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Open Access Publications from the University of California

Scholarly Works (15 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2017)

Today's Internet is aging. Connections are point-to-point and increasingly

protected by end-to-end encryption. This reduces security to data transport

instead of data itself. Content-Centric Networking (CCN) is a paradigm

shift away from this host- and channel-based design. CCN is an

architecture for naming, securing, and transferring named data from

producers to consumers upon request.

Consumers issue interests for named content. Routers forward interests towards

producers capable of providing authentic content with cryptographic

name-to-data bindings. Once found, routers forward content, in reverse,

towards consumers. Routers may also choose to cache content to serve duplicate

future interests. Object security, native authenticity, pull-based data

transfer, flow symmetry, and in-network services are among the notable

characteristics of CCN. In this dissertation, we study security and privacy

issues that stem from these architectural properties. Specifically, we study

variations and facets of access control, privacy risks and remedies, and

network-layer availability attacks and architectural mitigations. For each issue,

we describe the problem in detail and explain several countermeasures. We also present

detailed analyses and experimental assessments for each approach. We find that

sound engineering can mitigate several issues, while others remain insurmountable

challenges exacerbated by fundamental security and performance tradeoffs made by CCN.

    Cover page: Security and Privacy Challenges in Content-Centric Networks
    • Thesis
    • Peer Reviewed
    UC Irvine Electronic Theses and Dissertations (2019)

    Paleoclimate proxy records from U-Th dated speleothems (cave deposits) provide evidence of past climate change on a range of timescales. The oxygen isotope composition (δ18O) of speleothems from the East Asian Summer Monsoon (EASM) region have been critical in confirming large-scale changes in monsoon intensity linked to Earth’s orbital variations, which influence the spatial and temporal patterns of incoming solar radiation, and to abrupt millennial-scale changes in ocean circulation, which influence the meridional temperature gradient. However, multiple controls affect speleothem δ18O, and significant debate continues about the precise interpretation of these records in regard to monsoon precipitation patterns. Furthermore, a scarcity of records from Mainland Southeast Asia (MSEA) has thus far prevented confident reconstructions of past monsoon and precipitation changes across the entire Asian Monsoon region. The research presented in this dissertation addresses these issues through: (1) extending the spatiotemporal coverage of speleothem paleoclimate records in MSEA, and (2) developing more robust records of past monsoon history and local water balance through the use of multiple proxies in a ~38,000 year old stalagmite from Tham Doun Mai Cave, Laos.

    Through the application of cave monitoring data and geochemical modeling of the local environment, trace element ratios (Mg/Ca and Sr/Ca) and carbon isotopes (δ13C and 14C) in stalagmite TM-17 are determined to be responsive to local hydrology through various controls: prior calcite precipitation (PCP) increases trace elements and δ13C during drier periods, while the dead carbon proportion (DCP), calculated from 14C data, reveals a significant bedrock dissolution control on TM-17 carbon. DCP data also reveals alternate δ13C controls as dominant during disparate abrupt climate events during the last deglaciation and Holocene. During the Holocene, when PCP is likely a shared control, trace element ratios and δ13C provide evidence for a mid-Holocene peak in rainfall amounts, which is at odds with interpretations of EASM δ18O records that suggest an earlier peak in monsoon intensity during the Northern Hemisphere summer insolation maximum. The results of these studies emphasize the importance of multiproxy approaches to speleothem-based climate reconstruction and provide new data for comparison with other records and climate model simulations.

      Cover page: Multiproxy speleothem analyses applied to late Pleistocene and Holocene hydrologic reconstruction in Southeast Asia
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2021)
      Image-based cell classification has become a common tool to identify phenotypic changes in cell populations. However, this methodology is limited to organisms possessing well-characterized species-specific reagents (e.g., antibodies) that allow cell identification, clustering, and convolutional neural network (CNN) training. In the absence of such reagents, the power of image-based classification has remained mostly off-limits to many research organisms. We have developed an image-based classification methodology we named Image3C (Image-Cytometry Cell Classification) that does not require species-specific reagents nor pre-existing knowledge about the sample. Image3C combines image-based flow cytometry with an unbiased, high-throughput cell clustering pipeline and CNN integration. Image3C exploits intrinsic cellular features and non-species-specific dyes to perform de novo cell composition analysis and detect changes between different conditions. Therefore, Image3C expands the use of image-based analyses of cell population composition to research organisms in which detailed cellular phenotypes are unknown or for which species-specific reagents are not available.
        Cover page: Image3C, a multimodal image-based and label-independent integrative method for single-cell analysis.
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2014)

        Purpose

        Cytoreductive nephrectomy remains the standard of care for appropriately selected patients with metastatic renal cell carcinoma. Although the role of partial nephrectomy is well accepted in patients with localized disease, limited data are available on partial nephrectomy in the metastatic setting. We identified the indications for and outcomes of partial nephrectomy in the setting of metastatic renal cell carcinoma with particular attention to partial nephrectomy subgroups.

