United States

Background
This study aimed to investigate the impact of COVID-19 on perioperative adverse outcomes in patients undergoing Per Oral Endoscopic Myotomy (POEM) procedures. As the COVID-19 pandemic has presented unique challenges in healthcare, understanding its association with adverse outcomes during POEM is crucial for optimizing patient care and management. 

Methods
The study utilized data from the Nationwide Inpatient Sample (NIS) 2020, a comprehensive and nationally representative database. 464% (p&lt;0.001) more likely to experience pulmonary embolism during POEM.
Results
The cohort included 5,776 adults who underwent POEM, with 118 individuals diagnosed with COVID-19. Demographic variables, comorbidities, and perioperative adverse outcomes were examined. Univariable and multivariable logistic regression analyses were conducted to assess the relationship between COVID-19 and adverse outcomes, while controlling for potential confounding factors. Among the cohort, individuals with COVID-19 had higher rates of complications, including pneumonia, DVT or other thromboembolism, pulmonary collapse or atelectasis, pulmonary embolism, and portal vein thrombosis, compared to those without COVID-19 (p&lt;0.001). In the univariable analysis, individuals with COVID-19 254% (p&lt;0.001) more likely to develop pneumonia and 515% (p&lt;0.001) more likely to develop pulmonary embolism during POEM. In the multivariable analysis, after adjusting for age, gender, race, hospital characteristics, region of the country, insurance, and comorbidities, individuals with COVID-19 were 230% (p&lt;0.001) more likely to develop pneumonia and 464% (p&lt;0.001) more likely to experience pulmonary embolism during POEM. 
Conclusion
This study reveals a significant association between COVID-19 and increased risk of perioperative adverse outcomes, particularly pneumonia and pulmonary embolism, in patients undergoing POEM. These findings emphasize the importance of considering COVID-19 status when evaluating perioperative risks and implementing appropriate preventive measures to improve patient outcomes. The results underscore the need for tailored approaches to mitigate the impact of COVID-19 in the perioperative period and enhance patient safety.


AMA Research Challenge 2023

Perioperative Outcomes in Patients Undergoing Per Oral Endoscopic Myotomy (POEM) During the COVID 19 pandemic, a Nationally Representative Study

Background
This study aimed to investigate the impact of COVID-19 on perioperative adverse outcomes in patients undergoing Per Oral Endoscopic Myotomy (POEM) procedures. As the COVID-19 pandemic has presented unique challenges in healthcare, understanding its association with adverse outcomes during POEM is crucial for optimizing patient care and management. 

Methods
The study utilized data from the Nationwide Inpatient Sample (NIS) 2020, a comprehensive and nationally representative database. 464% (p<0.001) more likely to experience pulmonary embolism during POEM.
Results
The cohort included 5,776 adults who underwent POEM, with 118 individuals diagnosed with COVID-19. Demographic variables, comorbidities, and perioperative adverse outcomes were examined. Univariable and multivariable logistic regression analyses were conducted to assess the relationship between COVID-19 and adverse outcomes, while controlling for potential confounding factors. Among the cohort, individuals with COVID-19 had higher rates of complications, including pneumonia, DVT or other thromboembolism, pulmonary collapse or atelectasis, pulmonary embolism, and portal vein thrombosis, compared to those without COVID-19 (p<0.001). In the univariable analysis, individuals with COVID-19 254% (p<0.001) more likely to develop pneumonia and 515% (p<0.001) more likely to develop pulmonary embolism during POEM. In the multivariable analysis, after adjusting for age, gender, race, hospital characteristics, region of the country, insurance, and comorbidities, individuals with COVID-19 were 230% (p<0.001) more likely to develop pneumonia and 464% (p<0.001) more likely to experience pulmonary embolism during POEM. 
Conclusion
This study reveals a significant association between COVID-19 and increased risk of perioperative adverse outcomes, particularly pneumonia and pulmonary embolism, in patients undergoing POEM. These findings emphasize the importance of considering COVID-19 status when evaluating perioperative risks and implementing appropriate preventive measures to improve patient outcomes. The results underscore the need for tailored approaches to mitigate the impact of COVID-19 in the perioperative period and enhance patient safety.

poster

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Background: Intraductal Papillary Mucinous Neoplasms (IPMNs) are the most common subset of cystic neoplasms and are currently only managed by surgery and surveillance; however, because pancreatic surgery proves to be an unnecessary risk in benign cases, an alternative treatment plan is crucial. Previous experimentation showed that IPMNs exhibited higher levels of MAP kinase, a signaling cascade that regulates cell proliferation and differentiation, than pancreatic ductal adenocarcinoma (PDAC). We hypothesized that IPMNs would be more susceptible to MEK (upstream regulator in the MAP kinase pathway) inhibition than conventional PDAC cells due to the significant increase of MAPK phosphorylation in IPMNs.

