세자르 프랑크에 관한 연구 - 그의 피아노 작품을 중심으로

주 단 군산대학교 2023 국내박사

세자르 프랑크는 19세기 프랑스의 작곡가, 피아니스트, 오르가니스트로 프랑스 명성 악파의 뛰어난 대표자이다. 그의 음악은 종교적 특성과 균형 잡힌 특징을 가지고 있다. 음악 창작 영역은 매우 넓으며, 장르는 주로 관 현악『교향곡 d단조』, 실내악 『피아노 3중주』, 『피아노와 바이올린 소 나타』, 『Prelude Choral et Fugue』, 『Prelude Aria et Final』등을 포 함한다. 본문은 프랑크의 피아노 작품을 연구대상으로 하고, 작곡가의시대 순에 따 라 전기, 중기, 후기로 나눈다. 작곡가의 초기 피아노 작품은 대부분 현란한 기술을 위주로 하며, 또한 전 해 내려오는 것도 비교적 적다. 프랑크는 초창기 경력 때문에 작곡 중기에 피아노 작품을 작곡하지 않았다. 따라서 그의 중기에 작곡 된 작품은 파이 프 오르간 작품을 위한 피아노 버전이라고 할 수 있다. 『Prelude Fugue et Variation』작품은 필자가 악보를 분석한 후 오르간 원보와 비교 분석했 다. 1884년 『Prelude Choral et Fugue』작품이 나오면 부터 비로소 그의 후 기 피아노 음악 작품이 시작되었다. 본 논문에서는 『Prelude Choral et Fugue』와『Prelude Aria et Final』을 각각비교 분석하였다. 첫째, 외적 특 징의 공통성은 고전성 낭만성과 종교성이다. 둘째, 내적 특징의 공통성은 정 신적 의미의 차이와 음악적 성격의 차이이다. 두 작품은 전체적으로 볼 때 모두 세 도막 구조이다. 프랑크의 종교 신앙의 원 인과 결합하여, 두 작품은 서양 회화사 중의 "삼면화(Triptych)" 구조를 연상할 수 있다. 가운데 그림은 이야기의 가장 중요한 중심이자 가장 중요 한 정신이다. 이러한 관점에서 두 작품의 핵심 주제를 결합하면 성가와 아 리아는 두 작품 각각의 정신적인 함의를 살릴 수 있다. 『Choral』와 『Aria』부분은 두 작품의 장르적 혁신의 상징으로서 전체 작품에 대하여 연결 및 과도적인 역할을 할 뿐만 『Aria』그 안의 『Choral』주제와 『Aria』주제도 전곡의 정신적 핵심으로서 순환 수법의 방식을 통해 『Choral』의 정신적 함의를 표출하였다. 표제의 각도에서 보면, 코랄과 『Aria』의 의미는 결코 다르기 때문에 두 작품의 정신적인 내포는 각각의 특성을 가지고 있다. 『Prélude, Choral et Fugue, Op. 21』의 음악적 성격은 적극적이고 순결 하여 프랑크는 젊은이와 같은 창작열과 독실한 종교적 신앙으로 자아에 대 한 구원을 실현하였으며, 프랑스 피아노 음악의 부흥과 발전에 활력을 불어 넣었다. 『Prélude, Aria et Finale, Op. 23』의 음악적 성격은 절제되고 성 숙하다. 『Prélude, Choral et Fugue, Op. 21』만큼 활발하지는 않지만, 프 랑크의 섬세한 개인적인 감정 표현은 이 작품을 더욱 흥미롭게 만든다. 피아노 작품의 연출은 연주 기교를 활용하여 작품의 내용을 충분히 표현 하는 과정이다. 그러므로 논문의 끝은 연주자의 시각에서 앞의 글의 비교 연구의 결과와 결합하여 리듬과 빠르기와 음악적 강도의 조절의 관점에서 두 작품의 구체적인 스타일을 어떻게 연출할 것인지를 탐구하고자 한다.

