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Methods Project Introduction

Submitted by sditelberg on Thu, 02/21/2019 - 17:48

The methods section of a scientific article allows researchers to determine the validity of a study based off of its replicability. When developing an experiment, factors that may interfere with replicability should be controlled in an effort to minimize discrepancies between iterations. The methods project attempts to practice and develop these skills, as well as distinguish between observation and inference through the examination and replication of a multi-panel scientific figure illustrating an interspecific interaction.

    In this project, the interspecific interaction between mallard ducks (Anas platyrhynchos) and Canada geese (Branta canadensis) will be examined. On campus, mallard ducks and Canada geese are commonly found by the pond during the winter months. Due to this proximity, both species often interact with each other in multiple ways. The most commonly observed interaction between these two species is the sharing of their space. The two species are easily photographable together since they are typically not shy, in the same general region, and quite prevalent. Therefore, images taken of them in this environment would be feasibly replicable.

Elements of this process to account for replicability include photography, location, weather, time, and levels of specificity. The location of the ducks and geese are on the pond in the center of campus, making them easy to find. Due to its vast size and the mobility of these two organisms, a camera with zooming capabilities should be chosen to document them individually as well as their interaction. The ducks and geese are typically observed near the end of the pond closest to the Fine Arts Center, either in the water or along the shore. It may take a while for the ducks and geese to trust a human enough to get close for pictures. If it is raining or snowing outside, the ducks and geese are away from the pond, so photography should be performed on a day with fairer weather. The geese, ducks, and their interaction should be photographed with non-specific surroundings to maximize the chances of successful replication. Out of these three images, the interaction of the two species especially should not be particular about the exact location on the pond due to the mobility of these organisms and the size of their environment.

The Engineered Liposome

Submitted by sditelberg on Thu, 02/21/2019 - 17:37

The researchers would like to assess dosage efficiency through repeated titrations for a standard therapeutic threshold of 50% or greater based on liposomal binding and delivery of its interior components. If a certain percentage of tumor cells are sensitized with each dose, it will allow the researchers to further assess binding efficiencies of the liposome to its targets as well as therapeutic efficiency. Due to its phospholipid bilayer and biochemical interactions with water that hold its structure together, this liposome will be delivered intravenously to the patient suspended in an aqueous or hydrophilic solution. Hydrophilic drugs (ONC201, ABT263, and Cbl) will be located in the interior, while antibodies for pancreatic adenocarcinoma-specific antigens (CA 19-9, MUC-1, and NT5E) will be dispersed among the exterior.

Apoptosis Background

Submitted by sditelberg on Wed, 02/20/2019 - 15:15

Apoptosis is a crucial cellular function that can become misregulated in cancers, along with cell growth and proliferation. It can be activated in multiple ways throughout the cell, but is mainly characterized by two pathways: intrinsic and extrinsic. The intrinsic pathway is activated in response to cellular stress, which then affects the mitochondria either by swelling through pores or increasing permeability of the membranes (Kroemer et al. 2007). Second mitochondria-derived activator of caspases (SMAC) proteins are then released into the cytoplasm, which deactivate inhibitor of apoptosis proteins (IAPs), allowing the caspases involved in apoptosis to become active (Fesik and Shi, 2001). The extrinsic pathway of apoptosis is activated in response to external signals, which bind to receptors of the tumor necrosis factor (TNF) families. The binding of these ligands to their receptors can activate caspases and indirectly activate transcription factors involved in the inflammatory response and cell death (Adler 2007).

Liposomal Therapy Additions

Submitted by sditelberg on Tue, 02/19/2019 - 08:46

It is crucial for the selected antibodies on the liposome to work in conjunction with each other to bind to only pancreatic adenocarcinoma tumor cells. Although their respective antigens are overexpressed in tumors, they may be still present in lower concentrations in healthy cells. Therefore, the liposome would be best engineered for the antibodies to only bind to antigens when the displayed antigens are present in high enough concentrations. This threshold could be determined through titration experiments until the effective concentrations of antigens are achieved. The use of liposomal therapy also appeals to the researchers due to its adaptability and lower toxicity. In a study involving paclitaxel, the liposomal form induced fewer cardiovascular and hematologic complications than the standard form (Huang et al. 2018). Encapsulation efficiency has also been measured by injection of a doxorubicin liposomal solution into liquid chromatography (Yamamoto et al. 2018). The researchers would like to use this method to further assess liposomal drug delivery.

Methods Project Introduction

Submitted by sditelberg on Mon, 02/18/2019 - 11:10

The methods section of a scientific article allows researchers to determine the validity of a study based off of replicability. When developing an experiment, certain factors that may affect the replicability of a study should be controlled in an effort to minimize discrepancies between iterations. The methods project attempts to practice and develop these skills, as well as distinguish between observation and inference through the examination and replication of a multi-panel figure illustrating an interspecific interaction.

    The interspecific interaction between mallard ducks (Anas platyrhynchos) and canada geese (Branta canadensis) will be examined in this project. At UMass, mallard ducks and canada geese are commonly found around or near the campus pond during the winter months. As a result, both species often interact with each other in multiple ways. The most commonly observed interaction between these two species is the sharing of space on the campus pond. These two species are easily photographable together since they are typically not shy, in the same general region, and quite prevalent. Therefore, images of them in this environment would be feasibly replicable.

Elements of this process to take into account for replicability include photography, location, weather, time, and levels of specificity. The location of the ducks and geese are on the campus pond, which is in the center of campus, making it easy to find. Due to its vast size and the mobility of these two organisms, a camera with zooming capabilities should be chosen to document their interaction as well as the organisms individually. The ducks and geese are typically observed near the end of the campus pond closest to the Fine Arts Center, either swimming or along the shore. It may take a while for the ducks and geese to trust a human enough to get close for pictures. If it is raining or snowing outside, the ducks and geese are away from the campus pond, so photography should be performed on a day with fairer weather. Pictures of the geese, ducks, and their interaction should be made as broadly as possible to maximize the chances of successful replication. Out of these three images, the interaction especially should not be particular about exact location on the campus pond due to the mobility of these organisms and the size of their environment.

Liposomal Drug Delivery Backup and Extensions

Submitted by sditelberg on Sun, 02/17/2019 - 15:10

An estimated 10-15% of pancreatic adenocarcinomas are attributed to genetic causes (Klein 2012). Germline mutations in the BRCA1 and BRCA2 genes are the most common, occurring in 13-19% of families (Lal et al. 2000). The PALB2 and ATM genes are also some that are commonly mutated in hereditary pancreatic adenocarcinomas (Jones et al. 2009). These mutations could be further examined in an effort to detect pancreatic adenocarcinoma earlier in those that are at higher risk. An early screening mechanism of detecting pancreatic adenocarcinoma in patients, regardless of family history, would be significantly beneficial in increasing survivability.

In terms of resistance to the developed ONC201 liposome treatment, a fluorinated-ONC201 analogue, ONC212, has been developed and has shown preclinical efficacy in melanomas and hepatocellular models. A study demonstrated ONC212’s efficacy in in vivo models with ONC201-resistant tumors (Lev et al. 2017). The researchers found an effective combination of ONC212 with the inhibitor AG1024 in vivo for pancreatic adenocarcinoma. ONC212 is effective in pancreatic adenocarcinomas alone and in combination with other drugs such as 5-fluorouracil, irinotecan, oxaliplatin, and RTK inhibitor crizotinib (Lev et al. 2017). This may serve as a backup treatment if resistance to ONC201 develops, and another synergistic combination may be developed from these drugs.

