Mechanisms of therapy resistance in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a highly aggressive pediatric cancer that can affect both B cells and T cells. The advent of new therapies has increased the cure rates for both B-ALL and T-ALL patients. However, some patients still experience relapse with a variable response to the treatment and display poor survival. Thus,identification of novel predictive biomarkers that can predict therapy resistance may help to stratify this group of patients. This could also aid in developing an effective treatment strategy.Glucocorticoids are widely used along with the chemotherapeutic regimens for treating ALL patients. The response to glucocorticoids can predict long-term remission outcome. To understand the mechanisms of resistance to glucocorticoids, such as dexamethasone, we generated dexamethasone-resistant B-ALL cell lines in paper I. One such resistant cell line was found to possess increased FLT3 expression levels with FLT3-ITD and FLT3-R845G mutations that led to the activation of oncogenic RTK signaling. Further, second-generation FLT3 inhibitors, such as AC220 and crenolanib, suppressed this signaling both in vitro and in vivo.We continued exploring the dexamethasone resistance mechanisms in paper II using a different approach. We observed that dexamethasone exposure caused upregulation of Aurora kinase and its various downstream effector kinases such as JAK, p38, mTOR, and S6K. These kinases lead to β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β either directly or indirectly. Indeed, we observed partial restoration of dexamethasone sensitivity with a combination of dexamethasone and inhibitors targeting either these kinases or β-catenin.The expression of BCL2 varies in T-ALL depending on its stage of maturation, thereby T-ALL displays a heterogenous response to the BCL2-specific inhibitor venetoclax. We thus studied the mechanisms of venetoclax resistance using a panel of T-ALL cell lines in paper III. We observed that all the venetoclax-resistant T-ALL cell lines displayed non-universal changes in the expression of BCL2 family members and cancer stem cell markers, along with specific enrichment of cytokine signaling pathways. However, further investigations are warranted to identify additional mechanisms of venetoclax resistance in T-ALL.Combination therapy is usually the choice of treatment to overcome monotherapy resistance. With this in mind, in paper IV we identified that inhibiting BCL2 by venetoclax synergizes with PLK1 inhibition by volasertib in T-ALL cell lines and PDX models. We observed that BCL2L13 and PMAIP1 genes get upregulated upon PLK1 inhibition, probably through transcriptional regulation by FOXOs in interaction with β-catenin. Thus, the pro-apoptotic functions exhibited by BCL2L13 and PMAIP1 probably synergize with BCL2 inhibition in T-ALL, with the help of sustained β-catenin levels. Moreover, we also identified upregulation of oxidative phosphorylation (OXPHOS) in T-ALL PDXs that didn’t display synergy, which could be treated with a combination of venetoclax and oligomycin. However, additional experiments will be required to verify the above results

Haven in the Meadows

This project began with an investigation about creating an environment that facilitates the healing the process for mental health patients. The state of mental hospitals in current scenario lacks the continuum of care. To fill this gap of care, this project caters to the need of behavioral health facilities from acute care to residential treatment. In today's scenario, the need for mental health services have increased. The attention to overall health can only be achieved if both physical and mental health are taken care. There are many counties in the United States which lack basic mental health services. This project is located in Larimer County, Colorado, the county lacked any behavioral health services for its residents. Hence the need for facility was evident. With this intention, the "Larimer County Community Master Plan for Behavioral Health: Changing the Paradigm" was created to comprehensively evaluate the behavioral health service needs; identify gaps in the continuum of treatment and support services and outline a Five Year Strategic Plan to address them. The project consists of 16- bed unit cluster each for acute mental health patients, substance use, outpatient facility, and residential treatment. The design is based on principles of biophilic design and salutogenic approach. The research carried out for this project aims to identify the design guidelines to explore how architecture can be of aid in relieving psychological disorders by promoting a eunoia state of mind. The planning process was more focused on creating secured and unsecured environments without a physical barrier and facilitating spatial orientation in a more natural way. The investigation ahead will act as toolbox for designing behavioral health facilities with new outlook. The environment around the facility gives the patient a sense of coherence and choice control leading to feel more like home. At the end, the architecture needs to make a person believe that this mental and behavioral disorder can be controlled and this place will heal them. Hence the facility is a "Haven" for all the patients to give them new life purpose and the Zen to feel "Eunoia.

The Efficacy of Osteopathic Manipulative Treatment in Reducing Pain Medication Usage in Chronic Pain Patients: A Brief Literature Review

Chronic pain is one of the most common complaints for adult patients. Chronic pain almost always includes a pharmacological approach which can involve opioids and non opioids. Non-pharmacological approaches are less commonly used by patients with chronic pain, despite the significant misuse of opioids in the treatment of chronic pain. There is a need for nonpharmacological therapies in the treatment of chronic pain patients to lessen the misuse of opioids. One underused form of nonpharmacological therapy for chronic pain is OMT. There have been several studies demonstrating OMT to be effective in treating chronic pain conditions. In addition, there is an assortment of studies demonstrating how OMT has been effective in reducing the amount of non-opioid medications patients take. However, there is a lack of information in the field detailing if OMT can decrease the amount of opioids a patient with chronic pain may take

Incorporating Agile with MDA Case Study: Online Polling System

Nowadays agile software development is used in greater extend but for small organizations only, whereas MDA is suitable for large organizations but yet not standardized. In this paper the pros and cons of Model Driven Architecture (MDA) and Extreme programming have been discussed. As both of them have some limitations and cannot be used in both large scale and small scale organizations a new architecture has been proposed. In this model it is tried to opt the advantages and important values to overcome the limitations of both the software development procedures. In support to the proposed architecture the implementation of it on Online Polling System has been discussed and all the phases of software development have been explained.Comment: 14 pages,1 Figure,1 Tabl

Evaluation of Antioxidant Activity of Cedrela toona Roxb. Leaf Extracts

Antioxidant potency of fruits of Cedrela toona Roxb. crude methanol and its fractionated extracts (hexane, acetone and water) have been investigated, employing three different established in vitro testing systems, such as scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, reducing power assay and β-carotene method. The methanol extract of fruits of Cedrela toona Roxb. showed the best DPPH scavenging activity with the lowest EC 50 34 μg/ml, followed by the acetone (EC 50 39 μg/ml), hexane (EC 50 48 μg/ml) and water extract (EC 50 54 μg/ml). The reducing power of Cedrela toona Roxb. fruit extracts increased steadily with increasing concentrations and varied significantly with different concentrations. The methanol and acetone extracts appeared to possess the highest significant reducing activity among the extracts. The stronger reducing power in the methanol and acetone extracts was probably due to the concentration of antioxidant compounds like flavonoids and phenolics in the extract. In the β-carotene bleaching assay, the antioxidant activities of all the fruits extracts gradually increased with increasing concentration of the extracts and varied significantly with different concentrations. The water extract showed the lowest significant antioxidant activity, while the methanol extract showed the highest significant antioxidant activity. The high antioxidant activity of methanol extract tested using β-carotene model may be correlated with the high phenolic content of the methanol extract.  In conclusion, antioxidant study suggested that fruits of Cedrela toona Roxb. are potential source of natural antioxidants. However, further investigations on in vivo antioxidant activities are highly recommended. In the present study, the antioxidant potency of Cedrela toona Roxb. crude methanol and its fractionated extracts (hexane, acetone and water) have been investigated, employing three different established in vitro testing systems, such as scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, reducing power assay and β-carotene method. There is no antioxidant study reported for Cedrela toona Roxb.Thus, antioxidant activity of Cedrela toona Roxb. was evaluated as it had not been determined previously

