Artificial Intelligence and the Challenge for Rural Medicine

Recent advances in artificial intelligence, machine learning, and deep learning are beginning to have an impact on everyday experiences, from natural language processing used in automated telephone call centers to semi-autonomous vehicles. These techniques have also been applied to medical care. In this editorial we discuss applications of AI to medicine and argue for a proactive approach to include rural medicine in this paradigm shift

Leveraging a Public-Private-Academic Collaborative Partnership to confront challenges in the COVID-19 pandemic.

Like all viruses, the SARS-CoV-2 virus mutates over time, creating new viral variants that have the potential to transmit more rapidly, cause more severe disease, or avoid treatment and prevention strategies. A critical component of the public health response to COVID-19 is identifying and tracking emergence of SARS-CoV-2 variants. In West Virginia, this effort is coordinated via a public-private-academic collaboration

Effect of Removing Outliers on Statistical Inference: Implications to Interpretation of Experimental Data in Medical Research

Background Data editing with elimination of “outliers” is commonly performed in the biomedical sciences. The effects of this type of data editing could influence study results, and with the vast and expanding amount of research in medicine, this effect would be magnified. Methods and Results We first performed an anonymous survey of medical school faculty at institutions across the United States and found that indeed some form of outlier exclusion was performed by a large percentage of the respondents to the survey. We next performed Monte Carlo simulations of excluding high and low values from samplings from the same normal distribution. We found that removal of one pair of “outliers”, specifically removal of the high and low values of the two samplings, respectively had measurable effects on the type I error as the sample size was increased into the thousands. We developed an adjustment to the t score that accounts for the anticipated alteration of the type I error (tadj=tobs-2(log(n)^0.5/n^0.5)), and propose that this be used when outliers are eliminated prior to parametric analysis. Conclusion Data editing with elimination of outliers that includes removal of high and low values from two samples, respectively, can have significant effects on the occurrence of type 1 error. This type of data editing could have profound effects in high volume research fields, particularly in medicine, and we recommend an adjustment to the t score be used to reduce the potential for error

Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Receptors

Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell differentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)-dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no effect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR-dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68

RGS16, a novel p53 and pRb cross-talk candidate inhibits migration and invasion of pancreatic cancer cells

Data collected since the discovery of p53 and pRb/RB1 suggests these tumor suppressors cooperate to inhibit tumor progression. Patients who have mutations in both p53 and RB1 genes have increased tumor reoccurrence and decreased survival compared to patients with only one tumor suppressor gene inactivated. It remains unclear how p53 and pRb cooperate toward inhibiting tumorigenesis. Using RNA expression profiling we identified 179 p53 and pRb cross-talk candidates in normal lung fibroblasts (WI38) cells exogenously coexpressing p53 and pRb. Regulator of G protein signaling 16 (RGS16) was among the p53 and pRb cross-talk candidates and has been implicated in inhibiting activation of several oncogenic pathways associated with proliferation, migration, and invasion of cancer cells. RGS16 has been found to be downregulated in pancreatic cancer patients with metastases compared to patients without metastasis. Expression of RGS16 mRNA was decreased in the pancreatic cancer cell lines tested compared to control. Expression of RGS16 inhibited migration of the BxPC-3 and AsPC-1 but not PANC-1 cells and inhibited invasion of BxPC-3 and AsPC-1 cells with no impact on cell viability. We have identified for the first time p53 and pRb cross-talk candidates and a role for RGS16 to inhibit pancreatic cancer migration and invasion

Global analysis of gene expression changes during retinoic acid-induced growth arrest and differentiation of melanoma: comparison to differentially expressed genes in melanocytes vs melanoma

