METHODS: An evidence based review was conducted beginning with a Pubmed database literature search using the terms ‘EPA esophageal cancer’, ‘Eicosapentaenoic acid esophageal cachexia’, ‘Eicosapentaenoic acid esophageal’, ‘Eicosapentaenoic acid cachexia head and neck cancer’, and ‘EPA cachexia head and neck cancer’ for human clinical trials. The results were reviewed for relevance and the data from original research was abstracted for amount of EPA enriched formula supplemented, EPA intake, method of intake, LBM measurements, study design, intervention duration, and population characteristics.

RESULTS: Three trials were identified that met the criteria and were reviewed.  EPA supplementation in enteral nutrition was provided at concentrations ranging between 1.6 g/day and 2.2 g/day for a time span ranging between 3 weeks and 14 weeks. Two randomized clinical trials showed maintenance of > 1.5 kg LBM relative to the control group while a single arm trial showed a gain of 3.2 kg LBM in patients. Differences in results could be attributed to variability in the degree of cachexia, the contents of each enteral nutrition formula, duration of supplementation, and cancer treatments that subjects in each trial were undergoing.

CONCLUSIONS: All three trials showed a trend in EPA enriched enteral nutrition improving the loss of LBM in esophageal, head and neck cancer patients at risk for cachexia progression. This type of formula should therefore be considered in treatment of these types of cancers and possibly, in the treatment of other seriously ill patients with cachexia.

Background

Methods

Results

Conclusions

Context and Objective: Bone resorption and formation markers increase when turnover increases, whether there is net bone gain or net loss. The objective was to determine if resorption and formation markers can be combined to gauge net bone balance.

Design: Cohort followed across menopause transition; Study of Women’s Health Across the Nation

Setting and Participants: Community-dwelling women, 42-52 years old, premenopausal or early perimenopausal at baseline.

Outcome Measures: 1) Bone balance index (BBI) created by estimating the in-balance relationship between resorption and formation markers in 685 women in stable bone balance (>5 years before the final menstrual period, FMP), and applying this relationship to measured turnover markers in 216 women beginning to lose bone (<2 years from FMP). 2) Annualized percent declines over the following 3-4 years in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD).

Results: Adjusted for covariates, BBI was greater (more favorable) in women with greater body mass index (p=0.03), and lower (less favorable) in women closer to the FMP (p=0.007). Each standard deviation decrement in BBI was associated with 0.27%/year faster LS BMD decline (p=0.04) and 38% higher odds of faster-than-average loss of LS bone mass (p=0.008, c-statistic=0.76). BBI was not associated with decline in FN BMD. Urinary N-telopeptide (U-NTX) alone was not associated with either LS or FN BMD decline.

Conclusions: An index that quantifies net bone formation versus resorption can be created from turnover markers, and may help identify individuals at high risk for bone loss.

This dissertation comprises three chapters representing a body of work examining the domestic and global implications of Chinese monetary policy. In order to better understand the conduct of Chinese monetary policy, this dissertation explores issues related to the proper identification of policy shocks, puzzles in the relationship between Chinese financial markets and monetary policy conduct, the role global supply chains play in the worldwide transmission of Chinese monetary policy shocks, and the role Chinese monetary policy plays in the creation of credit in both the traditional and shadow banking systems.

In the first chapter, published in the Journal of International Money and Finance (Shieh, 2024a), I answer the question: do Chinese monetary policy announcements matter? This chapter evaluates how relevant Chinese monetary policy announcements are to Chinese financial markets and the real side of the economy. The primary contribution of this chapter is developing an identified monetary policy shock measure. Chinese monetary policy is identified by estimating a ``target" factor measuring policy surprises and a ``path" factor measuring future expectations of policy using price changes to Chinese financial derivatives on policy announcement dates. Local projection results show a few key findings. First, Chinese Treasury yields and interbank rates respond persistently, suggesting that policy transmission through an interest-rate channel exists. Second, equities and exchange rates do not respond to policy announcements instantaneously but with a lag. Third, future expectations of Chinese monetary policy play a larger role than surprises. Fourth, real variables show evidence of policy transmission, and fifth, policy transmission may be sticky due to information frictions.

The second chapter, written jointly with Anirban Sanyal, explores whether or not Chinese monetary policy matters on a global stage. We characterize and evaluate how Chinese monetary policy shocks are transmitted globally by examining the role production linkages play in Chinese monetary policy shock transmission through global stock returns. Using a spatial autoregression with identified shocks, we explore how Chinese policy shocks propagate up and downstream through supply chains. Firms on both ends of the Chinese production network show negative country-industry level equity returns in response to a contractionary monetary policy shock. Notably, most of the observed equity responses to monetary policy shocks can be attributed to the network effect of firms being connected across global supply chains, highlighting China's role in supply chains. We attribute the heterogeneity in equity responses across countries and industries to a country's degree of home-bias by simulating a standard small-open economy model with supply chain integration. Our results highlight the importance supply chains play in the transmission of Chinese monetary policy.

In the third and final chapter, I examine the relationship between Chinese monetary policy and the Chinese shadow banking sector. More specifically, I evaluate the effect of Chinese monetary policy shocks on credit creation through the shadow banking sector in mainland China. I identify monetary policy shocks by constructing a measure of monetary policy surprises based on changes to the 1-Year Interest Rate Swaps on the 7-Day Repo Rate on monetary policy announcement dates. A two-stage local projection was then estimated using the surprise measure as an instrument. The results give two key findings. First, shadow credit expands in response to contractionary monetary policy and second, I provide additional evidence of the transmission of monetary policy through the interest rate channel.

Mutations that deregulate Ras signaling are prevalent in hematopoietic malignancies. Previous work has shown that expressing oncogenic Kras^G12D in the hematopoietic compartment of mice leads to growth factor-independent and a hypersensitive pattern of myeloid progenitor colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF), and a fatal myeloproliferative disorder (MPD). This mirrors human myelomonocytic leukemias that are associated with Ras pathway mutations. Oncogenic Ras proteins accumulate in the active GTP-bound form and constitutively activate numerous downstream effector pathways. However, it is unclear which effectors are necessary to initiate and maintain malignant hematologic disease as well as the contributions of specific effector pathways to disease phenotypes.

I performed functional studies utilizing second site K-Ras^G12D mutant proteins to explore the role of the three main effector pathways - Raf/MEK/ERK, Phosphotidyl-Inositol-3Kinase(PI3K), RalGDS - in Kras^G12D-driven oncogenesis. Using primary murine hematopoietic cells transduced with second site mutant constructs, I found that second site mutants maintaining hyperactive signaling down only one effector pathway were unable to confer hypersensitivity to GM-CSF in methylcellulose assays. However, second site mutants that engage two of the three major effector pathways, K-Ras^G12D,E37G and K-Ras^G12D,Y64G (which activate PI3K/RalGDS and Raf/RalGDS respectively), retain some growth factor hypersensitivity but do not exhibit cytokine-independent growth.

Transplantation of bone marrow cells transduced with K-Ras^G12D,E37G or K-Ras^G12D,Y64G into irradiated recipient mice induced invasive, monoclonal, CD4-CD8 double-positive T-cell acute lymphoblastic leukemias (T-ALLs) that originated in the thymus. A majority of these leukemias show elevated levels of activated Notch1, due to mutations in the PEST domain of Notch1. Tumors expressing K-Ras^G12D,E37G demonstrated elevated levels of this mutant K-Ras protein but no basal activation of the Raf/MEK/ERK pathway. Interestingly, T-ALLs initiated by K-Ras^G12D,Y64G acquired elevated levels of phosphorylated Akt, which was associated with diminished or absent PTEN expression. The strong selective pressure to increase signaling through PI3K by alternative mechanisms, increasing K-Ras^G12D,E37G protein levels or decreasing PTEN expression, supports the hypothesis that this pathway plays a central role in T-lineage leukemogenesis. An important therapeutic implication of these data is that inhibiting a single major effector pathway may be insufficient to fully reverse the growth advantage conferred by oncogenic Ras.