민족주의 음악을 통한 그리그 <피아노 협주곡 a단조, Op.16>에 대한 연구분석

양상미 군산대학교 2023 국내박사

그리그(Edvard Grieg, 1843-1907)는 낭만주의가 주를 이루던 19세기 후반에 활동하던 노르웨이의 대표적인 민족주의 음악가이다. 그는 독일 라이프치히 음악원에서 당시 주를 이루던 낭만주의 음악의 형식과 기법을 교육받았고, 낭만주의를 바탕으로 노르웨이 민족주의적 음악적 요소를 결합하여 자신만의 색채를 나타낸 작품들을 작곡하였다. 당시의 노르웨이는 오랜 식민지 생활로 왕가나 귀족 음악은 찾아볼 수 없었고, 농민들의 노동요나 춤곡 등이 정확한 기록 없이 구전되어왔다. 노르웨이 예술가들은 이렇게 구전된 노랫말을 수집하여 민요집을 출판하고, 이야기와 전설, 춤곡 리듬을 이용하여 창작활동을 하며 자국의 전통을 잃지 않고 애국심을 고취 시키기 위해 노력하였다. 그리그의 작품에서 민족주의적 요소들은 노르웨이의 전통적인 춤곡 리듬, 전설, 이야기, 노동요와 민요선율의 차용 등으로 다양하게 나타난다. 이러한 민족주의적 요소들은 그가 작곡한 바이올린 소나타, 피아노 소나타, 피아노 협주곡, 예술가곡 등 다양한 장르의 작품들에서 찾아볼 수 있으며, 그리그는 이러한 민족적인 요소가 포함된 작품들을 통해 노르웨이의 전통을 지키기 위해, 그리고 자국의 음악의 발전과 부흥을 위해 노력하였다. 그리그의 <피아노 협주곡(Piano Concerto a minor, Op. 16)>은 그의 작품 중 유일한 대규모 피아노 협주곡으로, 낭만주의 형식을 바탕으로 민족주의적 요소가 결합 된 대표적인 작품이다. 모든 예술작품은 당시의 시대를 반영하고 있고 당시의 상황은 작품에 큰 영향을 미친다. 본 논문에서는 그리그의 대표적인 작품인 <피아노 협주곡 Op. 16>을 보다 깊게 이해하기 위해 당시의 시대적 상황을 살펴보며 민족주의 개념과 민족주의 음악의 특징에 대해 알아보았다. 특히 북유럽의 음악 중 노르웨이의 민족주의 음악의 특징과 함께 <피아노 협주곡 Op. 16>의 구조를 살펴보며 그 안의 어떠한 낭만주의 요소들과 민족주의 요소들이 결합되어 있는지 이해하고 연주하는데 그 목적이 있다. Edvard Grieg(1843-1907) is a representative nationalism Composer who was active in the late 19th century when romanticism was the mainstream movement. He was educated on the romanticist music’s forms and techniques that were trending at the time at the Leipzig Academy of music, Germany. Based on romanticism, ht composed works showing his unique color by combing Norway’s nationalist musical elements. At the period, royal or aristocratic music could not be found in Norway due to prolonged colonization, and work songs, dance songs, etc. or farmers were passed down orally without accurate records. Norwegian artists collected these orally transmitted lyrics and published a collection or folk songs. They used stories, legends, dance song rhythms for creative activities, string to inspire patriotism while maintaining their national tradition. The elements of Nationalism are diversly exhibited in Grieg’s works as the borrowing of Norway’s traditional dance song rhythms, legends, stories, works songs and folk song melodies. These nationalist elements can be discovered in works of a variety of genres such as violin sonata, piano sonata, piano concerto, art songs he composed. Through these pieces including nationalist elements, Gireg’s endeavored to keep Norwegian traditions as well as advance and revive his homeland’s music. Grieg’s <Piano Concerto in a minor, Op. 16> is the only large-scale piano concerto among his compositions and is a classic work combining nationalist elements based on a romanticist form. All art works reflect the relevant times, and the circumstances at the relevant period have a massive influence on a work. This paper examines the historical background of the times and delves into the characteristics of the nationalism concept and nationalist music to understand Grieg’s signature work <Piano Concerto Op. 16> in more depth. In particular, along with the characteristics of Norway’s nationalist music among Northern Europe’s music, the purpose or the study is to review the structure of <Piano Concerto Op. 16> and to perform the work by comprehending the element of Romanticism and Nationalism.

Signal transduction pathways with respect to carbazole derivatives in candida albicans pathogenesis

박영광 Graduate School, Korea University 2022 국내박사

Morphogenesis is one of the virulence factors of Candida albicans, an opportunistic pathogen that colonizes the skin and mucosal surfaces of most individuals. Morphogenesis is the unique ability of C. albicans to change morphology from yeast to hyphae under various stress conditions. The pathogenesis and morphogenesis of C. albicans are closely related. In C. albicans morphogenesis, Ras1 is an important switch of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway plays an important role in C. albicans virulence by regulating cell growth, morphogenesis, and biofilm formation. In addition, in the morphogenesis process, Ume6 acts as a transcriptional factor and Nrg1 is a transcriptional repressor for the expression of hyphae specific genes (HSGs). Although azole or echinocandin class drugs for C. albicans have already been developed and used, recently, the development of drugs using a different pathway mechanism to suppress resistant C. albicans strains is required due to the chronic prescription of these drugs. In this study, Molecule B and Molecule C containing the carbazole structure attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. Molecule B and Molecule C suppressed morphogenesis by suppressing protein and RNA levels of Ras1/MAPK-related genes, including UME6 and NRG1. Furthermore, the antifungal effects of Molecule B and Molecule C have been demonstrated in vivo using a candidiasis murine model. These findings suggest that Molecule B and Molecule C, which inhibit the Ras1/MAPK pathway, are promising compounds for the development of novel antifungal agents for the treatment of systemic candidiasis and other fungal diseases.

JNC-1043, a novel podophyllotoxin derivative, exerts anti-cancer drug and radiosensitizer effects in colorectal cancer cells

권진희 Graduate School, Korea University 2022 국내석사

The objective of this study was to determine whether JNC-1043 (JNC43) could induce cell death and act as a radiosensitizer in colorectal cancer (CRC) cells. Firstly, we observed whether JNC43 could inhibit cell proliferation of HCT116 and DLD-1 cells by performing MTT assay. Its IC50 values for HCT116 and DLD-1 cell lines were calculated to be 0.1145 µM and 0.1570 µM, respectively. Using these IC50 values, we tested JNC43 might have effects on both CRC cells as a radiosensitizer. Cell counting assays showed that a combination of JNC43 and γ-ionizing radiation (IR) enhanced cell death. JNC43 only- and IR only-treatment induced 50~60% of cell death, while a combination of JNC43 and IR increased cell death of both cell lines by 20~30% than by JNC-1043 only or IR only treatment. Clonogenic assay revealed that dose enhancement ratios (DER) of HCT116 and DLD-1 were 1.53 and 1.25, respectively. Annexin V-Propidium iodide assay also revealed that apoptosis was enhanced by JNC43. Combination of JNC43 and IR increased apoptosis by 30~40% than by JNC43 only or IR only treatment. DCFDA-based and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by a combination of JNC43 and IR. Restraining ROS by N-acetylcysteine (NAC) restored the viability and apoptosis of HCT116 and DLD-1 cells suppressed by the combination of JNC43 and IR. These results imply that JNC43 has effects as a radio-sensitizer and an anti-cancer drug on CRC cells by promoting mitochondrial ROS.