Methods: 4619 cells were obtained from a mouse PDAC tumor carrying mutations in Kras and Trp53; 4838 cells were obtained from a mouse IPMN tumor carrying mutations in Kras and Gnas (doxycycline-inducible). Cells were treated with 1 ug/ml doxycycline for 24hr prior to treatment. Gene expression was determined by RT-qPCR at 24hr of 100nM Trametinib or vehicle (DMSO) normalizing to Pmm1 levels. Western blotting for phospho-ERK 1/2, total ERK1/2, and GAPDH was used to control for trametinib efficiency. Growth was determined by MT Viability Assay, following indicated concentrations of Trametinib at the indicated timepoints.

Results: Trametinib significantly inhibited expression of Aqp5 in both PDAC and IPMN cells. Mki67 fold change showed a significant decrease in both lines with Trametinib whereas Pcna fold change was significant between PDAC Trametinib vs. vehicle but not in the IPMN line. No significance was noted for Gnas, Spdef, Cdkn2a, and Cdkn1a. Growth and proliferation curves showed the highest concentration of Trametinib (100 nM) prohibiting growth the most in both cell lines.

Conclusion: MEK inhibition had similar effects on PDAC and IPMN cells. Trametinib decreased expression of proliferation markers similarly in both cell lines, consistent with a similar inhibition of growth. Expression of growth arrest markers was unaffected by trametinib. The role of MEK in regulating Aqp5 is novel and will be pursued in future experiments. These experiments were performed in 10% fetal bovine serum which is highly growth stimulatory. Future experiments could treat cells in low or no serum to determine if Trametinib has more of an effect under nutrient-limited conditions. Overall, IPMNs need to be studied more regarding their differences from PDAC and the MAP Kinase pathway.

Role of MAP Kinase in IPMN and PDAC

Background
SLC6A4 (SERT) is downregulated in IBD patients and pre-clinical models of IBD. Despite the established roles of serotonin (5-HT) and SERT in maintaining the gut and its microbiome, the mechanisms by which decreased SERT contributes to intestinal inflammation remain unclear.

Methods
SERT KO and WT mice administered Dextran sulfate sodium (DSS) induced chronic colitis underwent fecal and serum metabolomic analysis. Bioinformatic analysis identified enriched metabolic pathways and microbial-related metabolites. Disease severity was evaluated with myeloperoxidase (MPO) activity, RT-PCR, immunoblotting, immunohistochemistry. Tight junction perturbation was assessed by immunofluorescence, Western blotting, RT-PCR and serum endotoxin levels. We computed Spearman correlation coefficients between the abundance of the altered microbial metabolites and disease activity.

Results
SERT knockout (SERT KO) mice induced with chronic colitis revealed increased disease severity. The baseline metabolomic profiles of SERT KO mice resembled those of WT mice with chronic colitis, suggesting a predisposition to metabolic dysregulation. Metabolomic analysis demonstrated distinct profiles in feces and serum associated with chronic colitis in mice mimicking human IBD such as variations in purine and plasmalogen metabolites. SERT deficiency alone led to altered tryptophan metabolism, changes in oxidative metabolism, and dysregulation of phosphatidylcholines and plasmalogens in feces and serum. Mechanistically, SERT deficiency in an inflammatory context led to diminished ileal tight junction expression and increased serum endotoxin levels worsening disease. Furthermore, we identified several microbial metabolites in the feces and serum correlating with disease activity. 

Conclusion
SERT deficiency augmented chronic inflammation induced by DSS, perturbed intestinal barrier dysfunction, and caused microbially influenced metabolic alterations which corresponded to disease activity. The results of this study highlight novel changes in both host-derived and bacteria-derived serum metabolites and fecal metabolites occurring due to the loss of SERT. These findings demonstrate the functionally disruptive role of SERT in metabolic pathways associated with IBD and suggest potential therapeutic targets for intestinal inflammation.


