Life Milestones and Cancer-related Late Effects among Young Adult Survivors of Childhood Cancers

Given significant advancements in cancer treatment, close to 85% of children and adolescents diagnosed with cancer have long-term survival. In the United States, there are approximately 500,000 childhood cancer survivors looking forward to many years ahead. Yet, the aftermath of cancer poses substantial challenges, including cancer-related late effects, psychosocial struggles, and financial burdens. The objective of this dissertation is to further our understanding of life milestones (e.g., employment, educational attainment, living arrangement, relationship status) and cancer-related late effects among Young Adult Childhood Cancer Survivors (YACCS) using a population-based sample from the Los Angeles Cancer Surveillance Program, the Surveillance, Epidemiology, and End Results (SEER) Cancer Registry covering Los Angeles County.Study 1 aimed to examine the prevalence of life milestones among YACCS and non-cancer population-based cohort controls. The study conducted a matched-cohort case control to compare YACCS and a non-cancer comparison group from the California Health Interview Survey (CHIS) (matched by age, sex, year of survey, and race/ethnicity) on the prevalence of life milestones (e.g., full-time employment, educational attainment, living independently, relationship status). The results showed that YACCS were less likely to have a college degree, have a full-time employment, and married/partnered compared to their peers without a cancer history. In contrast, they were more likely to be unemployed, have a part-time employment, and live with a parent. The objective of study 2 was to assess the relationship between delays in achieving life milestones and depressive symptoms over time in YACCS. The study used linear regression model with depressive symptoms as the outcome variable and delay in life milestone as the exposure variable. Delays in educational attainment was a significant predictor of depressive symptoms, even when demographic factors and baseline depressive symptoms were controlled. The aim of study 3 was to identify the subgroups of YACCS based on their cancer-related late effects and how each subgroup is associated with life milestone achievement. The study used latent class analysis and logistic regression models. The latent class analysis revealed multimorbidity group and resilient group based on cancer-related late effects reported by the survivors. The multimorbidity group were less likely to have a college degree and be employed full-time compared with the resilient group after adjusting for demographic factors, years since diagnosis, and treatment intensity. This research is a population-based study that utilizes a diverse sample of recently treated YACCS in Los Angeles County. It offers valuable insights into their post-cancer experiences during a period marked by medical and treatment advancements in childhood cancers. The significance of this research lies in its potential to positively impact cancer survivorship research by enhancing our understanding of the risk and protective factors that affect the achievement of life milestones among YACCS. It also offers a window into the long-term effects of childhood cancer on the social determinants of health and wellbeing. The findings from this study not only contribute to the existing body of knowledge but also lay the groundwork for future research aimed at developing targeted interventions. These interventions will be tailored to the age-specific needs of survivors, focusing on promoting social integration and independence, which are pivotal in securing a high-quality survivorship experience

Introducing Competition to Boost the Transferability of Targeted Adversarial Examples through Clean Feature Mixup

Deep neural networks are widely known to be susceptible to adversarial examples, which can cause incorrect predictions through subtle input modifications. These adversarial examples tend to be transferable between models, but targeted attacks still have lower attack success rates due to significant variations in decision boundaries. To enhance the transferability of targeted adversarial examples, we propose introducing competition into the optimization process. Our idea is to craft adversarial perturbations in the presence of two new types of competitor noises: adversarial perturbations towards different target classes and friendly perturbations towards the correct class. With these competitors, even if an adversarial example deceives a network to extract specific features leading to the target class, this disturbance can be suppressed by other competitors. Therefore, within this competition, adversarial examples should take different attack strategies by leveraging more diverse features to overwhelm their interference, leading to improving their transferability to different models. Considering the computational complexity, we efficiently simulate various interference from these two types of competitors in feature space by randomly mixing up stored clean features in the model inference and named this method Clean Feature Mixup (CFM). Our extensive experimental results on the ImageNet-Compatible and CIFAR-10 datasets show that the proposed method outperforms the existing baselines with a clear margin. Our code is available at https://github.com/dreamflake/CFM.Comment: CVPR 2023 camera-read

Efficiency analysis of best management practices under climate change conditions in the So-okcheon watershed, South Korea