Endothelial-to-Mesenchymal Transition (EndMT) Regulates Tumor Regrowth and Normal Tissue Fibrosis After Radiation Therapy

Nam, Jae-Kyung 고려대학교 일반대학원 2022 국내박사

It is still controversial whether targeting the tumor vasculature improves the efficacy of radiation therapy and treats normal tissue side effects after radiation therapy. I reports that radiation-induced endothelial-to-mesenchymal transition (EndMT) induces tumor regrowth and fibrosis of normal tissues after radiation therapy. In this study, I report fibrotic changes and a suppressed in EndMT in tumors after high-energy radiation (neutron radiation) treatment compared to low-energy radiation (X-ray irradiation). Endothelial cell-specific Trp53 deletion inhibited fibrotic changes and the antitumor immune response after X-ray and neutron radiation therapy. The results of this study suggest that neutron radiation therapy, compared to X-ray radiation therapy, can efficiently suppress tumor environment fibrotic changes and enhance anti-tumor immune response, thereby delaying tumor regrowth. Radiation-induced pulmonary fibrosis (RIPF) is a chronic side effect of thoracic radiation therapy in patients with lung cancer. There is a need for research on how to increase the effect of radiation therapy on tumors while suppressing these side effects. In this study, I used vascular endothelial cell-specific HIF-a knock-out mice (EC-HIF1α) to investigate the direct contribution of endothelial HIF-1α (EC-HIF1α) on RIPF. EndMT and RIPF were inhibited after irradiation in HIF-1α knockout mice. Radiation-induced EndMT and RIPF were also inhibited when treated with the HIF-1α inhibitor, 2-methoxyestradiol (2-ME). To evaluate the effect of HIF-1α inhibitors on RIPF in a spontaneous lung cancer mouse model, a combination of high-dose radiation therapy and 2-ME with image-guided radiation therapy (IGRT) was employed. As a result, it was shown to efficiently inhibit the growth of multi and single tumors, simultaneously reducing radiation-induced EndMT in tumor areas and normal tissues. These results suggest that a regulator of HIF-1α inhibitor–mediated EndMT, such as 2-ME, may serve as a promising strategy against RIPF during radiation therapy.

A novel APP/hTau mouse model of Alzheimer’s disease with reactive astrogliosis exhibits accelerated pathology

LimSunhwa 고려대학교 대학원 2021 국내석사

Alzheimer’s disease (AD), a neurodegenerative disease causing dementia, is characterized by extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). In addition to Aβ plaques and NFTs, accumulating evidence has demonstrated the critical role of astrogliosis for neurodegeneration and memory deficits in AD. To elucidate the precise pathophysiology of AD, several AD mouse models have been utilized, including 3xTg, 5xFAD, and APP/PS1 transgenic mouse lines, the most commonly used model being the APP/PS1 mouse line. However, the absence of neuronal loss and NFTs in this model does not fully resemble human AD pathology. Moreover, memory deficits are not clearly observed within one year in this mouse model, which delays AD research. In this study, a novel AD mouse model expressing Aβ plaques, NFTs, and severe astrogliosis was developed through dual virus injection coupled with the conventional APP/PS1 transgenic mouse line. To express NFTs and exacerbate astrogliosis, AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses were injected into CA1 and dentate gyrus of bilateral hippocampi. This novel AD mouse model demonstrated accelerated degenerative changes such as neuronal loss, synaptic loss, and NFT formation with severe astrogliosis. In addition to these pathological changes, memory deficits were observed within postnatal 8 months assessed by behavioral experiments such as novel object recognition task, Y-maze and passive avoidance test that can evaluate cognitive functions. Taken together, I present an improved animal model of AD that more appropriately represents human AD pathology, which could facilitate research on a new therapeutic strategy against AD.

