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Open Access Publications from the University of California

Scholarly Works (100 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2021)

Purpose of review

Ras pathway mutations are one of the most common type of alterations in pediatric hematologic malignancies and are frequently associated with adverse outcomes. Despite ongoing efforts to use targeted treatments, there remain no Food and Drug Administration (FDA)-approved medications specifically for children with Ras pathway-mutated leukemia. This review will summarize the role of Ras pathway mutations in pediatric leukemia, discuss the current state of Ras pathway inhibitors and highlight the most promising agents currently being evaluated in clinical trials.

Recent findings

Efficacy using RAF and MEK inhibitors has been demonstrated across multiple solid and brain tumors, and these are now considered standard-of-care for certain tumor types in adults and children. Clinical trials are now testing these medications for the first time in pediatric hematologic disorders, such as acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and histiocytic disorders. Novel inhibitors of the Ras pathway, including direct RAS inhibitors, are also being tested in clinical trials across a spectrum of pediatric and adult malignancies.

Summary

Activation of the Ras pathway is a common finding in pediatric hematologic neoplasms. Implementation of precision medicine with a goal of improving outcomes for these patients will require testing of Ras pathway inhibitors in combination with other drugs in the context of current and future clinical trials.
    Cover page: Targeting the Ras pathway in pediatric hematologic malignancies.
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2013)
    While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.
      Cover page: Genetic predispositions to childhood leukemia
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2023)
      Introduction: Although dozens of studies have attempted to determine the metabolic cost of osmoregulation, mainly by comparing standard metabolic rates (SMR) in fish acclimated to different salinities, consensus is still lacking. Methods: In the present study, using the Gulf toadfish, Opsanus beta, we aimed to determine the metabolic cost of esophageal and intestinal osmoregulatory processes by estimating ATP consumption from known ion transport rates and pathways and comparing these estimates with measurements on isolated tissues. Further, we performed whole animal respirometry on fish acclimated to 9, 34 and 60 ppt. Results and Discussion: Our theoretical estimates of esophageal and intestinal osmoregulatory costs were in close agreement with direct measurements on isolated tissues and suggest that osmoregulation by these tissues amounts to ∼2.5% of SMR. This value agrees well with an earlier attempt to estimate osmoregulation cost from ion transport rates and combined with published measurements of gill osmoregulatory costs suggests that whole animal costs of osmoregulation in marine teleosts is ∼7.5% of SMR. As in many previous studies, our whole animal measurements were variable between fish and did not seem suited to determine osmoregulatory costs. While the esophagus showed constant metabolic rate regardless of acclimation salinity, the intestine of fish acclimated to higher salinities showed elevated metabolic rates. The esophagus and the intestine had 2.1 and 3.2-fold higher metabolic rates than corresponding whole animal mass specific rates, respectively. The intestinal tissue displays at least four different Cl- uptake pathways of which the Na+:Cl-:2 K+ (NKCC) pathway accounts for 95% of the Cl- uptake and is the most energy efficient. The remaining pathways are via apical anion exchange and seem to primarily serve luminal alkalinization and the formation of intestinal CaCO3 which is essential for water absorption.
        Cover page: Metabolic cost of osmoregulation by the gastro-intestinal tract in marine teleost fish.
        • Article
        • Peer Reviewed
        Faculty Publications (1997)

        The current generation of land-surface models used in GCMs view the soil column as the fundamental hydrologic unit. While this may be effective in simulating such processes as the evolution of ground temperatures and the growth/ablation of a snowpack at the soil plot scale, it effectively ignores the role topography plays in the development of soil moisture heterogeneity and the subsequent impacts of this soil moisture heterogeneity on watershed evapotranspiration and the partitioning of surface fluxes. This view also ignores the role topography plays in the timing of discharge and the partitioning of discharge into surface runoff and baseflow. In this paper an approach to land-surface modeling is presented that allows us to view the watershed as the fundamental hydrologic unit. The analytic form of TOPMODEL equations are incorporated into the soil column framework and the resulting model is used to predict the saturated fraction of the watershed and baseflow in a consistent fashion. Soil moisture heterogeneity represented by saturated lowlands subsequently impacts the partitioning of surface fluxes, including evapotranspiration and runoff. The approach is computationally efficient, allows for a greatly improved simulation of the hydrologic cycle, and is easily coupled into the existing framework of the current generation of single column land-surface models. Because this approach uses the statistics of the topography rather than the details of the topography, it is compatible with the large spatial scales of today’s regional and global climate models. Five years of meteorological and hydrological data from the Sleepers River watershed located in the northeastern United States where winter snow cover is significant were used to drive the new model. Site validation data were sufficient to evaluate model performance with regard to various aspects of the watershed water balance, including snowpack growth/ablation, the spring snowmelt hydrograph, storm hydrographs, and the seasonal development of watershed evapotranspiration and soil moisture.

          Cover page: An Efficient Approach to Modeling the Topographic Control of Surface Hydrology for Regional and Global Climate  ModelingCreative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Santa Barbara Previously Published Works (2018)
          Indigenous people worldwide suffer from higher rates of morbidity and mortality than neighboring populations. In addition to having limited access to public health infrastructure, indigenous people may also have priorities and health perceptions that deter them from seeking adequate modern healthcare. Here we propose that living in a harsh and unpredictable environment reduces motivation to pursue deliberate, costly action to improve health outcomes. We assess whether variation in Health Locus of Control (HLC), a psychological construct designed to capture self-efficacy with respect to health, explains variation in treatment uptake behavior among Tsimane Amerindians (N = 690; age range: 40-89 years; 55.8% female; data collection: 2008-2012), a high mortality and morbidity indigenous population in the Bolivian Amazon, Beni Department. Comparisons with two industrialized populations in Japan (Miyagi prefecture; e0 = 76.6 years) and the United Kingdom (Caerphilly county borough; e0 = 81.2 years) confirm that Tsimane (e0 = 54.1 years) have a more externalized HLC. Multilevel level models were used to investigate whether HLC predicts treatment uptake, and mediates the relationship between modernization and treatment uptake. External HLC scores were predictive of treatment outcomes: Powerful others scores were positively associated with probability of receiving modern treatment (adjusted odds ratio [OR] = 1.33), while Chance scores were negatively associated with probability of receiving modern treatment (adjusted OR = 0.76). We found no effects, however, of Internal HLC or educational capital on treatment uptake. Overall, our findings indicate that health-related decision-making is influenced more by a psychological orientation affecting self-efficacy, shaped in part by perceptions of environmental unpredictability and harshness, than by limited knowledge, education or other indicators of modernization.
            Cover page: Low perceived control over health is associated with lower treatment uptake in a high mortality population of Bolivian forager-farmers
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2021)
            Juvenile myelomonocytic leukemia is an overlapping myeloproliferative and myelodysplastic disorder of early childhood . It is associated with a spectrum of diverse outcomes ranging from spontaneous resolution in rare patients to transformation to acute myeloid leukemia in others that is generally fatal. This unpredictable clinical course, along with initially descriptive diagnostic criteria, led to decades of productive international research. Next-generation sequencing now permits more accurate molecular diagnoses in nearly all patients. However, curative treatment is still reliant on allogeneic hematopoietic cell transplantation for most patients, and additional advances will be required to improve risk stratification algorithms that distinguish those that can be observed expectantly from others who require swift hematopoietic cell transplantation.
              Cover page: Juvenile myelomonocytic leukemia in the molecular era: a clinician's guide to diagnosis, risk stratification, and treatment.
              • Article
              • Peer Reviewed
              UC Santa Barbara Previously Published Works (2020)
              Humans have the longest post-reproductive lifespans and lowest rates of actuarial ageing among primates. Understanding the links between slow actuarial ageing and physiological change is critical for improving the human 'healthspan'. Physiological dysregulation may be a key feature of ageing in industrialized populations with high burdens of chronic 'diseases of civilization', but little is known about age trajectories of physiological condition in subsistence populations with limited access to public health infrastructure. To better characterize human physiological dysregulation, we examined age trajectories of 40 biomarkers spanning the immune (n = 13 biomarkers), cardiometabolic (n = 14), musculoskeletal (n = 6) and other (n = 7) systems among Tsimane forager-horticulturalists of the Bolivian Amazon using mixed cross-sectional and longitudinal data (n = 22 115 observations). We characterized age-related changes using a multi-system statistical index of physiological dysregulation (Mahalanobis distance; Dm) that increases with age in both humans and other primates. Although individual biomarkers showed varied age profiles, we found a robust increase in age-related dysregulation for Tsimane (β = 0.17-0.18) that was marginally faster than that reported for an industrialized Western sample (β = 0.14-0.16), but slower than that of other non-human primates. We found minimal sex differences in the pace or average level of dysregulation for Tsimane. Our findings highlight some conserved patterns of physiological dysregulation in humans, consistent with the notion that somatic ageing exhibits species-typical patterns, despite cross-cultural variation in environmental exposures, lifestyles and mortality. This article is part of the theme issue 'Evolution of the primate ageing process'.
                Cover page: Multi-system physiological dysregulation and ageing in a subsistence population.
                • Article
                • Peer Reviewed
