저위도 MALT형 림프종을 제외한 원발성 위장관 림프종에서 초치료로 사용된 항암화학요법의 효과

Thesis (master`s)--서울대학교 대학원 :의학과 내과학전공,2002.Maste

아드레날린성 B-수용체 자극에 의한 림프구 단백의 인산화

의학과/박사[영문] [한글] 단백의 가역적인 인산화과정이 세포의 생리적 최종반응을 매개하거나 수행한다고 알려 져 있다. 글라이코젠의 해당반응 등의 탄수화물대사, 세포증식반응, 세포막에서의 이온운 반 등의 생체반응 뿐 아니라 면역반응계에서도 특정단백의 인산화가 조절을 한다고 한다. 각종 조직에서 β아드레날린성 효과의 약리적 특성은 잘 알려져 있으며 특히 림프구에 서 β수용체에 의하여 면역 및 생체의 항상성 유지가 조절된다고 한다. β 아드레날린성 수용체가 자극되면 GTP 결합단백을 통하여 adenylate cyclase 활성으로 cAMP가 생성되고, cAMP는 cAMP 의존성 kinase (A-kinase)를 활성화시킨다. 활성화된 A-kinase는 단백을 인 산화 시킴으로써 인산화단백이 최종적으로 반응조절에 관여한다고 한다. 그러나 림프구에 서 어느 특정단백이 A-kinase에 의해 활성화되어 반응을 매개하는지에 대한 체계적인 연 구는 되어있지 않다. 따라서 이번 연구에서는 흰쥐의 림프구에서 β아드레날린성 수용체흥분후에 나타나는 단백 인산화 양상을 관찰하고, 중간과정을 점검하여 β수용체자극후에 A-kinase에 의하여 인산화되는 특이 기질단백을 찾고자 하였다. 실험 재료로는 흰쥐(Sprague-Dawley)의 동맥혈의 림프구를 이용하였고, β수용체흥분후 반응의 출현까지의 중간단계를 추구하기 위하여 isoproterenol, propranolol, forskolin , cAMP 및 H-8을 사용하였다. 분리된 림프구를 [(32)**P ] orthophosphate로 표지시킨 후 림프구를 균질화한 후 원심 분리하여 단백분획을 얻고, 이를 NEPHGE와 SDS-PAGE를 이용한 이차원전기영동법을 이용하 여 단백을 분리한 후 건조시킨 gel을 자가방사기록법으로 인산화단백을 관찰하였다. 한편 림프구를 미리 균질화시켜 만든 각 세포분회에서도 약물처리후 [γ-(32)**P ]ATP로 인산 화시킨 후 동일한 방법으로 인산화 단백을 관찰함으로써 앞에서 얻어진 인산화단백이 세 포의 어느 분획에 위치하는가를 확인하였다. 실험결과는 다음과 같다. 1. Isoproterenol (10**-5 M)은 흰쥐 림프구외 여러 단백을 인산화 하였으며, 그중 분 자량 44kD 등전위점 6.3(44kD/6.3) 단백의 인산화가 나타났다. 2. 림프구의 44kD/6.3 단백의 인산화는 propranolol 10**-5 M 전처치에 의하여 억제되 었다. 3. 44kD/6.3단백은 forskolin에 의하여 농도의존적으로 인산화정도가 증가하였다. 4. 림프구 균질액의 세포막 분획에 cAMP를 첨가하였을 때 44kD/6.3 단백의 인산화가 유 발되었다. 5. 44kD/6.3 단백의 인산화는 A-kinase 억제재인 H-8에 의하여 인산화가 억제되었다. 6. 44kD/6.3 단백은 세포막 분획에서는 관찰되었으나, 세포질분획에서는 관찰되지 않았 다. 이상의 실험결과로 보아 흰쥐 림프구 단백중 분자량 44kD, 등전위점 6.3의 단백은 β수 용체 자극, adenylate cyclase 활성화, cAMP 생성 및 A-kinase 활성화에 의하여 인산화되 는 단백임을 알 수 있었으며. 이 단백의 인산화가 β수용체자극에 의한 림프구 기능변동 에 관여할 것으로 추측된다. Protein Phosphorylation in Murine Peripheral Lymphocytes by β Adrenoceptor Stimulation De Yeun Oh Deparment of Medical Science The Graduate School, Yonsei University (Directed by Associate Prof, Young Soo Ahn. M.D.) Reversible protein phosphorylation has been known as an important biological mechanism of cellular regulation such as carbohydrate metabolism, cell proliferation, ion transport through cell membrane and also in immunologic system. Beta adrenergic stimulation causes