Serotonin transporter deficiency-driven metabolomic derangements drive intestinal inflammation

There is a role for the gut virome in numerous dysbiosis-associated states including obesity, inflammatory bowel diseases, and C. difficile infection. These findings are likely related to the ecological function of bacteriophages (phages) in regulating the structure, composition, and diversity of the gut microbiome. Dysregulation in the gut phage community may therefore lead to microbiome dysbiosis. To study whether exogenous phage administration may have therapeutic potential as a treatment for dysbiosis, our lab purified phages from lactic acid bacteria-fermented sauerkraut to test the effect of sauerkraut phages in a mouse model for stress-induced dysbiosis. Stress is strongly associated with dysbiosis, decreased microbiome diversity, and the growth of pro-inflammatory bacteria in the gut microbiome. Sauerkraut and other fermented foods have been shown to promote microbiome diversity and our lab hypothesized that phages may have a role in mediating this effect.

Bacteriophages derived from fermented food increase cecal microbiome diversity in the setting of stress-induced dysbiosis

Background: From neoangiogenesis to tissue regeneration, the greater omentum has been used in a variety of unlikely, but innovative ways in surgical research. Despite its surgical importance, the greater omentum’s anatomy has not been systematically characterized. Previously collected cadaveric omenta revealed statistical differences between sex and omental mass and volume without any available information on BMI. This research will continue to collect greater omenta metrics and further investigate the role of BMI in biometrics using cadaveric omenta and estimations of stature and body mass.  

Methods: Greater omenta were collected and measured from 30 embalmed cadavers. Maximum femoral length (MFL) and femoral head diameter (FHD) were collected from each respective cadaver to estimate height and weight, respectively. Statistical analysis using R compared anatomical parameters with age, sex, body mass, stature, and BMI using a student’s t-test and linear regression.   

Results: Sex differences in omental mass, volume, and surface area (P < 0.05). Sex differences in estimated body mass, stature, and BMI (P < 0.01). Age negatively correlated with estimated BMI, stature, and body mass (P < 0.001). Age negatively correlated with omental length (P < 0.05). Estimated stature positively correlated with omental biometrics, body mass, and BMI (P < 0.001). 

Conclusion: Recent studies claim that BMI plays a role in omental biometrics. Since height, weight, and BMI were unavailable from the cadavers, this research used published equations to estimate body mass and stature. Omental mass, volume, and surface area demonstrated significant differences between males and females, correlating well with the significant differences between anthropometrics between sexes. Omental mass and volumes were positively correlated with estimated cadaver height. Omental length, estimated stature, body mass, and BMI decrease with increased age. Future studies aim to validate cadaveric height with estimated stature as well as increase sample size. Delineating the factors that influence omental biometrics will improve predicted omental size prior to operation.

Gaining Momentum on the Greater Omentum’s Biometric Correlation with Human Size

The neuropeptide hormone, endothelin (specially, ET-1) plays an important role in the invasiveness of breast cancer. High ET-1 levels are associated with decreased disease-specific survival. Very few studies highlight the differential expression of ET-1 and its receptors ETAR and ETBR among triple negative breast cancer (TNBC), non-TNBC, and normal phenotypes. The purpose of the present study was to find out whether the expression of ET-1, ETAR and ETBR is higher in TNBC cells versus non-TNBC and normal cells. An association between higher expression of ET-1 axis and promotion of aggressive TNBC phenotype could represent ET-1 axis as useful biomarkers of TNBC prognosis and potential therapeutic targets. Our hypothesis is that expression levels of ET-1 and its receptors might play an important role in the development and progression of TNBC cells as compared to non-TNBC and normal cells. We aimed to assess the possible prognostic and predictive values of ET-1, ETAR and ETBR by studying their mRNA expression and protein levels in TNBC and non-TNBC via formalin fixed paraffin embedded breast tissue from 4 subjects with TNBC and 4 normal subjects, representing non-TNBC. Western blot, immunofluorescent, and immunohistochemical analysis served to quantify the differential expression. Results from Western Blotting showed ET1 levels were 81.6% higher, ETAR levels were 35% higher, and ETBR levels were 30% higher in TNBC vs non-TNBC cell lines. Immunofluorescence revealed greater intensity of ETBR in all cell lines compared to ETAR, greater expression of ET-1 and ETBR in TNBC cell lines, HCC-1806 and MDA- 231, and greater expression of ETBR in the nucleus of all cell lines and of all proteins in MDA- 231. Immunohistochemistry visually depicted greater staining of ET1, ETAR, and ETBR and quantitatively showed approximately 20% higher ET1, 40% higher ETAR, and 20% higher ETBR positive cells in TNBC vs normal breast tissue. Due to the similar results obtained from Western blot analysis with cell lines and immunohistochemical analysis with breast tissue, our hypothesis that expression of ET-1 and its receptors is higher In TNBC than non- TNBC and control is validated and thus could guide subsequent investigations for targeted pharmaceuticals against these biomarkers in TNBC.

