Acute myeloid leukemia (AML) is a subset of leukemia that is characterized by the clonal expansion of cytogenetically and molecularly abnormal myeloid blasts. These blasts are highly proliferative accumulating in bone marrow and blood which leads to severe infections, anemia, and bone marrow failure. The poor prognosis of AML patients caused by the low tolerance to intensive chemotherapy has encouraged the pursuit of alternative therapeutic approaches. Differentiation therapy which involves the use of agents that can release the differentiation block in these leukemic blasts has emerged as a promising therapeutic approach. The use of All-trans retinoic acid (ATRA) represents a successful example of such an approach, nonetheless its efficacy is restricted to one subtype of AML. Efforts have been focused on finding differentiation agents which are effective for the other more common AML subtypes. Anti-CD44 targeted antibodies that activate the CD44 cell surface antigen are a promising candidate. Previous studies have shown that anti-CD44 treatment has been able to release the differentiation block in AML1 through AML5 subtypes. The exact mechanism by which anti-CD44 treatment is able to induce its effects has not been fully elucidated. Recent studies highlight the role that epigenetic mechanisms play during haematopoiesis and leukemogenesis and therefore, in this work we investigated the epigenetic mechanisms associated with anti-CD44 induced differentiation. Using AML cell lines from different subtypes, we demonstrated that anti-CD44-induced differentiation results in an extensive change of histone modification levels. We found that inhibiting enzymes responsible for the H3K9ac, H3K4me, H3K9me, and H3K27me modifications, attenuated the anti-proliferative and differentiation promoting effects of antic-CD44 treatment. Taken together, these data highlight the promising potential of using anti-CD44 as a therapeutic agent across multiple subtypes in AML

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Objective: This study was carried out to determine the prevalence of leptospirosis among febrile patients with a suspicious clinical diagnosis of dengue fever in northern Peru. Results: A total of 276 serum samples from patients with acute febrile illness (AFI) and suspected diagnosis for dengue virus (DENV) were analyzed. We identified an etiological agent in 121 (47.5%) patients, DENV was detected in 30.4% of the cases, leptospirosis in 11.2% and co-infection by both pathogens was observed in 5.9% of the patients. In this study the most common clinical symptoms reported by the patients were: headache 89.1%, myalgias 86.9% and arthralgias 82.9%. No differences in symptomatology was observed among the different study groups. / National Research Foundation of Korea / Revisión por pares

Background: Gastroenteritis by rotavirus is responsible for approximately 810 annual deaths/year in children under 5 years in Peru and emerging rotavirus genotypes have led to concerns regarding cross-protection by the vaccines available. Moreover, there are no reports on the molecular-epidemiology of rotavirus diarrhea in Peru Methodology: A total of 131 stool samples were obtained from children under 5 years old hospitalized from January 2010 to December 2012 in the Hospital Regional de Cajamarca, Peru. ELISA and RT-PCR techniques were performed for rotavirus detection. G and P typing of rotavirus-positive samples were obtained by semi-nested multiplex RT-PCR and sequencing was performed to confirm the PCR results. Results: Of the 117 samples available, 18.80% (22/117) tested positive for rotavirus by ELISA and 35.90% (42/117) by RT-PCR. Among the G-genotype identified, G9 in 35.71% (15/42) and G12 in 33.33% (14/42) were the most prevalent. With the most common combination being G12/P6 in 23.81% (10/42). Conclusions: A high prevalence of the G12/P6 genotype was detected. It is know that this genotype is not covered by the current vaccines available. More in depth studies are needed to know the current rotavirus genotypes presents in Peru. / Tesis

The CGRP monoclonal antibodies are the first class of medication developed specifically for migraine prevention, in contrast to previous preventative medications, that were in the anti-hypertensive, anti-epileptic and anti-depressant class. There are two notable divisions within the CGRP inhibitor class: the CGRP monoclonal antibodies (CGRP mAbs), and the small molecule CGRP antagonists (gepants). This thesis conducts a retrospective analysis of notable clinical trials such as the ACHIEVE I, ACHIEVE II, LIBERTY, ARISE, STRIVE, PREEMPT, and COMPEL studies to determine the efficacy of CGRP inhibitors. In ACHIEVE I, 38.6% of participants in the 50 mg ubrogepant group experienced pain freedom 2 hours post dose (p=0.002) and in ACHIEVE II trial in the 50 mg ubrogepant group, 21.8% reported pain freedom 2 hours. In participants that received Rimegepant at a 75mg dose, 21%of participants reported more freedom from pain at 2 hours than placebo (p<0.0001).^40 In another study, participants received placebo, 50 mg and 100 mg of sumatriptan.^43 Results of the study showed that more than half of participants, 57%, in the 100 mg Sumatriptan group and exactly half of participants in the 50 mg group had pain relief at 2 hours post-dose.^43 In the LIBERTY trial, at 12 weeks, 30% of individuals that received erenumab reported a fifty percent or more reduction in the monthly number of migraine days than individuals in the placebo group (p=0.002).^45 In the STRIVE trial, the average number of migraine days experienced by the participant at baseline was 8.3, and was assessed by the 4th month through the 6th month. This baseline decreased to 5.1 days (a 3.2 difference) in the participants that received an injection of 70 mg of erenumab (p<0.001).^46 The participants that received an injection of 140 mg erenumab, decreased from the baseline to 4.6 days of migraine (a 3.7 difference) (p<0.001) . 46 Participants that received placebo reported the least change from baseline, only a 1.8 day change (p<0.001).46 In the ARISE Trial patients receiving erenumab experienced a change of 2.9 monthly migraine days, a 1.1 increase from the reported change of 1.8 days reported by study participants for the monthly migraine days in the placebo group (p<0.001).^47 The PREEMPT1 trial did not meet statistical significance for their primary endpoint or study measure, which was to assess for a mean change in monthly mean headache episode frequency between baseline and week 24 of the trial (p=0.344)^48. Participants in the PREEMPT2 trial experienced a reduction by 9 days when compared to placebo for the primary end point, frequency of headache days per 28 days relative to baseline (p<0.001)^49. In the COMPEL study, participants experienced -10.7 day reduction in headache days by 108 weeks (p<0.0001).^50 There are several advantages to CGRP mAbs. Patients are more likely to adhere to CGRP mAbs medication and tolerate this medication than other medication options^17, CGRP mAbs do not give rise to toxicity in the liver because these medications do not interact with the liver^17, and CGRP mAbs have a long duration in the human body as they have a half-life of 20 to 30 days which provides patients with the opportunity to not take the medication as frequently.^51 Another reason why CGRP mAbs are advantageous compared to traditional treatment options is that they have a strong affinity and specificity for the CGRP receptor or CGRP molecule. This high specificity prevents the medication from causing undesirable effects on other receptors^51.

1 Abstract The goal of the thesis is to determine acute toxicity indices of seven alcohols (2-ethoxyethanol, 1-propanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 3-hexanol, 2-methyl-3-hexanol, 1-nonanol) by two different alternative methods. Another goal is to create QSAR models to predict the acute toxicities of alcohols which belong into model limits. First of the methods used is based on the movement inhibition of lower animals Tubifex tubifex. The method provides the acute toxicity indices EC50. The second method uses the cell line of mouse fibroblasts called Balb/c 3T3 and it provides the acute toxicity indices IC50. The IC50 were recalculated to the LD50 values that correspond to the oral administration of alcohols to a rat. It has been found that 1-nonanol is included into the category of alcohols classified as acute oral toxic according to the EU CLP system. Other six alcohols are non-classified as acute oral toxic. Subsequently, accurate QSAR models has been created in order to predict the acute toxicity of other alcohols using Tubifex tubifex specie or Balb/c 3T3 cell line. The models are suitable for saturated, branched, ethoxy- and cyclic alcohols with the log POW value from −0.74 to 3.07. It was necessary to exclude the acute toxicity indices of 1-nonanol from these models as some solubility...

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Acute coronary syndrome (ACS) is a continuum of disease that includes non-ST-segment elevation ACS and ST-segment elevation myocardial infarction. The purpose of this article is to define the developing role of ticagrelor in ACS and compare it to currently available P2Y12 receptor inhibitors. While clopidogrel remains the "workhorse" P2Y12 receptor inhibitor for many patients with ACS and prasugrel has an established role in select situations, clinicians must now assimilate the evolving role of ticagrelor. Although ticagrelor offers important advances in the management of ACS (eg, reversibility), there are also notable clinical considerations (eg, unique adverse effects such as dyspnea). Based on the current evidence, we propose an algorithm to aid clinicians in the selection of a P2Y12 receptor inhibitor for patients with ACS in various clinical situations.

Newer biological treatment strategies have been developed in the last decade with some promising outcomes. Their safety, however, has been questioned lately with multiple reports of increased risk for malignancies and infectious complications. These reports render their use suboptimal. We report a 44-year-old woman receiving adalimumab (Humira®) for advanced juvenile rheumatoid arthritis who then developed acute myelogenic leukemia.

Since their introduction in the late 1980s, proton pump inhibitors (PPI) have demonstrated gastric acid suppression superior to that of histamine H2-receptor blockers. This class of drugs has improved the treatment of various acid-peptic disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-inflammatory drug-induced gastropathy. PPIs have minimal side effects and few significant drug interactions. They are generally considered safe for long-term treatment. We present a rare side effect, acute pancreatitis, occurring in a patient who was treated with the proton pump inhibitor omeprazole.

Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to nondependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.