Switched Capacitor Loop Filter 와 Source Switched Charge Pump 를 이용한 Phase-Locked Loop 의 설계

학위논문(석사) -- 서울대학교대학원 : 공과대학 전기·정보공학부, 2022.2. 정덕균.This thesis proposes a low integrated RMS jitter and low reference spur phase locked loop (PLL) using a switched capacitor loop filter and source switched charge pump. The PLL employs a single tunable charge pump which reduces current mis match across wide control voltage range and charge sharing effect to get high perfor mance of reference spur level. The switched capacitor loop filter is adopted to achieve insensitivity to temperature, supply voltage, and process variation of a resistor. The proposed PLL covers a wide frequency range and has a low integrated RMS jitter and low reference spur level to target various interface standards. The mechanism of switched capacitor loop filter and source switched charge pump is analyzed. Fabricated in 40 nm CMOS technology, the proposed analog PLL provides four phase for a quarter-rate transmitter, consumes 6.35 mW at 12 GHz using 750 MHz reference clock, and occupies an 0.008 mm2 with an integrated RMS jitter (10 kHz to 100 MHz) of 244.8 fs. As a result, the PLL achieves a figure of merit (FoM) of -244.2 dB with high power efficiency of 0.53 mW/GHz, and reference spur level is -60.3 dBc.본 논문에서는 낮은 RMS jitter 와 낮은 레퍼런스 스퍼를 가지며 스위치축전기 루프 필터와 소스 스위치 전하 펌프를 이용한 PLL 을 제안한다. 제안된 PLL 은 레퍼런스 스퍼의 성능을 위해 넓은 컨트롤 전압의 범위 동안 전류의 오차를 줄여주고 전하 공유 효과를 줄여주는 하나의 조절 가능한 전하 펌프를 사용하였다. 저항의 온도, 공급 전압, 공정 변화에 따른 민감도를 낮추기 위해 스위치 축전기 루프 필터가 사용되었다. 다양한 인터페이스 표준을 지원하기 위해 제안하는 PLL 은 넓은 주파수 범위를 지원하고 낮은 RMS jitter 와 낮은 레퍼런스 스퍼를 갖는다. 스위치 축전기 루프 필터와 소스 스위치 전하 펌프의 동작 원리에 대해 분석하였다. 40 nm CMOS 공정으로 제작되었으며, 제안된 회로는 quarter-rate 송신기를 위해 4 개의 phase 를 만들어내며 750 MHz 의 레퍼런스 클락을 이용하여 12 GHz 에서 6.35 mW 의 power 를 소모하고 0.008mm2 의 유효 면적을 차지하고 10 kHz 부터 100 MHz 까지 적분했을 때의 RMS jitter 값은 244.8fs 이다. 제안하는 PLL 은 -244.2 dB 의 FoM, 0.53 mW/GHz 의 power 효율을 달성했으며 레퍼런스 스퍼는 -60.3 dBc 이다CHAPTER 1 INTRODUCTION 1 1.1 MOTIVATION 1 1.2 THESIS ORGANIZATION 3 CHAPTER 2 BACKGROUNDS 4 2.1 CLOCK GENERATION IN SERIAL LINK 4 2.2 PLL BUILDING BLOCKS 6 2.2.1 OVERVIEW 6 2.2.2 PHASE FREQUENCY DETECTOR 7 2.2.3 CHARGE PUMP AND LOOP FILTER 9 2.2.4 VOLTAGE CONTROLLED OSCILLATOR 10 2.2.5 FREQUENCY DIVIDER 13 2.3 PLL LOOP ANALYSIS 15 CHAPTER 3 PLL WITH SWITCHED CAPACITOR LOOP FILTER AND SOURCE SWITCHED CHARGE PUMP 19 3.1 DESIGN CONSIDERATION 19 3.2 PROPOSED ARCHITECTURE 21 3.3 CIRCUIT IMPLEMENTATION 23 3.3.1 PHASE FREQUENCY DETECTOR 23 3.3.2 SOURCE SWITCHED CHARGE PUMP 26 3.3.3 SWITCHED CAPACITOR LOOP FILTER 30 3.3.4 VOLTAGE CONTROLLED OSCILLATOR 35 3.3.5 POST VCO AMPLIFIER 39 3.3.6 FREQUENCY DIVIDER 40 CHAPTER 4 MEASUREMENT RESULTS 43 4.1 CHIP PHOTOMICROGRAPH 43 4.2 MEASUREMENT SETUP 45 4.3 MEASURED PHASE NOISE AND REFERENCE SPUR 47 4.4 PERFORMANCE SUMMARY 50 CHAPTER 5 CONCLUSION 52 BIBLIOGRAPHY 53 초 록 58석

Hydrogel cross-linking-programmed release of nitric oxide regulates source-dependent angiogenic behaviors of human mesenchymal stem cell

Angiogenesis is stimulated by nitric oxide (NO) production in endothelial cells (ECs). Although proangiogenic actions of human mesenchymal stem cells (hMSCs) have been extensively studied, the mechanistic role of NO in this action remains obscure. Here, we used a gelatin hydrogel that releases NO upon crosslinking by a transglutaminase reaction ("NO gel"). Then, the source-specific behaviors of bone marrow versus adipose tissue-derived hMSCs (BMSCs versus ADSCs) were monitored in the NO gels. NO inhibition resulted in significant decreases in their angiogenic activities. The NO gel induced pericyte-like characteristics in BMSCs in contrast to EC differentiation in ADSCs, as evidenced by tube stabilization versus tube formation, 3D colocalization versus 2D coformation with EC tube networks, pericyte-like wound healing versus EC-like vasculogenesis in gel plugs, and pericyte versus EC marker production. These results provide previously unidentified insights into the effects of NO in regulating hMSC source-specific angiogenic mechanisms and their therapeutic applications. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).ope

A single-arm phase II study of olaparib maintenance with pembrolizumab and bevacizumab in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer (OPEB-01)

Background: The optimal treatment of BRCA wild-type patients with platinum-sensitive recurrent ovarian cancer remains unknown. Recently, there is an increase in the evidence to support the role of the combination of a poly(adenosine diphosphate-ribose) polymerase inhibitor, anti-angiogenic agents, and immunotherapy as maintenance therapy in BRCA wild-type patients with platinum-sensitive recurrence. We hypothesized that adding pembrolizumab and bevacizumab to olaparib maintenance can increase progression-free survival (PFS) in BRCA wild-type patients with platinum-sensitive recurrent ovarian cancer. Methods: BRCA wild-type patients who received two previous courses of platinum-containing therapy, achieved complete or partial response to last treatment, and the treatment-free interval is >6 months after the penultimate platinum-based chemotherapy offered olaparib maintenance with pembrolizumab and bevacizumab. Forty-four patients will be included from 4 sites across Singapore and Korea. The primary endpoint of the study is 6-month PFS rate. Trial registration: ClinicalTrials.gov Identifier: NCT04361370, Clinical Research Information Service Identifier: KCT0005144.ope

White Blood Cell Count and the risk of colon cancer

Dept. of Epidemiology and Biostatistics/석사[한글] 연구배경 염증이 대장암, 직장암 발생과 관련있을 것이라는 가설이 꾸준히 제시되고 있으나, 최근 비특이적 염증지표인 C-reactive protein (CRP)가 대장암, 직장암의 발생위험을 높인다는 보고와 대장암, 직장암 발생과 관련이 없다는 상반된 역학 연구가 발표되었다. 연구목적 저자들은 전향적인 대규모 코호트 연구를 통해 비특이적 염증지표인 백혈구수와 대장암, 직장암 발생의 관계에 대해 알아보고자 한다. 연구방법 한국 암 예방 연구 코호트 (Korean Cancer Prevention Study : KCPS) 중에서 연구시작 당시 백혈구수 측정이 가능했던 40세 - 95세 사이의 424,319명 (남 : 108,907명, 여 : 315,512명)을 대상으로 백혈구수 구간을 4구간으로 구분한 후 1994년부터 2003년까지 대장암, 직장암의 발생률 및 사망률과 각각의 상대위험도를 구하였다. 또한, 흡연여부에 따른 대장암 발생의 상대위험도를 구하였다. 연구결과 10년의 추적관찰 기간 동안 제 4구간의 대장암으로 인한 사망위험이 기준집단에 비해 남성에서는 1.55배 높았으며 (95% 신뢰구간 1.10-2.18, p for trend=0.0014), 여성에서는 1.51배 높았다 (95% 신뢰구간 1.12-2.03, p for trend=0.0049). 대장암 발생도 대장암으로 인한 사망과 비슷한 양상이었다. 제 4구간의 대장암 발생 위험이 기준집단에 비해 남성에서는 1.38배 높았으며 (95% 신뢰구간 1.09-1.76, p for trend=0.0017), 여성에서는 1.46배 높았다 (1.20-1.78, p for trend=0.0003). 흡연여부에 따른 대장암 발생의 위험도 남성과 여성 모두 비흡연자에서 대장암 발생의 상대위험도가 높았다. 남성과 여성 모두 백혈구수 구간별 직장암 발생과 사망의 상대위험도는 유의한 차이가 없었다. 결론 비특이적 염증지표인 백혈구수가 높을수록 대장암 발생의 위험과 사망의 위험이 높아진다. [영문]Background : Increasing evidence suggests that inflammation may be linked to the pathogenesis of colorectal cancer. However, recently, two conflicting observational results were reported on the relationship between the inflammatory marker C-reactive protein (CRP) and the risk of colorectal cancer. Few epidemiologic studies have examined the association between inflammatory markers and the risk of colorectal cancer. Purpose We aimed to examine the association between WBC count and the risk of colon and rectal cancer in this prospective cohort study. Methods We prospectively examined the mortality and incidence risk for colon and rectal cancers among 424,419 Koreans (108,907 men and 315,512 women). The subjects were 40 to 95 years of age and from the Korean Cancer Prevention Study (KCPS) cohort. All subjects received medical examination from the National Health Insurance Corporation in 1993 and 1995. The maximum follow-up period was 10 years, from January 1, 1994 to December 31, 2003. Results An elevated WBC count was associated with a higher mortality risk of colon cancer (highest versus lowest quartile: men, 1.55, 95% CI 1.10-2.18, p for trend=0.0014; women, 1.51, 95% CI 1.12-2.03, p for trend=0.0049). Similarly, an elevated WBC count was associated with a higher incidence risk of colon cancer (highest versus lowest quartile: men, 1.38, 1.09-1.76, p for trend=0.0017; women, 1.46, 95% CI 1.20-1.78, p for trend=0.0003). A positive linear trend was also observed in non-smokers. There was no significant association between WBC count and the risk of rectal cancer. Conclusion Our findings demonstrate that an elevated WBC count is associated with an increase in both the mortality and incidence rates of colon cancer. These results support our hypothesis that inflammation increases the risk of colon cancer.ope

Real-World Experience of Pembrolizumab Monotherapy in Patients with Recurrent or Persistent Cervical Cancer: A Korean Multi-Center Retrospective Study (KGOG1041)