Study of autophagy-related proteins with respect to DNA damage response and translation

공은빈 Graduate School, Korea University 2021 국내박사

There are a lot of molecular mechanisms for cell to maintain optimal environmental conditions, called homeostasis. Autophagy is a one of the representative processes involved in the intracellular homeostasis using lysosomal degradation systems. Since it is induced by a variety of stresses including starvation, hypoxia, DNA damage, or infection, each steps of autophagy should be carefully regulated. As a stress-induced process, moreover, autophagy also can affect other types of intracellular signaling pathways, including innate immunity, DNA damage responses or protein synthesis. Here, in terms of translation regulation, I demonstrated the molecular mechanism of relationship between autophagy and other intracellular processes. At first, I investigated the RACK1 depletion-induced noncanonical autophagy. It is due to increased selective translation of such mRNA including LC3 and Bcl-xL mediated by ribosome heterogeneity, resulting from RACK1 depletion in the ribosome. The experiments with cells expressing ribosome binding defective mutant RACK1 (RACK1R36D/K38E) confirmed the results. In succession, the interaction between impairment of genome stability, cytoplasmic dsDNA response related to innate immunity and tumorigenic process was also uncovered in this study. In ATG5- or ATG7-depleted cells, genome stability is impaired to increase cytosolic dsDNA accumulation. Cytosolic dsDNA promotes the production of type I IFN via cGAS-STING pathway, and thus, the expression of STAT1-ISG15 axis are upregulated by type I IFN signals. In addition, autophagy inhibition caused by ATG5 or ATG7 depletion inducing ISG15 expression promotes acquisition of tumor-related phenotypes such as migration, invasion and proliferation. In conclusion, integrated molecular mechanism related to genome stability, innate immunity, tumorigenesis and autophagy are demonstrated in this study. This implies that combined with autophagy control, regulating those processes could be a novel strategy for cancer immunotherapy. 생명체를 이루는 가장 기본적인 단위인 세포는 여러 분자적인 기전으로 외부 조건에 적절히 반응하며, 이를 통해 최적의 환경을 유지하기 위해 노력한다. 이러한 세포의 특성을 항상성이라고 한다. 본 연구는 포유동물의 세포에서 항상성을 유지하기 위한 분자 기전들이 어떻게 상호작용하는가에 대해 초점을 맞추었다. 특히, autophagy와 mRNA 번역 (mRNA translation)의 조절 측면에서 다양한 세포 내 신호 전달 경로들을 분석하였다. 우선, 리보솜 이질성 (ribosome heterogeneity)이 특정한 mRNA들의 선택적 번역 (selective translation)을 조절해 autophagy의 활성화에 영향을 끼친다는 사실을 확인했다. LC3는 다양한 스트레스에 반응하여 활성화되는 대표적인 세포 내 기전인 autophagy에 필수적인 단백질로 알려져 있다. 이러한 LC3 mRNA의 조절이 리보솜과 RACK1의 결합 여부에 의해 결정된다는 사실이 본 연구를 통해 밝혀졌다. 즉, 리보솜에서 RACK1이 제거되면 LC3 mRNA 번역 효율이 증가하여 autophagy 활성화되는 것이다. 또한, 유전체 안정성 (genome stability)과 선천성 면역 (innate immunity)과 관련된 세포질 내의 이중 가닥-DNA (dsDNA) 반응과 autophagy의 상관관계 역시 본 연구에서 확인하였다. Autophagy에 필수적인 요소인 Atg5와 Atg7의 발현이 억제된 상태에서는 유전체 안정성이 저해되어 세포질 내의 dsDNA가 증가하게 된다. 이에 따라 선천적 면역 반응의 일종인 cGAS-STING 기전과 제1종 인터페론(type-I IFN) 매개 반응을 거쳐서 ISG15 단백질의 발현이 증가한다. 이렇게 증가한 ISG15 단백질을 통하여 세포는 암세포의 여러 특성들을 획득하게 된다. 즉, 면역반응과 autophagy, 종양형성과정 (tumorigenesis) 등 세포 내의 스트레스와 관련된 여러 기전들이 서로 밀접하게 연관되어 있다는 사실을 본 연구에서 확인했다. 또한 이렇게 밝혀진 다양한 분자 기전들 사이의 새로운 상관관계를 응용한다면 면역요법을 통한 종양치료를 비롯한 다양한 분야에 보다 효율적인 새 접근 방법이 제시될 수 있으리라 기대된다.