activation of adenylate cyclase and subsequent accumulation of intracellular cyclic adenosine monophosphate (cAMP) and activation of cAMP-dependent protein kinase (A-kinase). Lymphocytes possess β adrenoceptors on their plasma membranes and stimulation of β adrenoceptor causes inhibition of antibody production, lymphocyte proliferation and T cell mediated cytolysis. Specific substrate protein for A-kinase is thought to be a final mediator for those cellular responses. In this study, therefore, it was attempted to characterize the substrate protein for the A-kinase after β receptor stimulation in murine peripheral lymphocytes, Rat peripheral lymphocytes were isolated by centrifugation with Histopaque and incubated with isoproterenol, propranolol, forskolin, cAMP or H-8. Proteins were labelled with [(32)**P ] orthophosphate for the intact lymphocyte or [γ-(32)**P ] ATP for the lymphocyte homogenate. The proteins were separated by means of two dimensional gel electrophoresis using non-equilibrium pH gradient electrophoresis and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Gels were dried and phosphorylated proteins were observed by autoradiogrhphy. Results obtained were as follows; 1. Beta adrenergic stimulation of the lymphocyte with isoproterenol (10**-5M ) caused intense phosphorylation of a protein having 44 kD mol wt. and pl 6.3 (44 kD/6.3) which was not observed in the absence of isoproterenol stimulation. 2. Phosphorylation of 44kD/6.3 protein induced by isoproterenol was inhibited by the pretreatment with propranolol (10**-5M ). 3. Activation of adenylate cyclase by forskolin caused a phospherylation of the 44 kD/6.3 protein dose-dependently, 4. The 44 kD/6.3 protein was phosphorylated by the addition of cAMP in the lymphocyte homogenate, 5. The phosphorylation of the 44 kD/6.3 protein was selectively inhibited by H-8. 6. The 44 kD/6.3 protein was present in lymphocyte membrane fraction but not in cytosolic fraction. These results suggest that the 44 kD/6.3 protein may be the substrate protein phosphorylated by β-adrenergic stimulation and the phosphorylation of this protein would be related to the functional changes in rat lymphocytes by β-adrenergic stimulation.restrictio

