Browsing by Author "Huang, Lu"

With the extensive use of outsourcing and more frequent technological innovations, global supply chains become vastly stretched and dynamic networks. As a result, firms face increasingly significant challenges to managing their fragile supply networks and responding to more rapidly changing demand evolutions. In this dissertation, we analyze three aspects of these challenges and summarize the findings in three essays. The first essay considers firms' problem of managing social and environmental non-compliance risk at its sub-tier suppliers. We figure out under what circumstances the firms should delegate the sub-tier supplier non-compliance management to its direct suppliers and under what directly control. In the second essay, we analyze the firm's strategy to deal with random demand surges. We develop a new demand model that captures important non-Markov characteristics of possible random demand surge trajectories and derive the optimal safety stock and reactive capacity strategy. Eventually, we establish a useful framework for supply chain planning under a variety of surge demand characteristics (e.g., frequency, intensity, duration, and shape). In the third essay, we examine a dynamic customer-base management problem for a firm with finite capacity, when its customers are prone to disruption and retention risks. We show that the optimal base size is an adding-up-to policy and derive the firm's optimal capacity allocation policy when capacity shortage occurs. In summary, our studies in this dissertation provide useful modeling ideas, decision tools, insights, and guidance for firms to build up resilient supply chains from both the supply and demand sides.

The Ras family of small GTPases, comprised of the KRAS, NRAS, and HRAS genes, are mutated to encode constitutively-active, GTP-bound, oncogenic proteins in upwards of one quarter or more of all human cancers, which is well established to promote tumorigenesis. Despite the prominent role these genes play in human cancer, the encoded proteins have proven difficult to pharmacologically inhibit. Therefore, it is important to understand how Ras proteins are activated.

RAS proteins cycle between a GDP-bound inactive state and a GTP-bound active state through guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs facilitate the GDP-to-GTP exchange of RAS and promote RAS activation. Similar to GEFs, reactive oxygen/nitrogen species can also promote RAS activation through reactions with the thiol residue of cysteine 118 (C118). This residue may therefore play a role in RAS activation in cancer. To test this possibility, I investigated the effect of mutating C118 to serine (C118S) in Kras on (1) carcinogen-induced lung tumorigenesis, and (2) xenograft tumor growth of HRAS12V-transformed cells.

To explore the impact of the C118S mutation in Kras on carcinogen-induced lung tumorigenesis, I introduced a C118S mutation into the endogenous murine Kras allele and exposed the resultant mice to the carcinogen urethane, which induces Kras mutation-positive lung tumors. Kras+/C118S and KrasC118S/C118S mice developed fewer and smaller lung tumors than Kras+/+ mice. Although the KrasC118S allele did not appear to affect tumorigenesis when the remaining Kras allele was conditionally oncogenic (KrasG12D), there was a moderate imbalance of oncogenic mutations favoring the native Kras allele in tumors from Kras+/C118S mice treated with urethane. Therefore, mutating C118 of Kras impedes urethane-induced lung tumorigenesis.

To explore the the impact of the C118S mutation in Kras on xenograft tumor growth of HRAS12V-transformed cells, I tested and found that redox-dependent reactions with cysteine 118 (C118) and activation of wild type KRAS are critical for oncogenic HRAS-driven tumorigenesis. Such redox-dependent activation of KRAS affected both PI3K-AKT and RAF-MEK-ERK pathways. These findings were confirmed in the endogenous mouse Kras gene. Speicfically, oncogenic HRAS-transformed KrasC118S/C118S MEFs grew in soft agar and as xenograft tumors more slowly than similarly transformed Kras+/+ MEFs, suggesting that redox-dependent reactions with C118 of Kras promotes transformation and tumorigenesis.

Taken together, I have demonstrated a critical role of redox-dependent reactions with Kras C118 in tumorigenesis.