        Materials and methods

        We analyzed data on a consecutive cohort of 33 patients with metastatic renal cell carcinoma who underwent partial nephrectomy at a single institution between 1996 and 2011. Nonparametric statistics were used to compare partial nephrectomy subgroups. Overall survival was estimated using the Kaplan-Meier method and survival functions were compared using the log rank test.

        Results

        At presentation 8 patients had bilateral synchronous renal masses, 20 had a metachronous contralateral renal mass and 5 had a unilateral renal mass. A total of 22 patients (67%) died of disease a median of 27 months postoperatively. Patients who underwent partial nephrectomy for a metachronous contralateral renal mass and a renal mass 4 cm or less had the best overall survival (61 and 42 months, respectively). Median overall survival in patients with vs without metastatic disease at original diagnosis was 27 vs 63 months (p = 0.003).

        Conclusions

        Our findings suggest that metastasis at the original diagnosis and the timing of presentation of the partial nephrectomy index lesion have an important role in survival. These factors should be considered when determining which patients would benefit from partial nephrectomy in the setting of metastatic renal cell carcinoma.
          Cover page: Partial Nephrectomy in the Setting of Metastatic Renal Cell Carcinoma
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2013)

          Purpose

          Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance.

          Experimental design

          Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo.

          Results

          Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC.

          Conclusions

          Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib.
            Cover page: Autotaxin–Lysophosphatidic Acid Signaling Axis Mediates Tumorigenesis and Development of Acquired Resistance to Sunitinib in Renal Cell Carcinoma
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2018)

            Purpose

            Lymphadenectomy is a well established practice for many urological malignancies but its role in renal cell carcinoma is less clear. Our primary objective was to determine whether lymphadenectomy impacted survival in patients with fully resected, high risk renal cell carcinoma.

            Materials and methods

            Patients with fully resected, high risk, nonmetastatic renal cell carcinoma were randomized to adjuvant sorafenib, sunitinib or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial. Lymphadenectomy was performed for cN+ disease or at surgeon discretion. Patients treated with lymphadenectomy were compared to patients in the trial who did not undergo lymphadenectomy. The primary outcome was overall survival associated with lymphadenectomy. Secondary outcomes were disease free survival, factors associated with performing lymphadenectomy and surgical complications.

            Results

            Of the 1,943 patients in ASSURE 701 (36.1%) underwent lymphadenectomy, including all resectable patients with cN+ and 30.1% of those with cN0 disease. A median of 3 lymph nodes (IQR 1-8) were removed and the rate of pN+ disease in the lymphadenectomy group was 23.4%. There was no overall survival benefit for lymphadenectomy relative to no lymphadenectomy (HR 1.14, 95% CI 0.93-1.39, p = 0.20). In patients with pN+ disease who underwent lymphadenectomy no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy did not confer an increased risk of surgical complications (14.2% vs 13.4%, p = 0.63).

            Conclusions

            The benefit of lymphadenectomy in patients undergoing surgery for high risk renal cell carcinoma remains uncertain. Future strategies to answer this question should include a prospective trial in which patients with high risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
              Cover page: Retroperitoneal Lymphadenectomy for High Risk, Nonmetastatic Renal Cell Carcinoma: An Analysis of the ASSURE (ECOG-ACRIN 2805) Adjuvant Trial
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2014)

              Background

              High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. The authors compared the survival rates of patients with UTUC who received neoadjuvant chemotherapy before surgery with the rates among patients who did not.

              Methods

              A retrospective review was conducted of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery from 2004 to 2008 (study group) compared with a matched cohort who underwent initial surgery from 1993 to 2003 (control group). Fisher exact tests, Wilcoxon rank-sum tests, and Kaplan-Meier methods were used. The log-rank test and Cox proportional-hazards models were used to evaluate the association of the 2 outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models.

              Results

              Of 112 patients, there were 31 in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved overall survival (OS) and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = .0204 and P = .0015, respectively). In multivariate analyses, the neoadjuvant group had a lower risk of mortality (OS: hazard ratio, 0.42 [P = .035]; DSS: hazard ratio, 0.19 [P = .006]).

