化学因素： 长期接触苯、甲醛等化学物质可能诱发血液肿瘤。 放射因素： 接受过量电离辐射可能增加患血液肿瘤的风险。 病毒感染： 某些病毒感染，如EB病毒、HTLV-1病毒等，可能与淋巴瘤的发生有关。 免疫因素： 免疫功能低下或免疫系统紊乱可能增加患血液肿瘤的风险。 五、如何诊断？ 血液肿瘤的诊断需要进行一系列的检查，以明确肿瘤的类型、分期及预后。常见的诊断方式有血常规、骨髓穿刺、活检、影像学检查、 基因检测等。 六、血液肿瘤的治疗与希望 随着医学技术的不断进步，血液肿瘤的治疗方法也日益丰富。常见的治疗方式有： 化疗： 利用化学药物杀灭肿瘤细胞，是血液肿瘤治疗的常用方法，但可能误伤正常细胞。 靶向治疗： 利用靶向药物针对肿瘤细胞的特定靶点进行攻击，具有疗效好、副作用小的优点。 免疫治疗： 利用免疫系统自身的力量杀灭肿瘤细胞，是近年来备受关注的新型治疗方法。 造血干细胞移植： 将患者自身（自体移植）或健康供者（异基因移植）的造血干细胞移植到患者体内，重建正常的造血功能，是治疗部分急性白血病、多发性骨髓瘤、原发性中枢神经系统淋巴瘤、重型β-地中海贫血、部分非霍奇金淋巴瘤等疾病的重要治疗选项。 七、预防与早筛建议 血液肿瘤≠绝症 随着医学进步，许多血液肿瘤已成为“慢性病”（如慢性粒细胞白血病患者可长期生存），淋巴瘤的治愈率也大幅提高。早发现、规范治疗是关键，无需过度恐慌！ 高风险人群：长期接触苯类化学物（如油漆工）、有血液肿瘤家族史、接受过放化疗者需定期体检。 重视血常规异常：体检报告中的“箭头”↑↓可能是早期信号，需进一步检查。 避免接触致癌物：戒烟、减少染发剂使用、新房注意甲醛污染。 以科研之力，共克血液肿瘤挑战 汇宇制药始终致力于 血液肿瘤疾病的探索和治疗 在化疗及造血干细胞移植领域不断突破 已获批上市10余款血液肿瘤产品 汇涞®普乐沙福注射液 汇必定®克拉屈滨注射液 汇芙安®注射用盐酸美法仑 汇立泰®注射用塞替派 汇昕®注射用阿扎胞苷 汇祺®注射用盐酸苯达莫司汀 汇固®注射用硼替佐米 汇赛®注射用甲氨蝶呤 汇栖®注射用地西他滨 汇赛®甲氨蝶呤注射液 汇璘®注射用环磷酰胺等 以期为患者带来更多福祉 守护血液生命之河的健康

ROCKVILLE, Md. and SUZHOU, China, May 22, 2025 (GLOBE NEWSWIRE) -- Ascentage Pharma (NASDAQ: AAPG; HKEX: 6855), a global biopharmaceutical company dedicated to addressing unmet medical needs in cancers, today announced that new clinical data from two ongoing investigational studies evaluating lisaftoclax in various blood cancers and alrizomadlin in solid tumors will be presented during an oral presentation and poster presentation, respectively, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30 - June 3 in Chicago, Ill., USA. Both lisaftoclax and alrizomadlin demonstrated antitumor activity, and the data support their further clinical development. The Bcl-2 inhibitor lisaftoclax and the MDM2-p53 inhibitor alrizomadlin are both key drug candidates in Ascentage Pharma’s apoptosis-targeted pipeline. The oral report on lisaftoclax will feature results from a Phase 1b/2 study evaluating lisaftoclax in combination with azacitidine in patients with treatment-naïve (TN) or prior venetoclax-exposed myeloid malignancies. Data from this global, multicenter study that has enrolled nearly one hundred patients show that lisaftoclax in combination with azacitidine was well tolerated with preliminary efficacy. Moreover, this study released the first dataset of lisaftoclax in patients with venetoclax-refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and it also demonstrated promising therapeutic potential. Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented: “We are pleased that results from the ongoing Phase 1b/2 study of lisaftoclax will be featured in an oral presentation at the 2025 ASCO Annual Meeting, which will highlight how lisaftoclax demonstrated significant activity when combined with azacitidine in patients with various myeloid malignancies. This novel Bcl-2 inhibitor has shown antitumor activity in both previously untreated patients and those who were treated with venetoclax, addressing a critical treatment gap for these difficult-to-treat conditions. The recent new drug application submission for lisaftoclax in China was a milestone for our program, and, if approved, lisaftoclax would become the second Bcl-2 inhibitor to be approved anywhere in the world. We are grateful to the patients who participated in these trials and the investigators for sharing our commitment to developing innovative therapies that can make a meaningful difference for patients with cancer who have limited options.” Highlights of the two abstracts selected for presentations at ASCO 2025 are as follows: Phase 1b/2 Study of Lisaftoclax (APG-2575) Combined with Azacitidine (AZA) in Patients with Treatment-Naïve or Prior Venetoclax-Exposed Myeloid Malignancies Abstract #: 6505 Format: Oral Presentation Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant Date and Time: Monday, June 2, 2025, 3:00 PM-6:00 PM, Central Time (Tuesday, June 3, 2025, 4:00 AM-7:00 AM, Beijing Time) Principal Authors: Michael Francis Leahy, MBChB, Royal Perth Hospital, Australia; Shaun Fleming, MBBS(Hons), PhD, The Alfred Hospital & Australian Centre for Blood Diseases, Australia; Patricia Kropf, MD, Novant Health Cancer Institute, United States, et al. Highlights: The Phase 1b/2 study was designed to evaluate the safety and efficacy of lisaftoclax in combination with azacitidine