                UC Santa Barbara Previously Published Works (2012)
                The rise in blood pressure with age is a major risk factor for cardiovascular and renal disease, stroke, and type 2 diabetes mellitus. Age-related increases in blood pressure have been observed in almost every population, except among hunter-gatherers, farmers, and pastoralists. Here we tested for age-related increases in blood pressure among Tsimane forager-farmers. We also test whether lifestyle changes associated with modernization lead to higher blood pressure and a greater rate of age-related increase in blood pressure. We measured blood pressure longitudinally on 2248 adults age ≥ 20 years (n=6468 observations over 8 years). Prevalence of hypertension was 3.9% for women and 5.2% for men, although diagnosis of persistent hypertension based on multiple observations reduced prevalence to 2.9% for both sexes. Mixed-effects models revealed systolic, diastolic, and pulse blood pressure increases of 2.86 (P<0.001), 0.95 (P<0.001), and 1.95 mmHg (P<0.001) per decade for women and 0.91 (P<0.001), 0.93 (P<0.001), and -0.02 mmHg (P=0.93) for men, substantially lower than rates found elsewhere. Lifestyle factors, such as smoking and Spanish fluency, had minimal effect on mean blood pressure and no effect on age-related increases in blood pressure. Greater town proximity was associated with a lower age-related increase in pulse pressure. Effects of modernization were, therefore, deemed minimal among Tsimane, in light of their lean physique, active lifestyle, and protective diet.
                  Cover page: Does Blood Pressure Inevitably Rise With Age?
                  • Article
                  • Peer Reviewed
                  UC Santa Barbara Previously Published Works (2024)
                  Although still prevalent in many human societies, the practice of cousin marriage has precipitously declined in populations undergoing rapid demographic and socioeconomic change. However, it is still unclear whether changes in the structure of the marriage pool or changes in the fitness-relevant consequences of cousin marriage more strongly influence the frequency of cousin marriage. Here, we use genealogical data collected by the Tsimane Health and Life History Project to show that there is a small but measurable decline in the frequency of first cross-cousin marriage since the mid-twentieth century. Such changes are linked to concomitant changes in the pool of potential spouses in recent decades. We find only very modest differences in fitness-relevant demographic measures between first cousin and non-cousin marriages. These differences have been diminishing as the Tsimane have become more market integrated. The factors that influence preferences for cousin marriage appear to be less prevalent now than in the past, but cultural inertia might slow the pace of change in marriage norms. Overall, our findings suggest that cultural changes in marriage practices reflect underlying societal changes that shape the pool of potential spouses.
                    Cover page: Cross-cousin marriage among Tsimane forager-horticulturalists during demographic transition and market integration.
                    • Article
                    • Peer Reviewed
                    UC Riverside Previously Published Works (2019)
                    Crude oil and polycyclic aromatic hydrocarbon (PAH) exposure in early life stage fish has been well-characterized to induce phenotypic malformations such as altered heart development and other morphological impacts. The effects of chemical oil dispersants on toxicity are more controversial. To better understand how chemical dispersion of oil can impact toxicity in pelagic fish, embryos of mahi-mahi (Coryphaena hippurus) were exposed to three concentrations of the chemical dispersant Corexit 9500A, or Corexit 9500A-oil mixtures (chemically enhanced water accommodated fractions: CEWAF) of Deepwater Horizon crude oil for 48 h. RNA sequencing, gene ontology enrichment, and phenotypic measurements were conducted to assess toxicity. Exposure to Corexit 9500A altered expression of less than 50 genes at all concentrations (2.5, 5, and 10 mg/L nominal concentration) and did not induce acute mortality or phenotypic malformations, corroborating other studies showing minimal effects of Corexit 9500A on developing mahi-mahi embryos. CEWAF preparations contained environmentally relevant ∑PAH concentrations ranging from 1.4 to 3.1 μg/L and similarly did not alter larval morphology. Differentially expressed genes and significantly altered pathways related to cardiotoxicity, visual impairments, and Ca2+ homeostasis reinforced previous work that expression of genes associated with the heart and eye are highly sensitive molecular endpoints in oil-exposed early life stage fish. Differential expression and gene ontology pathways were similar across the three CEWAF treatments, indicating that increased chemical dispersion did not alter molecular outcomes within the range tested here. In addition, significant sublethal molecular responses occurred in the absence of observable phenotypic changes to the heart, indicating that effects of oil on early life stage fish may not be completely dependent on cardiac function.
                      Cover page: Effects of corexit 9500A and Corexit-crude oil mixtures on transcriptomic pathways and developmental toxicity in early life stage mahi-mahi (Coryphaena hippurus).
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