Supporting Vermont Families in Packing Healthy Lunches for Children in Childcare

Introduction. Partnering with Hunger Free Vermont, an organization that works to end hunger and malnutrition across the state, we investigated the nutritional value of the packed meals parents provide for their children in early childcare. The USDA\u27s My Plate resource was used as a measure to assess variety, dividing foods into five groups: grains, dairy, vegetables, fruits, and protein. The results will help Hunger Free Vermont design nutrition education materials for childcare centers to provide to the families they serve. Methods. Online surveys were distributed, asking parents to report the foods they recently provided for their children in packed lunches, to rate how \u27healthy\u27 they thought those lunches were, and to note any barriers they experience to packing healthy foods. Results. Survey results showed that the average number of sweets packed by parents who had low confidence in their ability to pack healthy meals was significantly higher than the average number packed by parents with high confidence (p \u3c 0.05). Additionally, the total number of cited barriers was significantly higher in parents who had low confidence in their ability to pack healthy meals (p \u3c 0.01). Conclusions. Many parents cited time constraints and ‘picky’ children as barriers to providing healthy meals, with concerns about the expense of healthy items and lack of childcare for shopping or food-prep time following close behind. In the future, education materials that address children’s unhealthy food preferences or further investigations into barriers to providing healthy lunches may facilitate development of resources for Vermont families.https://scholarworks.uvm.edu/comphp_gallery/1259/thumbnail.jp

Comparison of etomidate and propofol as an induction agent to study hemodynamic effects and serum cortisol level following endotracheal intubation in hypertensive patients

Background: The present study aimed to compare hemodynamic parameters (heart rate, blood pressure) and adverse effects (injection pain, myoclonus, postoperative nausea/vomiting) between Etomidate and propofol groups. Methods: Patients were divided into two groups: Etomidate Group E and a Propofol Group P. All hemodynamic data were measured during induction, intubation, and post-intubation up to 15 min. Intravenous cortisol levels were measured at baseline, just after induction and at 24 hours after induction. Results: At 3 min and 5 min SBP was decreased by 22.04% and 18.39% in Group P. At 3 min there was fall in DBP by 20.13% in group P whereas there was an increase in group E by 0.13% which is statistically significant (p<0.001). At 1 min, 3 min and 5 min after intubation, fall in the MAP by 26.07%, 21.08% and 18.60% in group P and 0.77%, 0.42% and 1.30% in group E (p value <0.001). Serum cortisol level immediate after surgery was decrease (54%) in Group E (p value <0.001). In Group P, 40% of the patients and in group E 16.66 % of the patients complained of pain on injection (p value 0.046). Conclusions: The cortisol suppression by Etomidate may be beneficial for intubation stress response. Etomidate is better for its hemodynamic stability over propofol

Comparative study of bupivacaine alone and bupivacaine along with buprenorphine in axillary brachial plexus block: a prospective, randomized, single blind study

Background: Different additives have been used to prolong brachial plexus block. We performed a prospective, randomized single-blind study to compare Bupivacaine alone and Bupivacaine along with Buprenorphine for onset, quality, and duration of block as well as post-operative analgesia and any complication in axillary brachial- plexus block.Methods: Randomized controlled study was carried out among 60 patients of either sex, aged 20-60 years. ASA grade I or II undergoing elective hand, forearm, elbow surgery under axillary brachial plexus block. Patients were randomly divided into two groups.Group-l received 30 ml of 0.35% Bupivacaine alone in axillary block.Group-II received 30 ml of 0.35% Bupivacaine with 3µg/kg Buprenorphine in axillary block. Time taken for onset and completion of motor and sensory block as well as complete duration of block were noted in both groups. Any complication during procedure, during surgery as well as post-operatively were noted and treated.Results: Addition of Buprenorphine (3µg/kg) to Bupivacaine mixture in peripheral nerve block did not affected the onset time for motor as well as sensory block. Mean duration of motor block was 284.33±78.94 mins. in group I and in group II 307.33±60.26 mins. Mean duration of sensory block 305.066±83.64 mins. in group I while 580.166±111.45 mins. in group II. It suggests duration of sensory block was prolonged in group II then group I.Conclusions: Addition of Buprenorphine to local anesthetic drug provides good post-operative analgesia. Buprenorphine significantly prolongs sensory block and lengthens duration of analgesia without prolonging duration of motor block