Biological evaluation of novel poly(ADP-ribose) polymerases (PARPs) inhibitors as cancer therapeutic agents

유화니 Graduate School, Korea University 2021 국내박사

Poly(ADP-ribose) polymerases (PARPs) are the enzymes that recognize damaged DNA and activate DNA repair-related proteins through a post-translational process. Of the 17 PARP families, PARP-1 and PARP-2 are the DNA repair enzymes capable of poly(ADP-ribosyl)ation (PARylation). In many cancers, including ovarian and breast cancers, DNA damage response-associated breast cancer susceptibility gene 1 and 2 (BRCA1/2) is mutated or deleted. PARP inhibitors can cause synthetic lethality in such cases. In order to develop a novel PARP-1 inhibitor, 38 compounds were synthesized using the in silico virtual screening approach. I discovered a potential novel PARP-1 inhibitor, termed N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated PI-28d), by measuring the inhibitory activity of PARP-1. PI-28d confirmed the growth inhibition of non-small-cell lung cancer (NSCLC) cells, in addition to inhibiting NSCLC tumor growth in vivo. Further, PI-28d showed synergistic anticancer effects when combined with conventional anticancer drugs or radiation therapy. The tankyrase 1 (TNKS1/ PARP5a) and tankyrase 2 (TNKS2/ PARP5b) play important roles in Wnt/β-catenin signaling. Abnormal activation of the Wnt signaling pathway triggers accumulation of β-catenin and promotes transcription of various oncogenes. This leads to the development and progression of cancers. More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal Wnt/β-catenin activation. Tankyrases are attractive targets for cancer treatment because TNKS inhibitors can inhibit Wnt/β-catenin signaling. In this study, a novel TNKS inhibitor, termed N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (designated TI-12403), was discovered by measuring the inhibitory activity of TNKS. TI-12403 showed anti-cancer effects against colorectal cancer both in vitro and in vivo. It inhibited Wnt/β-catenin signaling by inhibiting β-catenin and increasing AXIN2 and showed synergistic anticancer effects when used in combination with 5-fluorouracil (5-FU) and TI-12403. In summary, novel PARP-1 and TNKS inhibitors have been identified that exhibit anticancer effects. Additionally, they showed synergistic results when used in combination with the existing anticancer therapies. Thus, this study shows that these compounds could potentially be used in clinical trials as PARP inhibitors.

Anti-cancer effects as a radiosensitizer of beta-apopicropodophyllin against colorectal cancer cells

이나경 Graduate School, Korea University 2021 국내석사

In previously study podophyllotoxin acetate (PA) was isolated, a derivative of podophyllotoxin (PPT), from Natural Product Library. PA had anti-cancer activities against one of the lung cancer cell lines, but it is physiologically unstable for therapeutic agents and contains high toxicity. For that, several new derivatives of PPT were synthesized and then identified β-apopicropodophyllin (APP) as a potential anti-cancer drug. In this study, APP was tested whether act as an anti-cancer drug against colorectal cancer. Colorectal cancer (CRC) is the third most common cancer both in women and men. First, APP acted as a radiosensitizer in CRC cells, enhanced growth retardation effect of γ-ionizing radiation (IR). Additionally, APP had anti-cancer effect against HCT116 and DLD-1 cell lines with IC50 values of 7.88nM and 8.22nM, respectively. Trypan blue cell counting assay, Annexin V-Propidium iodide assay and immunoblot analysis showed a co-treatment of APP and IR that increased apoptosis in CRC cells. Increment ROS levels in CRC cells by combination of APP and IR were confirmed through H2HCFHA assay. Also, Refraining ROS by N-acetylcysteine (NAC) could restore cell viability suppressed by a combination of APP and IR in HCT116 and DLD-1 cell lines. Taken together, co-treatment of APP and IR might promote increase of cell death followed by ROS induction in CRC cells.

Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated Osteosarcoma Cells and in Mice

Juyeon Oh 고려대학교 대학원 2020 국내석사

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, the purpose of this study was to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, this study provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS