Thesis advisor: Geoffrey Sanzenbacher / In recent decades, an increasing number of countries have adopted inflation targeting (IT) as a framework for monetary policy, wherein the country's central bank attempts to steer actual inflation toward a projected target rate. However, the question still remains whether or not IT can work in low-income countries experiencing hyperinflation, such as Venezuela. One of the main challenges facing such countries is the lack of credibility of their monetary institutions. Inflation targeting may help restore this credibility by committing the central bank to a transparent and accountable monetary policy. This paper delves into the theory of inflation targeting, examines the benefits and challenges associated with IT, and discusses the specific challenges that Venezuela may face when adopting IT. The paper also emphasizes the importance of accurate economic data in developing effective monetary policies and argues that forecasting can play a critical role in predicting the effectiveness of IT in Venezuela. Empirical evidence from other countries that have implemented inflation targeting will also be used to provide insights into the potential benefits and challenges of this policy for Venezuela. / Thesis (BA) — Boston College, 2023. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Economics.

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Hypoxia is a characteristic pathophysiological feature of many solid tumors, which contributes significantly to resistance to chemotherapy and radiotherapy. It also induces numerous intracellular signaling pathways, which in turn trigger the upregulation of various key proteins promoting tumor cell survival, progression and metastasis. In this context, novel therapeutic approaches are urgently needed to facilitate the early detection and improve the treatment of hypoxic tumors. Focusing on the hypoxic tumor microenvironment, one can recognize that the membrane bound carbonic anhydrase IX (CA IX) isozyme represents a potential biomarker and a compelling therapeutic target for better diagnosis and management of hypoxic tumors. CA IX is significantly overexpressed under hypoxic conditions as compared to normal tissues and it assists tumor cell to maintain neutral intracellular pH values. Building on this hypothesis, we are focusing our efforts in this thesis towards the development and the optimization of drug delivery nanosystems capable of selectively targeting CA IX that is overexpressed in the hypoxic tumor niche, which in turn will enhance the early detection of hypoxic tumors as well as improve the accumulation of chemotherapeutic drugs in hypoxic cancer cells. This strategy is expected to overcome the chemoresistance associated with tumor hypoxia and minimize the systemic side effects associated with chemotherapeutic drugs administration. In chapter 2, we focused our efforts towards the development of the in vitro biological models for testing our nanoparticles. This process was achieved through screening a series of cancer cell lines for the expression of our target epitope under hypoxic conditions. We induced hypoxia either chemically, using cobalt chloride, or physicochemically, using a hypoxia chamber purged with hypoxia gas mixture containing 1% O2. Screening for CA IX overexpression under hypoxic conditions was done both in 2D monolayer cells and 3D tumor spheroids, which become naturally hypoxic due to their 3D growth. Western blot analysis was used to confirm the expression of our target protein and we have identified three cell lines with a high level of expression of CA IX under hypoxic conditions, namely HT-29 colorectal cancer, SKOV-3 ovarian cancer and MDA-MB-231 breast cancer cell lines. In chapter 3, we optimized a theranostic liposomal delivery system through the use of a combination of zwitterionic amphiphilies of different packing parameters to encapsulate a potent fluorescent carbonic anhydrase inhibitor (CAI), as a novel approach to facilitate the detection of colorectal cancer. Our main focus was to increase the aqueous concentration of poorly water-soluble CAI, to correlate its delivery efficiency with the lipid type and composition of the liposomal nanosystem, as well as to enhance the tissue permeability, allowing easy detection of small tumor polyps. Our optimized DMPC/DOPE liposomal formulation demonstrated an optimum size, high encapsulation efficiency of CAI, and a phase transition temperature below 37 ᴼC that allows efficient delivery of CAI and good tissue penetrability towards the hypoxic tumor cells overexpressing CA IX. In chapter 4, we optimized a CAI-targeted long circulating liposomal delivery system encapsulating doxorubicin. Our main focus was to enhance the accumulation of doxorubicin in hypoxic tumors through targeting CA IX protein overexpressed under hypoxic conditions. This strategy proved to enhance the internalization of the drug carrier into hypoxic cancer cells thus overcoming chemoresistance associated with hypoxia and also minimize the systemic side effects associated with the intravenous administration of non-targeted Doxil®-like formulations. In chapter 5, we optimized a pH sensitive gold nanoplatform functionalized with CAI based moieties to enhance the selective delivery of doxorubicin to hypoxic tumors in a controlled release manner. Our main focus was to combine the advantage of targeting CA IX overexpressed under hypoxic conditions with the intracellular triggered release of doxorubicin in the lysosomes inside the cell in order to enhance the delivery of doxorubicin inside the cancer cells and to overcome the chemoresistance associated with hypoxia. / Pharmaceutical Sciences