Treatment Analysis of Liposomal Drug Delivery

Submitted by sditelberg on Sat, 02/16/2019 - 13:16

Regarding the liposome decorated with TAB004 and an antibody for CA 19-9 on the exterior and ONC201 along with another synergistic drug on the interior, blood tests for antigen biomarkers could be run and evaluated. The CA 19-9 radioimmunoassay (RIA) measures the amount of CA 19-9 in the blood (Pancreatic Cancer Action Network, 2019). CA 19-9 can either be bound to the surface of pancreatic adenocarcinoma cells or secreted by them, so this test can serve as a marker for treatment success. Changes in the levels of CA 19-9 in the blood would allow the researchers to assess the progression of the tumor and see if it is growing, shrinking, or maintaining its size. The normal CA 19-9 range in a healthy individual is 0-37 units per millimeter. Rising levels would indicate progression of the cancer, consistent levels would indicate the cancer has stabilized, and declining CA 19-9 levels would indicate shrinkage (Pancreatic Cancer Action Network, 2019). The researchers would assess this biomarker biweekly. An analogous test for MUC-1 will also be developed and performed by the researchers in an effort to fully assay the targeted treatment. An increase of MUC-1 in the blood would indicate growth, consistent levels would indicate stability, and decreasing levels would imply shrinkage of the tumor. The researchers would also like to develop a method to assess binding affinities of pancreatic adenocarcinoma-specific antigens to the respective antibodies in order to determine the efficacy of the treatment.

Observations and Inferences Page 25

Submitted by sditelberg on Fri, 02/15/2019 - 14:53

On page 25, there are a lot of differences between the two figure compilations created. I observe that the group on the left is smaller in size than the one on the right. The images of the flower in the compilation on the left have longer widths and shorter heights than the ones on the right. The image compilation on the right has labels in the top left corner of each image while the compilation on the left does not. The spacing between the images in each compilation is also different: the compilation on the left is more spaced while the one on the right is closer together. These could all be a result of lack of specificity when formatting the images on Inkscape. For example, the heights and widths of the image, as well as their spacing apart from each other, may not have been described in adequate detail.
There are also subtle differences between the two compilations that become apparent upon closer examination. In the compilation on the right, the image of the map has a slight blue background as opposed to the image of the map on the left, that has a white background. This causes the map on the left to blend into the background of the entire compilation. The map on the right also has less of Middle America highlighted in red than the image of the map on the left. These could also be due to a lack of specificity in formatting description, but could also just be a result of forgetfulness since the details are so minor.
The orientations of each image are also different between the two compilations. The image of the single flower on the left is more zoomed out and in a birds-eye-view orientation in comparison to the corresponding image on the right, which is more zoomed in and has a perspective set on the top and side of the flower. The image of the entire plant on the left is more zoomed out than the one on the right and includes more surroundings of the plant. The image of the entire plant on the right is slightly more zoomed in and oriented to the right. The last image of the map is zoomed in more on the right in comparison to the corresponding image on the left. These could all be due to height differences in the photographer or zoom capabilities of the camera. Perhaps there were different obstacles in the surrounding areas of each plant that caused this contrast in orientation of the images as well.

TRAIL Perfect Paragraph

Submitted by sditelberg on Thu, 02/14/2019 - 22:34

TNF-related apoptotic-inducing ligand (TRAIL) is a naturally-occurring cytokine that assists in initiating the extrinsic apoptotic process. TRAIL is a useful aspect of cancer therapy due to its death receptor binding properties for DR4 and DR5. This must be taken into account when engineering targeted treatments so normal, healthy tissue is not targeted and subsequently destroyed. ONC201, a hydrophilic small molecule, regulates the expression of TRAIL and can be put inside a liposome and transported into pancreatic adenocarcinomas. In an effort to regulate the specificity of this therapy, receptors as well as antibodies can be incorporated into the surface of the liposome that bind to pancreatic adenocarcinoma-specific antigens, such as MUC-1 and CA 19-9. In this way, a more resistant, targeted treatment for this cancer can be developed.

More on ONC201

Submitted by sditelberg on Thu, 02/14/2019 - 22:22

ONC201 also demonstrates synergistic effects with other cancer therapeutics to induce apoptosis in various types of cancers. In a study of glioblastoma, ONC201 synergized with ABT263 (Navitoclax), a small molecule inhibitor of the Bcl-2 protein family and BH3-mimetic, to induce apoptosis. Reduction of tumors were observed in vivo without any adverse side effects or toxicity (Karpel-Massler et al. 2015). In another study involving pancreatic adenocarcinoma, ONC201 activated both extrinsic (TRAIL-caspase-8-dependent) and intrinsic (caspase-9-dependent) apoptosis pathways while synergizing with gemcitabine, a common chemotherapy for this cancer, to inhibit Panc-1 xenograft growth in mice (Zhang et al. 2016). This combination therapy also increased the mice’s survivability.

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