Best management practices (BMPs) are widely applied to address water quality degradation issues attributed to non-point source pollutants. The objective of this study was to assess the efficiency of two types of BMPs, vegetation filter strips (VFS) and wetlands, in reducing total nitrogen (TN) and total phosphorus (TP) in a watershed, and to investigate whether the efficiency of the two BMPs is maintained under future climate scenarios by employing the Soil and Water Assessment Tool (SWAT). A set of parameters was calibrated using the SWAT Calibration and Uncertainty Program (SWAT-CUP) to ensure acceptable simulation results. Three BMP scenarios were developed by applying VFS and wetlands individually and in combination. Projected climate data from 18 global circulation models under Shared Socioeconomic Pathways (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5) were used to depict climate change conditions. VFS demonstrated 18.2% and 22.9% greater reduction efficiency for TN and TP, respectively, relative to wetlands. When the two BMPs were simultaneously applied, the reduction efficiency was even greater than that of single-BMP implementation (by 7.4% for TN and 6.8% for TP compared to VFS alone and by 25.5% for TN and 29.7% for TP compared to wetlands alone). To assess the effect of climate change, the model simulated results for the period of 2021–2,100. The differences in efficiency between the combined BMP scenario and the individual BMPs increased with greater intensity of climate change, especially in the distant future. Therefore, this study supports the effectiveness of nutrient pollution control by applying multiple BMPs rather than by applying individual BMPs. Furthermore, this research underscores the adaptability and reliability of natural-based solutions in mitigating non-point source pollution in a changing climate, which is essential for effective ecological restoration in complex urban-agricultural landscapes. The study provides valuable insights for watershed managers and policymakers seeking effective strategies to combat nutrient pollution in the face of a changing climate within the unique landscape of South Korea

Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels

<p>Abstract</p> <p>Background</p> <p>N-type Ca²⁺channels (Ca_v2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt^®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects.</p> <p>Results</p> <p>Here we identify a new CTx, FVIA, from the Korean <it>Conus Fulmen </it>and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca²⁺channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration.</p> <p>Conclusions</p> <p>The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.</p

Diacetyl odor shortens longevity conferred by food deprivation in C. elegans via downregulation of DAF-16/FOXO

Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors. © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley &amp; Sons Ltd.1

Physical organizing principles and technologies for genome organization

Chromatin, a nucleic acid and protein-based polymer, is dynamically organized into spatially andfunctionally distinct compartments. Given the densely crowded, polymeric nature of chromatin, the 3D architecture of the genome may be organized by phase transitions, including compartmentalization by liquid-liquid phase separation (LLPS). Telomeres are a particularly interesting genomic compartment comprised of kilobases of repetitive DNA and a six-protein complex named shelterin that work together as a unit to protect the single-stranded ends of chromosomes from aberrant recognition by DNA damage repair proteins. In this thesis, we tested the hypothesis that telomere organization is driven by LLPS and characterized the biophysical phase behavior of telomeres through quantitative imaging methods and in vitro experiments. However, because telomeres rarely encounter one another in living cells due to their constrained subdiffusive motion, it is difficult to test in cells whether two telomeres can coalesce, a key aspect of the liquid condensate model. To overcome this challenge, we developed a novel optogenetic approach, VECTOR, that brings two telomeres into close proximity, using capillary forces and found that telomeres readily coalesce into and remain as a single liquid-like droplet. These findings are consistent with in vitro experiments, which reveal that shelterin complex proteins readily phase separate together with telomeric DNA. Further studies will investigate the downstream functional consequences of these telomere merger events that lead to signs of genome instability, i.e. the formation of chromatin bridges, micronuclei, nucleolar defects with perturbed shelterin stoichiometry that has major implications in cancer, disease, and accelerated aging. This thesis work also includes efforts towards developing a new emerging model organism to study aging, the Euprymna berryi squid. We present an optimized protocol to isolate primary cells from squids of any life stage. Future work will investigate changes in nuclear organization with increasing age and will link molecular determinants of aging to physical signs of deterioration at the organismal level. This thesis uncovers physical organizing principles of genomic and nuclear compartmentalization and develops new technologies and systems to probe and measure properties and dynamics of the 3D nuclear space in living cells

Assessing Role of Drought Indices in Anticipating Pine Decline in the Sierra Nevada, CA

Tree mortality in Sierra Nevada’s 2012–2015 drought was unexpectedly excessive: ~152 million trees died. The relative performance of five drought indices (DIs: SPEI, AI, PDSI, scPDSI, and PHDI) was evaluated in the complex, upland terrain which supports the forest and supplies 60% of Californian water use. We tested the relative performance of DIs parameterized with on-site and modeled (PRISM) meteorology using streamflow (linear correlation), and modeled forest stand NDVI and tree basal area increment (BAI) with current and lagged year DI. For BAI, additional co-variates that could modify tree response to the environment were included (crown vigor, point-in-time rate of bole growth, and tree to tree competition). On-site and modeled parameterizations of DIs were strongly correlated (0.9), but modeled parameterizations overestimated water availability. Current year DIs were well correlated (0.7–0.9) with streamflow, with physics-based DIs performing better than pedologically-based DIs. DIs were poorly correlated (0.2–0.3) to forest stand NDVI in these variable-density, pine-dominated forests. Current and prior year DIs were significant covariates in the model for BAI but accounted for little of the variation in the model. In this ecosystem where trees shift seasonally between near-surface to regolithic water, DIs were poorly suited for anticipating the observed tree decline