Each year, thousands of femoral and tibial internal fracture repairs are performed by orthopedic surgeons in the United States. Internal fixation of long bones using intramedullary nails (IMN) has decreased incidence of non-union, allowed shorter hospitalization time, and earlier weight bearing for the patient compared to other fixation methods. Orthopedic surgeons have expressed that one of the most difficult parts of this intramedullary nailing of long bones, is locating and drilling the interlocking screw holes. IMN interlocking requires the surgeon to locate the holes in the nail, center the drill, and advance the bit through the bone to meet them. Many novel procedures and devices have been developed to assist the surgeon in distal locking of intramedullary nails, but have some disadvantages. These can include the need for extensive x-ray exposure, expensive x-ray equipment, high power consumption, active electronics in vivo, soft tissue damage, which all lead to inaccurate screw placement. For these reasons, a new prototype device for locating and drilling IMN distal interlocking holes has been developed. This prototype device uses magnetic sensors to locate a permanent magnet placed at a know distance from the IMN interlocking hole. A drill sleeve may be attached to the targeting sensors so that when they are aligned with the target magnet, the drill sleeve is aligned with the axis of the interlocking hole to be drilled. This new prototype device has significant advantages over existing devices, including the following. It has no active or passive electronics in vivo, no x-ray imaging is needed for targeting, while allowing real time feedback of alignment. It is a percutaneous technique, which can be adapted for use with existing IMN's. The new prototype also has low power requirements allowing battery operation, a single target magnet with unique axisymmetric field and novel magnet orientation, and adjustable sensitivity. Additionally, the new device allows visual, audible, or tactile positioning feedback. This prototype magnetic targeting device can improve orthopedic surgeons' ability to target and drill distal IMN interlocking screw holes. This device may allow shorter surgery, decreased x-ray exposure, and fewer complications for the surgeon and patient. / Master of Science

Inflation targeting is a monetary policy regime, characterized by public announcement of official target ranges or quantitative targets for price level increases and by explicit acknowledgement that low inflation is the most crucial long-run objective of the monetary authorities. There are three prerequisites for inflation targeting: 1)central bank independence,2)having a sole target,3)existence of stable and predictable relationship between monetary policy instruments and inflation.In many developing countries, the use of seigniorage revenues as an important source of financing public debts, the lack of commitment to low inflation as a primary goal by monetary authorities, considerable exchange rate flexibility, lack of substantial operational independence of the central bank or of powerful models to make domestic inflation forecasts hinder the satisfaction of these requirements. This study investigates the applicability of inflation targeting to the Turkish economy. Central bank independence in Turkey has been mainly hindered by "fiscal dominance" through monetization of high budget deficits. In addition, although serious steps have been taken recently under a new law to have an independent central bank, such as formal commitment to the achievement of price stability as the primary objective and the prohibition of credit extension to the government, the central bank does not satisfy independence criteria due to the problems associated with the appointment of the government and the share of the Treasury within the bank. Having a sole inflation target was hindered by the existence of fixed exchange rate system throughout the years. However, in February 2001, Turkey switched to a floating exchange rate regime, which is important for a successful inflation-targeting regime. Having a sole target within the system has also been supported by the new central bank law, which gives priority to price stability and supports any other objective as long as it is consistent with price stability. In this thesis, an empirical investigation has been made in order to assess the statistical readiness of Turkey to satisfy the requirements of inflation-targeting by making use of vector autoregressive (VAR) models. The results suggest that inflation is an inertial phenomenon in Turkey and money, interest rates and nominal exchange rates innovations are not economically and statistically important determinants of prices. Most of the variances in prices are explained by prices themselves. According to the VAR evidence, the direct linkages between monetary policy instruments and inflation do not seem to be strong, stable, and predictable. As a result, while the second requirement of the inflation-targeting regime seems to have been satisfied, there are still problems associated with the central bank independence and the existence of stable and predictable relationship between monetary policy instruments and inflation in Turkey. / Master of Arts

A inserção de DNA exógeno no genoma hospedeiro é conseguida principalmente através da utilização de vias de reparo como a junção de pontas não homólogas, que possui caráter aleatório, e a recombinação homóloga, que possibilita o gene targeting. Algumas ferramentas como as TAL Effector Nucleases (TALENs) e o RNA interferência (RNAi) podem ser utilizadas para aumentar a taxa de integração específica e assim melhorar a eficiência e o direcionamento da edição gênica. Nesse trabalho utilizamos o silenciamento gênico mediano por short interference RNA (siRNA) para inibição temporária dos genes ATF7IP uma metiltrasferase, EP300 uma acetiltransferase e KU70 (NHEJ) e um par de TALENs complementares a uma região do gene da distrofina canina. Células Caninas MDCK I foram transfectadas por lipofectamina 2000 (Invitrogen) com 320pmol de siRNAs para ATF7IP e Ep300; e 64 pmol do SiRNA para KU70 em diferentes grupos, 40 horas depois as células foram transfectadas com 15 μg vetor molde derivado do pEGFP-N1 (Clonatech) e com 10 μg dos RNAm das TALENs. A seleção se deu em meio DMEM high com 600μg/ mL de G418 (Lonza) por 14-16 dias. As colônias coletadas através de biópsias foram analisadas por Polimerase Chain Reaction e sequenciamento gênico. Três pares de primers foram utilizados; um controle endógeno (GAPDH), um controle interno do inserto (Neo qPCR) e um para confirmação da recombinação homóloga (DMD3). Os grupos apresentaram grande variação na taxa de mortalidade celular e consequentemente no número de colônias: Com o grupo ATF7IP+Vetor (648c) apresentando maior número de colônias e o grupo EP300+Ku70+Vetor+TALENs o menor (1c). A maior taxa de recombinação ocorreu nos grupos no grupo ATF7IP +Ku70+Vetor+TALENs com 40% das células positivas para neomicina apresentado o evento gene targeting, um aumento considerável na taxa de recombinação quando comparada a porcentagem de 3,1% do controle transfectado somente com o vetor molde. Mostrando que o uso conjunto das TALENs com siRNAs foi um sucesso para o aumento de eventos de edição gênica direcionada. / The insertion of exogenous DNA into a host genome is achieved primarily through the use of DNA repair pathways such as Non-Homologous End Joining (NHEJ) and the Homologous Recombination (HR). The integration by NHEJ has a random feature and is much more common than HR insertions, which are more likely to produce gene targeting events . TAL effector nucleases (TALENs) and RNA interference (RNAi) can be used to increase the rate of specific integration and thus improving the efficiency of gene editing. In this work, we used short interference RNA (siRNA)-mediated gene silencing for transient inhibition of genes ATF7IP (implicated in histone methylation), EP300 (acetyltransferase) and Ku70 (essential to NHEJ) and a pair of TALENs RNAm complementary to canine muscle dystrophin (DMD) gene. MDCK I Canine Cells were transfected by lipofectamine 2000 (Invitrogen) with 320 pmol of siRNAs for ATF7IP and EP300; and 64 pmol of siRNA for Ku70 in different groups. After 40 hours cells were transfected with 15 μg of a vector derived from pEGFP- N1 (Clontech) containing two regions homologous to the canine DMD gene (left arm length: 873 bp and right arm length: 1370 bp) and 10 μg of TALEN mRNA. The cell selection was achieved with DMEM high glucose with 600μg/ml G418 for 14-16 days. The colonies collected through biopsies were analyzed by polymerase chain reaction and gene sequencing. Three pairs of primers were used; an endogenous control (GAPDH) , an internal control of the insert (Neo qPCR) and a primer set to confirm the occurrence of homologous recombination events (DMD3). .Groups showed great variation in cell death rate and consequently in the number of colonies: ATF7IP+Vector had highest number of colonies (648c) and the group EP300+Ku70+Vetor+TALENs the lowest one (1c) The highest rate of homologous recombination was in ATF7IP +Ku70+Vetor+TALENs group that had 40% of the neomycin positives cells confirmed as gene targeting events, a considerable increase in the recombination rate compared to the 3.1% in the control group transfected only with the template vector. That shows that the combined use of siRNAs and TALENs was a success for increasing directed gene editing events.