Differential Expression of Endothelin-l (ET1) and its receptors, Endothelin Receptor Type A (ETAR) and Endothelin Receptor Type B (ETBR) between subjects with Normal, Triple

Background: Decidua natural killer (dNK) cells accumulate at the maternal-fetal interface during implantation and placentation. These cells are CD56brightCD16dim/neg, poorly cytotoxic, anti-inflammatory, and proangiogenic; characteristics shared by tumor infiltrated NK cells. We, and others, found that peripheral blood NK cells (pNK; CD56dimCD16bright) can be converted to dNK-like cells in vitro by exposure to hypoxia (1% O2) or TGFβ. However, it is unknown whether mechanisms driving these alterations are analogous or independent. We hypothesized that hypoxia inducible factor (HIF)1α, a known driver of VEGF, also induces TGFβ receptors to suppress NK function.

Methods: Healthy donors (HD) and kidney cancer (KCa) patient pNK were purified by negative selection. Flow cytometry, RT-qPCR, and ELISA assessed expression of NK markers (CD56, CD16), TGFβ receptors (R1, R2), and VEGF. HD pNK cells were cultured in 21% or 1% O2 and in presence or absence of TGFβ (2ng/mL). Functional conversion of HD pNK to dNK-like cells was gauged by VEGF and cytotoxicity. The impact of hypoxia on TGFβ receptors was assessed for pNK exposed to 1% O2 versuses 21% O2, and HIF1α-specific effects determined for cells transduced with lentivirus to overexpress HIF1α. Statistics (ANOVA/t-test) were performed using GraphPad Prism with p0.05 considered significant.

Results: Purity of HD/KCa pNK cells was ≥87%. Compared to HD pNK (n=3), RCC pNK (n=4) had significantly higher expression of TGFβ-R1 and TGFβ-R2, and 40% lower cytotoxic activity. HD pNK cells cultured under 21% O2 were potently cytotoxic, but hypoxia or TGFβ decreased cytotoxicity by 55% and 61%, respectively. Only hypoxia upregulated VEGF mRNA (10-fold) and protein (3-fold). The combination of hypoxia and TGFβ abolished cytotoxicity by ≥88%, but VEGF expression was not increased further. In both cohorts, hypoxia upregulated all TGFβ receptors, but particularly TGFβ-R2. Finally, HIF1α overexpression increased TGFβ-R2 levels (3.5-fold).

Conclusions: Hypoxia and TGFβ independently suppressed pNK cytotoxicity, but induction of VEGF and TGFβ receptors, particularly TGFβ-R2, was unique to hypoxia. In combination, hypoxia and TGFβ potently inhibited cytotoxicity, with no additive effect on VEGF or TGFβ-R2 expression. HIF1α overexpression confirmed these hypoxia-specific effects. These studies support dual roles for hypoxia and TGFβ in dNK-like conversion. While both independently and cooperatively impact cytotoxicity, hypoxia-induced HIF1α specifically drives VEGF and TGFβ-R2 expression changes. These cellular conversions are conceivably beneficial for placentation, but exploited to support tumor growth. Thus, regulation of HIF1α and consequential NK sensitization to TGFβ likely has implications both for healthy pregnancy and cancer therapy.

Hypoxia drives functional conversion of human peripheral blood NK cells to decidua-like NK cells through TGFβ receptor induction and sensitization

Hypoxia, or low oxygen, is a common feature of solid tumors correlating with poor survival in cancer patients. Tumors attempt to re-acquire oxygen by forming new blood vessels from nearby, pre-existing vessels, a process known as angiogenesis. In tumors, angiogenesis is notoriously dysfunctional resulting in leaky, under-perfused blood vessels which cannot adequately deliver oxygen and exacerbates hypoxia. One important immune cell affected by hypoxia is the macrophage. Normally, macrophages activate killer T cells to eliminate cancer and promote new blood vessel formation. However, tumor-associated macrophages (TAMs) suppress the proliferation and activity of killer T cells preventing them from eliminating cancer cells, and TAM overactivation leads to dysfunctional angiogenesis that perpetuates the treatment-resistant, hypoxic tumor environment. Thus, molecular mechanisms in which macrophages respond to hypoxia has been investigated as potential therapeutic targets. Hypoxia stabilizes hypoxia inducible transcription factor HIF-1α. Our previous work suggested HIF-1α prompts a pro-hypoxic phenotype in macrophages. We hypothesize that macrophage HIF-1α affects the recruitment of macrophage precursors, free endothelial cells, and T cells throughout tumor progression. Understanding where these differences occur may provide insight as to when best to start treatment or when treatment is no longer effective. 