<p>Abstract</p> <p>Background</p> <p>The incidence of malignant melanoma has significantly increased over the last decade. Some of these malignancies are susceptible to the growth inhibitory and pro-differentiating effects of all-<it>trans</it>-retinoic acid (RA). The molecular changes responsible for the biological activity of RA in melanoma are not well understood.</p> <p>Results</p> <p>In an analysis of sequential global gene expression changes during a 4–48 h RA treatment of B16 mouse melanoma cells, we found that RA increased the expression of 757 genes and decreased the expression of 737 genes. We also compared the gene expression profile (no RA treatment) between non-malignant melan-a mouse melanocytes and B16 melanoma cells. Using the same statistical test, we found 1495 genes whose expression was significantly higher in melan-a than in B16 cells and 2054 genes whose expression was significantly lower in melan-a than in B16 cells. By intersecting these two gene sets, we discovered a common set of 233 genes whose RNA levels were significantly different between B16 and melan-a cells and whose expression was altered by RA treatment. Within this set, RA treatment altered the expression of 203 (87%) genes toward the melan-a expression level. In addition, hierarchical clustering showed that after 48 h of RA treatment expression of the 203 genes was more closely related to the melan-a gene set than any other RA treatment time point. Functional analysis of the 203 gene set indicated that RA decreased expression of mRNAs that encode proteins involved in cell division/cell cycle, DNA replication, recombination and repair, and transcription regulation. Conversely, it stimulated genes involved in cell-cell signaling, cell adhesion and cell differentiation/embryonic development. Pathway analysis of the 203 gene set revealed four major hubs of connectivity: CDC2, CHEK1, CDC45L and MCM6.</p> <p>Conclusion</p> <p>Our analysis of common genes in the 48 h RA-treatment of B16 melanoma cells and untreated B16 vs. melan-a data set show that RA "normalized" the expression of genes involved in energy metabolism, DNA replication, DNA repair and differentiation. These results are compatible with the known growth inhibitory and pro-differentiating effects of RA. Pathway analysis suggests that CDC2, CHEK1, CDC45L and MCM6 are key players in mediating the biological activity of RA in B16 melanoma cells.</p

Effect of Removing Outliers on Statistical Inference: Implications to Interpretation of Experimental Data in Medical Research

Background Data editing with elimination of “outliers” is commonly performed in the biomedical sciences. The effects of this type of data editing could influence study results, and with the vast and expanding amount of research in medicine, this effect would be magnified. Methods and Results We first performed an anonymous survey of medical school faculty at institutions across the United States and found that indeed some form of outlier exclusion was performed by a large percentage of the respondents to the survey. We next performed Monte Carlo simulations of excluding high and low values from samplings from the same normal distribution. We found that removal of one pair of “outliers”, specifically removal of the high and low values of the two samplings, respectively had measurable effects on the type I error as the sample size was increased into the thousands. We developed an adjustment to the t score that accounts for the anticipated alteration of the type I error (tadj=tobs-2(log(n)^0.5/n^0.5)), and propose that this be used when outliers are eliminated prior to parametric analysis. Conclusion Data editing with elimination of outliers that includes removal of high and low values from two samples, respectively, can have significant effects on the occurrence of type 1 error. This type of data editing could have profound effects in high volume research fields, particularly in medicine, and we recommend an adjustment to the t score be used to reduce the potential for error

Grainyhead-like 2 inhibits the coactivator p300, suppressing tubulogenesis and the epithelial–mesenchymal transition

Developmental morphogenesis and tumor progression require a transient or stable breakdown of epithelial junctional complexes to permit programmed migration, invasion, and anoikis resistance, characteristics endowed by the epithelial–mesenchymal transition (EMT). The epithelial master-regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses and reverses EMT, causing a mesenchymal–epithelial transition to the default epithelial phenotype. Here we investigated the role of GRHL2 in tubulogenesis of Madin–Darby canine kidney cells, a process requiring transient, partial EMT. GRHL2 was required for cystogenesis, but it suppressed tubulogenesis in response to hepatocyte growth factor. Surprisingly, GRHL2 suppressed this process by inhibiting the histone acetyltransferase coactivator p300, preventing the induction of matrix metalloproteases and other p300-dependent genes required for tubulogenesis. A 13–amino acid region of GRHL2 was necessary for inhibition of p300, suppression of tubulogenesis, and interference with EMT. The results demonstrate that p300 is required for partial or complete EMT occurring in tubulogenesis or tumor progression and that GRHL2 suppresses EMT in both contexts through inhibition of p300

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Background: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations. Objective and Method: In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants. Results: Among the 720 nonsynonymous single nucleotide polymorphisms (SNPs) shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the presenilin 1 (PS1) protein. The presence of this same mutation in a French early-onset Alzheimer’s disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity. Conclusions: Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer’s disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia