sditelberg's blog

In the article “I Feel You: Emotional Mirror Neurons Found in the Rat,” published in Current Biology and from neurosciencenews.com (https://neurosciencenews.com/emotional-mirror-neurons-rats-11066/), the researchers found that mirror neurons in the anterior cingulate cortex respond to pain experienced by others. This article interests me because although I have learned about empathy in social psychology, I have not viewed it from the biological perspective. It is fascinating to be able to pinpoint a neuronal link to this complex social phenomenon and I hope we are able to uncover more of these links within my lifetime.

    In this study, researchers speculated that the cingulate cortex contains mirror neurons and that this is the reason why we feel pain seeing the pain of others. To examine this, researchers observed rats who were watching other rats receive an unpleasant stimulus. Rats tend to freeze when scared to avoid being detected by predators, and the researchers observed this behavior when rats watched other rats receiving this unpleasant stimulus. Upon inspection of the cingulate cortex, it was found that the observing rats activated the same neurons as the rats that received this stimulus, supporting this mirror neuron speculation. The researchers also administered a drug to these observing rats that suppressed the activity of these cingulate cortex cells and found that the rats no longer froze. This was an important find as previously, mirror neurons had only been found in the motor system.

Metastatic pancreatic adenocarcinoma is driven by cancer stem cells, formation and upregulation of the metastatic niche, EMT, and the largely hypoxic state of the tumor microenvironment (TME). Cancer stem cells are the central drivers of metastasis due to their inherent plasticities and contribute to chemoresistance, functioning of the premetastatic niche, and induction of EMT (Sancho et al. 2016). In the premetastatic niche, extracellular signaling contributes to a TME that facilitates the development of the cancer. EMT allows cancer cells to detach from a tumor site, relocalize, and change their phenotype to a less differentiated state. When tumor growth reaches a critical point, cancerous cells deprive their environments of oxygen, resulting in hypoxia and potential metabolic shifts including the Warburg effect or oxidative phosphorylation (Sancho et al. 2016).

The first biome has a climate diagram similar to that of a tropical rainforest or savanna on Earth, although there are a few key differences. The temperature pattern throughout the year ranges from about 5℃ in the winter months to about 25℃ in the summer months. The precipitation pattern is high throughout the year but drops significantly during the summer months. In a tropical rainforest biome on Earth, there is high precipitation throughout the year but a period of low precipitation in the summer, much like Biome 1 on the mystery planet. Also like Biome 1, the temperature pattern in a tropical rainforest or savanna is relatively constant throughout the year, the values just differ greatly. Based on the temperature values as well as the precipitation pattern, I would expect Biome 1 to be located close to the equator of this planet, provided the planet is farther away from the Sun than Earth is in its solar system, since the temperature range is closer to what would be found in Earth’s more temperate zones. Due to the precipitation pattern, I would expect the vegetation to be similar to the vegetation in Earth’s tropical rainforest biome. However, due to the temperature pattern, I would expect the vegetation to be similar to Earth’s temperate shrubland biome. Therefore, I would expect this biome to have vegetation with lots of foliage due to the precipitation, but I would also expect the vegetation to be able to withstand colder temperatures. Perhaps these plants would have the hardiness of an evergreen tree but the leaves of tropical trees.

Based on the current literature and to maximize engineering efficiency of treatment, the researchers plan on engineering two liposomes to successfully eliminate all PaCSCs throughout the body. One liposome will encompass the metabolic treatments and include phenformin (OXPHOS inhibitor), devimistat (Krebs cycle inhibitor), RRx-001 (c-Myc inhibitor), auranofin (glycolysis inhibitor), and ONC201 (Akt/ERK inhibitor, TRAIL regulator). The second liposome will encompass the self-renewal treatments and include navicixizumab (bispecific antibody for VEGFR and DLL4 in Notch), a bispecific antibody for VEGFR and JAG2 in Notch, vantictumab (frizzled receptor inhibitor), PRI-724 (β-catenin inhibitor), LGK974 (small molecule porcupine inhibitor), ETC-159 (small molecule porcupine inhibitor), BMS-833923 (smoothened inhibitor), and PF-0444913 (smoothened inhibitor). Both liposomes will be decorated with PaCSC specific antibodies that bind to PaCSC specific antigens cluster of differentiation 44 (CD44), cluster of differentiation 24 (CD24), and epidermal surface antigen (ESA) to ensure targeted delivery to cancerous stem cells. Cells positive to all these antigens had a 100-fold increased tumorigenic potential compared to non-tumorigenic pancreatic cancer cells (Lee et al. 2016). The researchers will therefore incorporate three monoclonal antibodies, one for each of these antigens, into the membranes of the two liposomes.

Metastatic pancreatic adenocarcinoma is driven by cancer stem cells, formation and upregulation of the premetastatic/metastatic niche, EMT, and the largely hypoxic state of the tumor microenvironment (TME). These characteristics of metastasis feed into each other continuously to further the development and distribution of the cancer. Cancer stem cells serve as the central driver of metastasis due to their inherent plasticities and contribute to chemoresistance, functioning of the premetastatic niche, and induction of EMT (Sancho et al. 2016). In the premetastatic niche, extracellular signaling contributes to a TME that facilitates the development of the cancer. EMT allows cancer cells to detach from a tumor site and relocalize, as well as change their phenotype to a less differentiated state. When tumor growth reaches a critical point, cancerous cells deprive their environments of oxygen, leading to hypoxia and potential metabolic shifts such as the Warburg effect or oxidative phosphorylation (Sancho et al. 2016).

It is essential for the three monoclonal antibodies for CD44, CD24, and ESA to bind to only PaCSCs. Although these antigens are overabundant in PaCSCs, variants may also be expressed in healthy pancreatic cells. As a result, the liposomes will be engineered so the antibodies will only bind to CD44, CD24, and ESA when these antigens are present in high enough concentrations. Titration assays can determine significant thresholds for these effective antigen concentrations. The liposomes will be administered weekly via intravenous infusion in an aqueous or hydrophilic solution to the patient due to their polar exteriors. Dosage efficiency can be evaluated through repeated titrations for a standardized therapeutic threshold of 95% or greater based on liposomal binding and delivery of contents. After approximately five rounds of treatment, 99.99% of PaCSCs should be eliminated, allowing for a relatively short duration of stem cell therapy.

Waterfowl ethograms for observational studies are of the specific type and can include differing categories of behaviors depending on the organisms observed. Muscovy duck (Cairina moschata) behavioral categories in one ethogram include social and reproductive, agonistic and alert, foraging and related, locomotive, resting and comfort, and other, each of which were further scrutinized into approximately seven observable behaviors (Downs et al. 2017). These were observed in a subtropical, urban university campus. An ethogram of Anas platyrhynchos categorized behavior through locomotion, resting, resting on water, comfort, courtship, agonistic, alert, surface feeding, subsurface feeding, and land feeding (Mason et al. 2013). These were observed in a semi-urban environment. Another ethogram of Anas platyrhynchos categorized behavior through locomotion, ingestion, vigilance, comfort, resting, and aggression (Welsh et al. 2017). These were observed in a rural environment. Although these behavioral categories assist in understanding waterfowl, it is crucial to evaluate when species display them based on their environment. It remains unclear exactly when Anas platyrhynchos display these behaviors on an urban university campus set in a rural environment.

Ethograms serve as useful tools to objectively categorize the behaviors of a species. Early ethologists such as Tinbergen, Lorenz, Frisch, Whitman, Craig, and Huxley utilized ethograms to record the frequencies of instinctive behaviors that occur under specific circumstances (Matthews 2009). These provide a database of behaviors for future researchers to check and further supplement with their own data. There are two different types of ethograms: species and experimental. The species ethogram describes all known behaviors for the given species, whereas the experimental ethogram focuses only on behaviors relevant to the hypothesis being tested.

Phenformin is a potent biguanic OXPHOS complex I inhibitor that has shown greater than 30% tumor growth inhibition in 5 out of 12 pancreatic adenocarcinoma xenograft models (Rajeshkumar et al. 2017). It is more potent than metformin, another OXPHOS complex I inhibitor, which only suppressed tumor growth in 3 out of 12 pancreatic adenocarcinoma xenograft models even at a five-fold higher dose (Rajeshkumar et al. 2017). In contrast to metformin, phenformin does not require a cellular transporter (Iversen et al. 2017) and has been shown to resensitize previously therapy-resistant cancer cells (Matassa et al. 2016). Due to its high efficacy, the researchers plan to incorporate phenformin into their treatment in conjunction with a Krebs cycle inhibitor, devimistat (CPI-613).

The Wnt/β-catenin pathway is another highly conserved pathway involved in cell growth and proliferation, as well as PaCSC self-renewal. In the canonical pathway, Wnt proteins that are modified by porcupine to become lipid-bound bind to frizzled receptor complexes and the co-receptor LRP5/6. The signal is then passed downstream via disheveled, which in its active state inhibits phosphorylation of β-catenin, allowing it to accumulate in the cytoplasm. β-catenin is then translocated to the nucleus, where it forms a transcriptional complex and acts on target genes. RNF43 and ZNRF3 were recently identified as Wnt target genes and negative feedback regulators that are inactivated in pancreatic adenocarcinoma (Zhan et al. 2017). Two regions of the pathway the researchers intend to target include upstream, such as porcupine and frizzled, and downstream between the interaction of β-catenin and its target genes. Small molecule inhibitors of porcupine such as LGK974 and ETC-159 have been highly effective in pancreatic cancer to block signaling (Novartis Pharmaceuticals 2018). The monoclonal antibody Vantictumab blocks frizzled receptors and has shown beneficial effects in treating pancreatic adenocarcinoma when combined with paclitaxel or gemcitabine (Messersmith et al. 2016). Additionally, the small molecule inhibitor PRI-724 has shown promising effects in blocking the interaction between β-catenin and its target genes (PRISM Pharma 2017). The researchers would like to include all of these in their treatment of halting the Wnt pathway, thereby stopping PaCSC self-renewal.