ARTICLE | doi:10.20944/preprints202210.0042.v1
Subject: Arts & Humanities, Philosophy Keywords: Bad Behavior; Institutions; Heterodox Economics; Development
Online: 5 October 2022 (12:43:21 CEST)
How important are institutions for the development of nations? Are there any existing measures which quantify the behavior of institutions? Is there any theoretical justification for measuring their behavior? This paper introduces a framework influenced by Plato’s needs theory to provide justification for measuring the behavior of institutions. This involves introducing the humanization hypothesis which states that the behavior of institutions can be measured as they, similar to human beings, are living entities with similar hierarchical needs which are essential for their survival. The paper employs an explanatory and descriptive research design which is highly theoretical in nature.
ARTICLE | doi:10.20944/preprints202210.0456.v1
Subject: Social Sciences, Library & Information Science Keywords: Bibliometric Analysis; Bad Behavior; Unethical Behavior; Composite Index; Development.
Online: 28 October 2022 (12:14:41 CEST)
Objective. Political instability, corruption, exclusive institutions et al. are some of the hypotheses backed by literature as to why some nations are more developed than others. One hypothesis which has not been intensively studied is the culpability of individual and institutional behavior and its impact on development. To examine the validity of such a hypothesis, a composite index which quantifies such development hindering behavior must be developed. The prelude to developing this index is to investigate whether such a quantitative measure exists to begin with. To achieve this objective, a bibliometric analysis of Scopus and Web of Science databases will be conducted. Method. A bibliometric and content analysis of Scopus and Web of science databases using Excel, VOSviewer, and R software. Results. The findings of the bibliometric analysis indicate the absence of such measure particularly within the scope of ‘bad behavior’, ‘unethical behavior’, and ‘development’. Conclusions. The study findings provide the greenlight to proceed with the construction of the ‘Bad Behavior Index’. Contribution. The practical contribution of this study is that it provides researchers with an improved methodology on how to conduct a bibliometric analysis to identify the absence of knowledge and provide a justification for the creation of such knowledge by integrating and analyzing two journal databases instead of one, using three mediums: Excel, VOSviewer, and R software.
ARTICLE | doi:10.20944/preprints202106.0169.v1
Subject: Life Sciences, Biochemistry Keywords: melanoma initiating cells; CD133; drug resistance; apoptosis; caspase activation; CRISPR-Cas9 knockout; AKT; BAD; BCL-2 family
Online: 7 June 2021 (12:11:10 CEST)
Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC), implicated in tumorigenesis, invasion, and drug resistance, and characterized by elevated expression of stem cell markers, such as CD133. We previously showed that siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. The current study investigates underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockdown or Dox-inducible expression of CD133. To maintain stable expression of CD133, MACS-sorted CD133(+) positive cells were expanded by ROCK-mediated conditional reprogramming of BAKP melanoma cells (BAKR). BAKR showed increased survival via reduced apoptosis after exposure to trametinib or DTIC, compared to BAKP. CRISPR-Cas9- mediated CD133 knockdown in BAKR cells (BAKR-T3) re-sensitized the cells, while CRISPR-Cas9 knockdown of CD133 in parental BAKP and POT cells even further increased trametinib-induced apoptosis (cleaved PARP) by reducing levels of anti-apoptotic BCL-xL, p-AKT, and p-BAD, and increasing pro-apoptotic BAD and active BAX. Dox-induced CD133 overexpression had the opposite effect, and blocked trametinib-induced apoptosis in both cell lines, coincident with elevated p-AKT, p-BAD, BCL-2 and BCL-xL and decreased levels of the active form of BAX and caspases-3 and -9. The roles of CD133 in AKT and BAD phosphorylation, or in the upregulation of anti-apoptotic BCL-2 family members, was further investigated by AKT knockout with siRNA, or inhibition of BCL-2 family members with navitoclax (ABT-263). Similar to CD133 knockdown, AKT1/2 siRNA knockdown in BAKP cells also reduced p-BAD. CD133 knockdown (T3)-mediated reduction of pBAD levels was equivalent in AKT-knockdown or AKT control cells indicating that CD133 may be upstream of AKT signaling. In BAKP cells treated with trametinib and/or ABT-263, effects of ABT-263 mirrored CD133 knockdown, since levels of active BAX and cleaved-PARP in BAKP-SC (CD133-) cells increased to the same level as that exhibited by BAKP-T3 cells (CD133+). CD133 may therefore activate a survival pathway where 1) increased phosphorylation of AKT induces 2) phosphorylation and inactivation of BAD, 3) decrease in the active form of BAX, and 4) reduction in caspase-mediated PARP cleavage, indicating apoptosis suppression leading to drug resistance in melanomas. Targeting survival pathways by which CD133 may confer chemoresistance in MICs can contribute to development of more effective treatments for patients with high-risk melanoma.
ARTICLE | doi:10.20944/preprints201708.0103.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: stem cells; somatic mutations; cancer prevention; carcinogenesis; whole genome sequencing; stem cell division theory of cancer; bad luck of cancer
Online: 30 August 2017 (12:14:52 CEST)
Recent evidence indicates that the risk of being diagnosed with cancer in a tissue is strongly correlated (0.80) with the number of stem cell divisions accumulated by the tissue. Since cell division can generate random mutations during DNA replication, this correlation has been used to propose that cancer is largely caused by the accumulation of unavoidable mutations in driver genes. However, no correlation between the number of gene mutations and cancer risk across tissues has been reported. Because many somatic mutations in cancers originate prior to tumor initiation and the number of cell divisions occurring during tumor growth is similar among tissues, here I use whole genome sequencing information from 22,086 cancer samples and incidence data from the largest cancer registry in each continent to study the relationship between the number of gene mutations and the risk of cancer across 33 tissue types. Results show a weak positive correlation (mean = 0.14) between these two parameters in each of the five cancer registries. The correlation became stronger (mean = 0.50) when gender-related cancers were excluded. Results also show that 1,003 samples from 29 cancer types have zero mutations in genes. These data suggest that cancer etiology can be better explained by the accumulation of stem cell divisions than by the accumulation of gene mutations. Possible mechanisms by which the accumulation of cell divisions in stem cells increases the risk of cancer are discussed.
ARTICLE | doi:10.20944/preprints201905.0213.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Poor prognosis; medically non-beneficial care; futility; breaking bad news; withdrawal of care; miracle; hope; goals of care; communication; health disparities; racial discrimination; ethnocultural discrimination
Online: 16 May 2019 (12:38:38 CEST)
Objective: To recommend how physicians can best respond to families whose hopes for a miracle via divine intervention influence their medical decisions, like, for example, making them not want to withdraw ventilatory support in cases of poor neurologic prognosis because they are still hoping for God to intervene. Methods: Auto-ethnographic analysis of chaplaincy experience in this clinical context yields a nuanced 90-second, point-of-care spiritual intervention physicians can use to address the religious aspect of families who base medical decisions on their hopes for a miracle via divine intervention. Explanation of how spiritual intervention dovetails with existing physician communication protocol for responding to families hoping for a miracle. Results: Spiritual intervention for religious aspect of miracle-hoping families is integrated into existing physician communication protocol for responding to families hoping for a miracle with recommendations for utilization of existing communication technology when necessary. Conclusion: Properly addressing the religious dimension of families hoping for a miracle may be helpful for physicians interested in decreasing their own stress levels, improving outcomes for this clinical context, and ensuring that unintentional discrimination does not perpetuate racial disparities in end-of-life care.