Simple Summary Immune checkpoint inhibitors have received considerable interest because of their ability to generate durable response in many intractable malignant solid tumors. The therapeutic results of immune checkpoint inhibitors in recurrent or advanced uterine cervical cancer, which associated with persistent infection with human papillomavirus, from several well-designed clinical trials are reported. However real-world experiences are not yet provided. In this study, we retrospectively assessed the efficacy and safety of pembrolizumab, one of the immune checkpoint inhibitors, in real-world practice among patients in Korea with recurrent or persistent cervical cancers. The results of this study show modest antitumor activity comparable to that found in previously reported clinical trials. Although in patients with favorable performance status, pembrolizumab showed effective antitumor activity. Some safety profiles should be carefully monitored during treatment. This study investigated the antitumor activity and safety of pembrolizumab in patients with recurrent cervical cancer in real-world practice. We conducted a multi-center retrospective study of patients with recurrent or persistent cervical cancer treated with pembrolizumab at sixteen institutions in Korea between January 2016 and March 2020. The primary endpoints were the objective response rate (ORR) and safety. Data were available for 117 patients. The median age was 53 years (range, 28-79). Sixty-four (54.7%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status of >= 2. Forty-nine (41.9%) patients were stage >= III at diagnosis. Eighty-eight (75.2%) patients had squamous cell carcinoma. The median number of prior chemotherapy lines was two (range, 1-6). During the median follow-up of 4.9 months (range, 0.2-35.3), the ORR was 9.4%, with three complete responses and eight partial responses. The median time to response was 2.8 months (range 1.3-13.1), and the median duration of response (DOR) was not reached. In the population of patients with favorable performance status (ECOG = 3 events, and two of them were suspicious treatment-related deaths. Pembrolizumab had modest antitumor activity in patients with recurrent cervical cancer comparable to that found in previously reported clinical trials. However, in patients with favorable performance status, pembrolizumab showed effective antitumor activity. Some safety profiles should be carefully monitored during treatment.ope

Real-World Experience of Olaparib Maintenance in High-Grade Serous Recurrent Ovarian Cancer Patients with BRCA1/2 Mutation: A Korean Multicenter Study

Background: Olaparib maintenance therapy has shown efficacy and tolerability in patients with platinum-sensitive, high-grade serous recurrent ovarian cancer (HSROC) with BRCA1/2 mutation (BRCAm). Our aim was to present real-world experience with olaparib in Korea. Method: We included HSROC patients with BRCAm treated with olaparib maintenance at four institutions in Korea between 2016 and 2018. Medical records were reviewed for clinico-pathologic characteristics, objective response, survival outcomes, and safety. Results: One hundred HSROC patients with BRCAm were included. BRCA1 mutation was present in 71 patients (71.0%), and BRCA2 mutation was present in 23 patients (23.0%). In terms of the best objective response with olaparib maintenance in 53 patients with partial remission from most recent chemotherapy, complete remission occurred in 12 (22.6%) and partial remission in four (7.5%), while 33 patients (62.3%) had stable disease. The 24 month progression-free survival was 42.4%, and 24 month overall survival was 82.1%. Grade 3 or more adverse events were as follows: anemia in 14 patients (14.0%), neutropenia in seven patients (7.0%), thrombocytopenia in two patients (2.0%), oral mucositis in one patient (1.0%), and soft tissue infection in one patient (1.0%). Conclusions: The safety and effectiveness of olaparib maintenance treatment in a real-world study were consistent with those reported in previous clinical trials.ope

Da Vinci SP Single-Port Robotic Surgery in Gynecologic Tumors: Single Surgeon's Initial Experience with 100 Cases

Purpose: To report preliminary experience of single-port robotic surgery using the da Vinci SP surgical system in gynecologic tumors. Materials and methods: This was a retrospective study on 100 consecutive patients who underwent da Vinci SP single-port robotic surgery between November 2018 and January 2021. All procedures were performed by an experienced gynecologic surgeon using a single 2.5-cm umbilical incision. Results: Of the 100 cases, the procedures included myomectomy (n=76), hysterectomy (n=2), endometrial cancer surgical staging (n=14), radical hysterectomy (n=3), radical trachelectomy (n=3), and ovarian cystectomy (n=2). None of the cases was converted to robotic multiport or open surgery. The median docking time was 5.0 minutes [interquartile range (IQR), 3.0-7.0], the median console time was 107.5 minutes (IQR, 78.7-155.8), and the median total operation time was 250.0 minutes (IQR, 215.0-310.0). The median estimated blood loss was 50.0 mL (IQR, 30.0-100.0), and the median change in hemoglobin level was 0.8 g/dL (IQR, 0.3-1.3). The median pain scores rated on a numerical rating scale immediately after and at 6, 12, and 24 hours after surgery were 5, 2, 2, and 2, respectively. The mean duration of postoperative hospitalization was 2.8 days. Conclusion: Da Vinci SP single-port robotic surgery was successfully performed in various gynecologic tumors without significant complications. Therefore, this surgical system could be applied in patients who want precise gynecologic surgery while minimizing surgical incision.ope