<p>Av flera anledningar har i många länder mål för prisstabilitet ersatt den aktiva stabiliseringspolitiken där mål för nationalprodukt och sysselsättning stått i centrum. Centralbanker bedriver och har bedrivit penningpolitik för att uppnå prisstabilitet på olika sätt och det ärdenna fråga som står i fokus i denna uppsats. Detta aktualiseras ytterligare då den europeiska centralbanken (ECB) är i ett startskede vad det gäller att bedriva penningpolitik med prisstabilitet som primärt mål. I detta perspektiv är det av intresse att studera Bundesbank närmare då denna under relativt lång tid bedrivit penningpolitik inriktad på prisstabilitet. För att belysa frågan om penningpolitik har, efter en teoretisk presentation, en empirisk studie av Bundesbank genomförts. Den studerade perioden sträcker sig från 1975 fram till 1996. Grunden för arbetet är följande frågeställningar: (1)Hur framgångsrik har Bundesbank varit med sin penningpolitik? (2)I vad mån har monetarismens läror satt sina spår i Bundesbanks penningpolitik? (3)Diskussion om ECB:s framtid med beaktande av de kunskaper studiet av Bundesbank ger. Bundesbank kan sägas ha bedrivit penningpolitik med prisstabilitet som primärt mål relativt framgångsrikt. Vissa fakta talar för att det är Bundesbanks styrka som institution, där transparens och trovärdighet spelat en stor roll, som ligger bakom framgången. Monetarismen kan sägas ha lämnat ett avtryck i Bundesbanks penningpolitik i form av en viss överhängande prägel på den penningpolitiska designen. I praktiken är dock spåren från monetarismen vaga. Penningmängdens betydelse vid genomförandet av penningpolitiken kan ifrågasättas. Den kanske viktigaste lärdomen är nog hur Bundesbank fungerat som institution.</p>

<p>Antibody-based targeting techniques play an increasingly important role in cancer research. By targeting a structure that is abundant in tumour cells, but rare in healthy tissues, an antibody can mediate the delivery of radioactivity specifically to tumour cells in the body. This idea is particularly appealing for head and neck squamous cell carcinoma (HNSCC), as the advanced stages have a large fraction of spread disease that is difficult to treat with procedures available today. </p><p>In this thesis, we have investigated possible radioimmunotargeting structures for HNSCC, and found that CD44v6 is a suitable target for antibody-based radiotherapy and diagnostics in this patient group. We have identified radiohalogens as attractive nuclides for such use, and have investigated the possibility of radiohalogenating the anti CD44v6 chimeric monoclonal antibody (cMAb) U36. Several feasible labelling methods were identified, using both direct and indirect labelling. The cMAb U36 was then successfully labelled with ²¹¹At and ¹³¹I, and preclinically evaluated for therapeutic use. Results proved the astatinated conjugate to be most efficient in this context, demonstrating a specific and dose-dependent cytotoxicity. The cMAb U36 was then evaluated for diagnostic use in thyroid anaplastic carcinoma, using ¹²⁴I as the diagnostic nuclide. Results in tumour-bearing mice were promising, with all of the tumours identified in micro-PET studies.</p><p>These results demonstrate how antibody-based radionuclide targeting can provide more sensitive and specific methods for identifying and treating head and neck cancer, and hopefully help improve long-term survival rates for this patient group in the future.</p>

<p>The diagnosis and treatment of patients with advanced tumors in the head and neck is an interesting challenge where there is a need for new approaches in diagnostics and adjuvant treatment. Differences in antigen expression between tumors and normal tissues provide a means for application of antibody-based targeting techniques. By targeting a structure that is abundant on tumor cells and limited on normal cells, radioactivity can be delivered.</p><p>The use of positron emission tomography (PET) in patients with head and neck tumors is evaluated in this thesis. PET using the tracer fluorodeoxyglucose (FDG) is found to play an important diagnostic role and often has a direct clinical impact on planned surgery or other treatment. Possible targeting structures are also investigated in this thesis, and it is concluded that the EGFR and CD44v6 stand out as possible antigens for targeting approaches of squamous cell carcinomas in the head and neck (HNSCC). A radioimmunoassay for quantification of EGFR and CD44v6 is validated and concluded to be a valuable complement to immunohistochemistry for the analysis of tumors and for the planning of radioimmunotherapy. Finally, promising results of radioimmunotherapy in tumor bearing mice with the monoclonal antibody U36 labeled with the alpha emitter astatine-211 are presented.</p><p>These results demonstrate how differences between tumors and normal tissues can be used to improve diagnostic outcomes and indicate that radioimmunotherapy can be a future adjuvant therapy or treatment of residual disease in HNSCC.</p>