in patients with treatment-naïve (TN) or relapsed/refractory (R/R) acute myeloid leukemia (AML)/mixed phenotype acute leukemia (MPAL) or high-risk myelodysplastic syndromes (HR-MDS)/chronic myelomonocytic leukemia (CMML). Lisaftoclax is a novel investigational oral selective Bcl-2 inhibitor that has shown enhanced treatment response when combined with azacitidine in prior preclinical and clinical studies. The combination of lisaftoclax and azacitidine was well tolerated, with initial signals of clinical activity. As of the data cutoff date of January 6, 2025, 97 patients were enrolled, with a median treatment duration of two cycles. In patients with TN-MDS/CMML, the overall response rate (ORR) was 64%, with complete response (CR) and marrow CR achieved by 29% and 36% of patients, respectively; in patients with R/R AML treated with lisaftoclax for 28 days or 14 days of repeated 28-day cycles, the ORRs were 39% and 50%, respectively, including CR rates of 28% and 37.5%, respectively; in patients with diseases refractory to venetoclax, the ORR was 17% in patients with AML/MPAL and 50% in patients with HR-MDS. The maximum tolerated dose (MTD) was not reached, and no dose-limiting toxicities (DLTs) were observed. Common grade 3/4 treatment-emergent adverse events (TEAEs) included neutropenia (40%), febrile neutropenia (31%), and thrombocytopenia (22%). Febrile neutropenia was the most commonly reported serious adverse event (SAE) (26.8%). Only 3% of participants experienced neutropenia that led to a dose reduction of lisaftoclax. There was no reported 60-day mortality. A Phase 2 Study of Novel MDM2 Inhibitor Alrizomadlin (APG-115) with or without Toripalimab in Patients with Advanced Adenoid Cystic Carcinoma (ACC) or Other Solid Tumors Abstract #: 6102 Format: Poster Presentation Session Title: Head and Neck Cancer Date and Time: Monday, June 2, 2025, 9:00 AM-12:00 PM, Central Time (Monday June 2, 2025, 10:00 PM – 1:00 AM the next day, Beijing Time) Principal Authors: Ye Guo, MD, Department of Medical Oncology, Shanghai East Hospital, China; Ning Li, MD, Chinese Academy of Medical Sciences Cancer Hospital, China; Xing Zhang, MD, Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, China; Meiyu Fang, MD, Department of Rare Cancer & Head and Neck Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, China; Shuhang Wang, MD, Chinese Academy of Medical Sciences Cancer Hospital, China, et al. Highlights: Alrizomadlin is a novel investigational oral MDM2 inhibitor that has shown a manageable safety profile with initial clinical activity in ACC. As of the data cutoff date of January 5, 2025, 54 patients with advanced ACC, malignant peripheral nerve sheath tumor (MPNST), liposarcoma (LPS), biliary-tract cancer (BTC) and other tumors were enrolled. Alrizomadlin monotherapy showed antitumor activity in patients with advanced ACC or MPNST. Alrizomadlin in combination with toripalimab was also well tolerated and demonstrated antitumor activity in patients with MPNST, BTC and LPS. In the monotherapy arm, 14 patients were efficacy-evaluable. The ORR was 22.2% and the disease control rate (DCR) was 100% in 9 patients with ACC. The DCR was 100% in all patients with MPNST, all 5 of whom achieved stable disease (SD). Grade 3 or higher treatment-related adverse events (TRAEs) included neutropenia (13.6%) and thrombocytopenia (9.1%). No treatment-related SAEs were reported. In the combination arm, 28 patients were efficacy-evaluable. The ORR was 20% and DCR was 80% in 5 patients with BTC. The ORR was 16.7% and DCR was 66.7% in 6 patients with LPS. The ORR was 14.3% and DCR was 53.6% in patients with MPNST; furthermore, 2 patients with MPNST had confirmed partial responses (PR) with prolonged progression free survival (PFS) of 60+ weeks and 96+ weeks, respectively. Grade 3 or higher TRAEs included thrombocytopenia (38.5%) and neutropenia (34.6%). Treatment-related SAEs were reported in 8 patients, with thrombocytopenia being the most common (n=6). One patient discontinued treatment because of grade 4 thrombocytopenia. No treatment-related deaths were reported. * Lisaftoclax (APG-2575) and alrizomadlin (APG-115) are investigational compounds and have not been approved by the U.S. FDA. About Ascentage Pharma Ascentage Pharma (NASDAQ: AAPG; HKEX: 6855) is a global biopharmaceutical company dedicated to addressing unmet medical needs in cancers. The company has built a rich pipeline of innovative drug candidates that includes inhibitors targeting key proteins in the apoptotic pathway, such as Bcl-2 and MDM2-p53 and next-generation kinase inhibitors. The lead asset, olverembatinib, is the first third generation BCR-ABL1 inhibitor approved in China for the treatment of patients with CML in chronic phase (CML-CP) with T315I mutations, CML in accelerated phase (CML-AP) with T315I mutations, and CML-CP that is resistant or intolerant to first and second-generation TKIs. It is covered by the China National Reimbursement Drug List (NRDL). The Company is currently conducting an FDA-cleared, global registrational Phase 3 trial, or POLARIS-2, of olverembatinib for CML, as well as global registrational Phase 3 trials for newly diagnosed Ph+ ALL patients and SDH-deficient GIST patients. The second lead asset, lisaftoclax, is a novel Bcl-2 inhibitor for the treatment of various hematological malignancies. The NDA for the treatment of relapsed and/or refractory CLL and SLL was accepted with Priority Review designation by China’s National Medical Products Administration. The Company is currently conducting an FDA-cleared, global registrational Phase 3 trial, or GLORA, of lisaftoclax in combination with BTK inhibitors for patients with CLL/SLL previously treated with BTK inhibitors for more than 12 months with sub-optimal response, as well as global registrational Phase 3 trials for newly diagnosed CLL/SLL, AML and MDS patients. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships and other relationships with numerous leading biotechnology and pharmaceutical companies, such as Takeda, AstraZeneca, Merck, Pfizer and Innovent, in addition to research and development relationships with leading research institutions, such as Dana-Farber Cancer Institute, Mayo Clinic, National Cancer Institute and the University of Michigan. For more information, visit https://ascentage.com/ Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. All statements, other than statements of historical facts, contained in this press release may be forward-looking statements, including statements that express Ascentage Pharma’s opinions, expectations, beliefs, plans, objectives, assumptions or projections regarding future events or future results of operations or financial condition. These forward-looking statements are subject to a number of risks and uncertainties as discussed in Ascentage Pharma’s filings with the SEC, including those set forth in the sections titled “Risk factors” and “Special note regarding forward-looking statements and industry data” in its Registration Statement on Form F-1, as amended, filed with the SEC on January 21, 2025, and the Form 20-F filed with the SEC on April 16, 2025, the sections headed “Forward-looking Statements” and “Risk Factors” in the prospectus of the Company for its Hong Kong initial public offering dated October 16, 2019, and other filings with the SEC and/or The Stock Exchange of Hong Kong Limited we made or make from time to time that may cause actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. The forward-looking statements contained in this presentation do not constitute profit forecast by the Company’s management. As a result of these factors, you should not rely on these forward-looking statements as predictions of future events. The forward-looking statements contained in this press release are based on Ascentage Pharma’s current expectations and beliefs concerning future developments and their potential effects and speak only as of the date of such statements. Ascentage Pharma does not undertake any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Investor Relations: Hogan Wan, Head of IR and Strategy Ascentage Pharma Hogan.Wan@ascentage.com +86 512 85557777 Stephanie Carrington ICR Healthcare Stephanie.Carrington@icrhealthcare.com +1 (646) 277-1282 Media Relations: Sean Leous ICR Healthcare Sean.Leous@icrhealthcare.com +1 (646) 866-4012 Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.