Motor Berve Conduction Velocity in Untreated Maturity-Onset Diabetes

의학과/석사[영문] [한글] 신경조직은 포도당의 세포내 투과에 인슐린을 필요로 하지 않으며 따라서 고혈당이 지 속될 경우 신경세포내의 포도당 및 그 대사산물 농도가 높아져서 신경세포의 퇴행성 변화 가 초래된다. 본 연구에서는 당뇨병환자에서 고혈당이 신경병변에 미치는 영향을 관찰하기 위하여 30 예의 당뇨병환자 및 15예의 정상대조군에서 운동신경전도속도를 측정하여 다음과 같은 결 과를 얻었다. 1. 당뇨병환자의 운동신경전도속도는 정상인에 비해 의의있게 감소되었다. 2. 당뇨병환자에서 운동신경전도속도는 공복시 혈당량과 역비례 관계를 나타내었다. 3. 당뇨병환자에서 운동신경전도속도와 당화혈색소 사이에는 유의한 상관관계가 없었다 . 4. 환자의 연령 및 당뇨병 이환기간과 운동신경전도속도 사이에는 유의한 상관관계가 없었다. 이상의 성적으로 보아 당뇨병성 및 말초신경염은 혈당과 밀접한 관계를 가지고 있다고 보며 혈당치의 지속적인 조절로 신경기능은 보존 내지 호전시킬 수 있다고 생각된다. Motor Nerve Conduction Velocity in Untreated Maturity-Onset Diabetes Do Yeun Oh Department of Medical Science The Graduate School Yonsei University (Directed by Prof. Kyung Hwan Kim, M.D.) Peripheral neuropathy is a frequent and often disabling complication of diabetes mellitus. Abnormalities of neural function in diabetes, such as slowed nerve conduction, may be related to the metabolic derangement in this disease, but the role of metabolic abnormalities in the development of diabetic neuropathy is controversial. To investigate the influence of hyperglycemia on nerve concution, conduction velocities of median, peroneal and tibial nerve were measured in 30 untreated maturity-onset diabetic patients and 15 normal control subjects. The results are as follows; 1. The motor nerve conduction velocities of median, peroneal, and tibial nerves were significantly slower in diabetics than normal. 2. Motor conduction velocity was inversely correlated with levels of fasting plasma glucose in diabetics. 3. Levels of glycosylated hemoglobin, an index of long-term glycemia, were not correlated with motor nerve conduction velocity. 4. Age and duration of diabetes were not related to the motor nerve conduction velocity. Theae findings suggest that the degree of hyperglycemia contributes to the slowing of motor nerve conduction velocity in untreated maturity-onset diabetes, but further studies are needed to clarify the relation with glycosylated hemoglobin and nerve conduction velocity diabetes.restrictio

구서의 CT26 선암 모델에서 종양의 진행에 따른 면역지표의 변화

학위논문(박사)--서울대학교 대학원 :의학과 내과학전공,2005.Docto

젊은 여성의 유방에 발생한 원발성 활막 육종 1예

활막 육종은 주로 관절 주위 조직에 호발하는 악성 종양이다. 종종 관절 이외의 다른 부위에 발생하는 경우도 보고되어있는데, 원발성 유방 활막 육종은 세계적으로도 보고된 예가 드물다. 본 증례는 원발성 유방 활막 육종으로 진단된 15세 여자 환자의 1예이다. 진단 후 유방 종괴에 대한 광범위 절제술을 시행하였으나 9개월 후 국소 재발하였고, 이에 재발 부위에 대한 광범위 절제술을 다시 시행하였다. 그러나, 27개월 후 폐의 우상엽에 고립성 폐 전이가 발견되었다. 이에 폐 병변에 대한 절제술 및 고식적 화학요법으로 doxorubicin 및 ifosfamide의 병합 화학요법을 시행하였다. 현재 항암화학요법 종료 후 28개월째 재발의 증거 없이 경과관찰 중이다. 이에 저자들은 본 증례를 문헌고찰과 함께 보고하는 바이다

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed

The Impact of Primary Tumor Resection on the Survival of Patients with Stage IV Breast Cancer