4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39 + CD8 T cells from primary and metastatic sites of epithelial ovarian cancers

Background: Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer. Methods: Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays. Results: We found that CD39+ CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39+ CD8 TILs with high PD-1 expression (PD-1high) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1high CD39+ CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39+ CD8 TILs, especially on PD-1high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites. Conclusion: Severely exhausted PD-1high CD39+ CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.ope

Expression Profiles of ID and E2A in Ovarian Cancer and Suppression of Ovarian Cancer by the E2A Isoform E47

The E2A and inhibitor of DNA binding (ID) proteins are transcription factors involved in cell cycle regulation and cellular differentiation. Imbalance of ID/E2A activity is associated with oncogenesis in various tumors, but their expression patterns and prognostic values are still unknown. We evaluated ID and E2A expression in ovarian cancer cells, and assessed the possibility of reprogramming ovarian cellular homeostasis by restoring the ID/E2A axis. We analyzed copy number alterations, mutations, methylations, and mRNA expressions of ID 1-4 and E2A using The Cancer Genome Atlas data of 570 ovarian serous cystadenocarcinoma patients. Incidentally, 97.2% cases exhibited gain of ID 1-4 or loss of E2A. Predominantly, ID 1-4 were hypomethylated, while E2A was hypermethylated. Immunohistochemical analysis revealed that ID-3 and ID-4 expressions were high while E2A expression was low in cancerous ovarian tissues. Correlation analysis of ID and E2A levels with survival outcomes of ovarian cancer patients indicated that patients with high ID-3 levels had poor overall survival. We also determined the effect of E2A induction on ovarian cancer cell growth in vitro and in vivo using SKOV-3/Luc cells transduced with tamoxifen-inducible E47, a splice variant of E2A. Interestingly, E47 induced SKOV-3 cell death in vitro and inhibited tumor growth in SKOV-3 implanted mice. Therefore, restoring ID/E2A balance is a promising approach for treating ovarian cancer.ope

Indocyanine green fluorescent image-guided inguinal sentinel lymph node biopsy in vulvar cancer

Objective: To demonstrate near-infrared fluorescence image-guided inguinal sentinel lymph node (SLN) biopsy in patients with vulvar cancer. Methods: A 40-year-old woman with a 3-cm-sized palpable left vulvar mass was diagnosed with vulvar cancer on biopsy with protrusion into the vaginal cavity. Pelvic contrast-enhanced magnetic resonance imaging and F-18 fluorodeoxyglucose positron-emission tomography-computed tomography showed a small ulcerative enhancing lesion confined to the left vulva without distant metastasis. The patient was scheduled for radical vulvectomy with a left inguinal SLN biopsy. Indocyanine green was injected directly into the vulvar mass to map lymphatic drainage. A 4-cm-sized linear incision was made on the left inguinal crease, and the lymphatic channels of the left inguinal area were dissected under fluorescent image guidance using a 1588 Advanced Imaging Modalities Platform laparoscopic camera (Stryker, Kalamazoo, MI, USA). Results: Fluorescence image-guided left inguinal SLN biopsy and radical vulvectomy were performed. The pathologic diagnosis confirmed vulvar adenoid cystic carcinoma with metastasis to the left inguinal lymph node (International Federation of Gynecology and Obstetrics stage IIIA). The patient was discharged without complications and received adjuvant radiotherapy. Conclusion: This video demonstrates a successful ICG fluorescence image-guided left inguinal SLN biopsy in a vulvar cancer patient using a laparoscopic camera. Mapping of inguinal SLNs in patients with vulvar cancer may help in retaining surgical radicality while minimizing operative complications.ope