              Conclusions

              Neoadjuvant chemotherapy improved the survival of patients with UTUC compared with a matched historic cohort of patients who underwent initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy.
                Cover page: Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2020)
                Between 5 and 4 thousand years ago, crippling megadroughts led to the disruption of ancient civilizations across parts of Africa and Asia, yet the extent of these climate extremes in mainland Southeast Asia (MSEA) has never been defined. This is despite archeological evidence showing a shift in human settlement patterns across the region during this period. We report evidence from stalagmite climate records indicating a major decrease of monsoon rainfall in MSEA during the mid- to late Holocene, coincident with African monsoon failure during the end of the Green Sahara. Through a set of modeling experiments, we show that reduced vegetation and increased dust loads during the Green Sahara termination shifted the Walker circulation eastward and cooled the Indian Ocean, causing a reduction in monsoon rainfall in MSEA. Our results indicate that vegetation-dust climate feedbacks from Sahara drying may have been the catalyst for societal shifts in MSEA via ocean-atmospheric teleconnections.
                  Cover page: End of Green Sahara amplified mid- to late Holocene megadroughts in mainland Southeast Asia
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2021)

                  Background

                  Risk stratification for localized renal cell carcinoma (RCC) relies heavily on retrospective models, limiting their generalizability to contemporary cohorts.

                  Objective

                  To introduce a contemporary RCC prognostic model, developed using prospective, highly annotated data from a phase III adjuvant trial.

                  Design, setting, and participants

                  The model utilizes outcome data from the ECOG-ACRIN 2805 (ASSURE) RCC trial.

                  Outcome measurements and statistical analysis

                  The primary outcome for the model is disease-free survival (DFS), with overall survival (OS) and early disease progression (EDP) as secondary outcomes. Model performance was assessed using discrimination and calibration tests.

                  Results and limitations

                  A total of 1735 patients were included in the analysis, with 887 DFS events occurring over a median follow-up of 9.6 yr. Five common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) were included in each model. Tumor histology was the single most powerful predictor for each model outcome. The C-statistics at 1 yr were 78.4% and 81.9% for DFS and OS, respectively. Degradation of the DFS, DFS validation set, and OS model's discriminatory ability was seen over time, with a global c-index of 68.0% (95% confidence interval or CI [65.5, 70.4]), 68.6% [65.1%, 72.2%], and 69.4% (95% CI [66.9%, 71.9%], respectively. The EDP model had a c-index of 75.1% (95% CI [71.3, 79.0]).

                  Conclusions

                  We introduce a contemporary RCC recurrence model built and internally validated using prospective and highly annotated data from a clinical trial. Performance characteristics of the current model exceed available prognostic models with the added benefit of being histology inclusive and TNM agnostic.

                  Patient summary

                  Important decisions, including treatment protocols, clinical trial eligibility, and life planning, rest on our ability to predict cancer outcomes accurately. Here, we introduce a contemporary renal cell carcinoma prognostic model leveraging high-quality data from a clinical trial. The current model predicts three outcome measures commonly utilized in clinical practice and exceeds the predictive ability of available prognostic models.
                    Cover page: Predicting Disease Recurrence, Early Progression, and Overall Survival Following Surgical Resection for High-risk Localized and Locally Advanced Renal Cell Carcinoma
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2022)

                    Objectives

                    To study the effects of adjuvant therapy in patients with sarcomatoid renal cell carcinoma (sRCC) enrolled in the randomised phase III clinical trial E2805.

                    Patients and methods

                    The original trial (E2805) was a randomised, double-blinded phase III clinical trial comparing outcomes in 1943 patients with RCC accrued between 2006 and 2010 and treated with up to 1 year of adjuvant placebo, sunitinib, or sorafenib. The present study analyses the cohort of patients with sRCC that participated in E2805.

                    Results

                    A total of 171 patients (8.8%) had sarcomatoid features. Of these, 52 patients received sunitinib, 58 received sorafenib, and 61 received placebo. Most patients were pT3-4 (71.1%, 63.7%, and 70.5%, respectively); 17.3%, 19.0%, and 27.9% had pathologically positive lymph nodes; and 59.6%, 62.1%, and 62.3% of the patients were University of California Los Angeles (UCLA) Integrated Staging System (UISS) very-high risk. In 49% of patients with subsequent development of metastatic disease, recurrence occurred in the lung, followed by 30% in the lymph nodes, and 13% in the liver. There was a high local recurrence rate in the renal bed (16%, 29%, and 18%, respectively). The 5-year disease-free survival (DFS) rates were 33.6%, 36.0%, and 27.8%, for sunitinib, sorafenib and placebo, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.45-1.20 for sunitinib vs placebo, and HR 0.82, 95% CI 0.53-1.28 for sorafenib vs placebo).

                    Conclusions

                    Adjuvant therapy with sunitinib or sorafenib did not show an improvement in DFS or OS in patients with sRCC.
                      Cover page: Adjuvant therapy in patients with sarcomatoid renal cell carcinoma: post hoc analysis from Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network (ECOG‐ACRIN) E2805
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