Purpose The main treatment for stage IV breast cancer is currently systemic therapy. Surgical resection of the primary tumor is usually done for treating the tumor-related complications Recent studies have suggested that surgery may improve the long-term survival of stage IV breast cancer patients We evaluated the impact of the primary surgical resection site on the survival of stage IV breast cancer patients. Methods We reviewed the records of the stage IV breast cancer patients who were treated at Seoul University Hospital between April 1992 and December 2007 The tumor and clinical characteristics, the type of treatments and the overall survival were compared between the surgically versus nonsurgically treated patients. Results. Of the 198 identified patients, 110 (55 8%) received surgical excision of their primary tumor and 88 (44 2%) did not The mean survival was 67 months vs. 42 months for the surgically treated patients vs the patients without surgery, respectively (p=0 0287) On a multivariate analysis with using the Cox model and after adjusting for the estrogen receptor status, visceral metastases, the number of metastatic sites and trastuzumab treatment, surgery was an independent factor for improved survival (hazard ratio, 0.55; 95% confidence interval, 0.31-0.97; p=0.041). Conclusion Surgical resection of the primary tumor in stage IV breast cancer patients was independently associated with improved survival. Randomized prospective trials are needed to firmly recommend surgical resection of the primary tumor in stage IV breast cancer patients본 연구는 폐암, 유방암/난소암 유전체 연구센터의 연구비를 지원받아 수행 되었음(01-PJ3-PG6-01GN07-0004).Bafford AC, 2009, BREAST CANCER RES TR, V115, P7, DOI 10.1007/s10549-008-0101-7Blanchard DK, 2008, ANN SURG, V247, P732, DOI 10.1097/SLA.0b013e3181656d32*KOR BREAST CANC S, 2008, BREAST CANC FACTS FI, V1, P5Fields RC, 2007, ANN SURG ONCOL, V14, P3345, DOI 10.1245/s10434-007-9527-0Gnerlich J, 2007, ANN SURG ONCOL, V14, P2187, DOI 10.1245/s10434-007-9438-0Rapiti E, 2006, J CLIN ONCOL, V24, P2743, DOI 10.1200/JCO.2005.04.2226Morrow M, 2006, J CLIN ONCOL, V24, P2694, DOI 10.1200/JCO.2006.05.9824Babiera GV, 2006, ANN SURG ONCOL, V13, P776, DOI 10.1245/ASO.2006.03.033Hotta T, 2006, ANTICANCER RES, V26, P1377Abe O, 2005, LANCET, V366, P2087Andre F, 2004, J CLIN ONCOL, V22, P3302, DOI 10.1200/JCO.2004.08.095Giordano SH, 2004, CANCER, V100, P44, DOI 10.1002/cncr.11859Khan SA, 2002, SURGERY, V132, P620, DOI 10.1067/msy.2002.127544Flanigan RC, 2001, NEW ENGL J MED, V345, P1655Demicheli R, 2001, BRIT J CANCER, V85, P490Dauplat J, 2000, SEMIN SURG ONCOL, V19, P42Overgaard M, 1999, SEMIN RADIAT ONCOL, V9, P292DOGHETTO GB, 1999, AM SURGEON, V65, P352BLAND KI, 1998, BREAST COMPREHENSIVE, V2Ragaz J, 1997, NEW ENGL J MED, V337, P956OREILLY MS, 1994, CELL, V79, P315FISHER B, 1989, CANCER RES, V49, P1996*NAT CANC I, BREAST CANC TREATM P

Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer

Background Patients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors.Methods In this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1.Results As of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7–32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) patients experienced treatment-related adverse events (TRAEs), most commonly rash (17%), maculopapular rash and fever (13% each), and increased lipase (10%). Eleven (37%) patients had grade ≥3 TRAEs; three patients had grade 5 events (septic shock due to bacteremia, n=1; interstitial lung disease (reported term: interstitial pneumonitis), n=2). The objective response rate was 20% (95% CI 8 to 39) per independent review committee (IRC), with five of six responses ongoing (12.5+ to 14.5+ months) at data cut-off. Two additional patients with durable stable disease had a partial response per investigator. Median progression-free survival assessed by IRC and overall survival were 2.5 months (95% CI 1.3 to 5.6) and 12.7 months (95% CI 6.7 to 15.7), respectively. Clinical activity was observed irrespective of PD-L1 expression and microsatellite instability-high status.Conclusions Bintrafusp alfa had clinical activity in Asian patients with pretreated BTC, with durable responses. Based on these results, bintrafusp alfa is under further investigation in patients with BTC (NCT03833661 and NCT04066491).Trial registration number NCT02699515