Hypoxia regulates vessel-modifying macrophages and vice versa in solid tumors


Background: Sterile inflammation and constitutive activation of pro-fibrotic cells in the stromal vascular fraction (SVF) of adipose tissue (AT) are hallmarks of obesity. Macrophages and AT progenitors play a key role in the development and progression of this pathology in fat depots. EphB2, a member of the EphB receptors, has been reported to promote hepatic and renal fibrogenesis in mice. The goal of this investigation is to test the hypothesis that defective EphB2 signalling in macrophages could potentially mitigate adipose tissue fibro-inflammation and insulin resistance in obesity. 

Methods: Disease phenotyping was performed in males and females' wild type (WT); EphB2KO (EphB2-/-); leptin-deficient ob/ob mice and in EphB2 specific deletion in macrophages (Cre+). Mice with EphB2-specific deletion in macrophages were generated by crossing EphB2-flox/flox mice with CSF1R-iMer-Cre-iMer & CX3CR1-CreERT2 and phenotype induced with tamoxifen. Mice were fed the obesogenic Gubra-Amylin NASH (GAN) diet for 6-26 weeks. Weight was recorded and glucose tolerance test (GTT) and Insulin tolerance test (ITT) performed. Mice were euthanized at the end of the study via isoflurane anesthesia in nonfasted state; liver tissue, inguinal white adipose tissue (iWAT), brown adipose tissue (BAT), epididymal white adipose tissue (eWAT) and heart were collected and weighed. Histology (H&E, Masson-trichrome and phosphor-EphB2 immunohistochemistry) was performed in iWAT and eWAT. Stromal vascular fraction and adipocyte were isolated from iWAT and eWAT and subjected to flow cytometry, and qPCR. 

Results: EphB2 receptors and EfnB2 ligands mRNA transcripts are upregulated in fat depots and liver of ob/ob mice. H&E staining, and Masson-trichrome staining of iWAT and eWAT, depicting accumulation of immune cells and fibrosis in crown-like structure of these fat depots. Immunohistochemistry of phosphoEphB1/2 shows EphB2 activation in adipose tissue of obese mice in the SVF. EphB2-/- mice displayed a reduced weight and improved glucose tolerance when fed an obesogenic diet compared to EphB2 wild type mice. Deletion of EphB2 in macrophages showed recapitulation of global knockout phenotype and diminished quantity of pro inflammatory M1 macrophages with increased M2 macrophages and polymorphonucleated neutrophils evaluated through flow cytometry. 

Conclusion: EphB/EfnB mRNA transcripts are upregulated in fat depots of obese mice and more specifically in the stromal vascular fraction of iWAT and eWAT. EphB2 signaling is activated in the stromal vascular fraction of eWAT. EphB2 deficiency mitigates weight gain and improves glucose tolerance in DIO mice. Deletion of EphB2 receptor in macrophages reduces weight gain, improves glucose tolerance, and dampens inflammatory response in obese mice producing similar phenotype to that of the global knockout. 


Dysregulation of macrophages EphB2 mitigates diet-induced obesity in mice

Background: Glycans are carbohydrate structures that can be found embedded within glycoproteins or glycolipids. They play an important role in cell membrane structure, cell signaling, and cell adhesions. Abnormal glycan expression caused by genetic mutations or cellular stressors is known in disease states like cancer. Thus, identifying variations of glycan expression in cancer tissue can be useful for diagnosis and staging. Previous research has shown that breast cancer tumor tissue has abnormal high mannose, complex, and hybrid glycan expression when compared to the surrounding unaffected tissue. The goal of our research is to look specifically at which glycans at different stages of breast cancer were abnormally expressed in tumor tissue when compared to the surrounding unaffected tissue.
Methods: Breast tissue tumor samples were collected from 39 breast cancer patients at the time of diagnosis and provided for analysis by the Prisma Health Cancer Institute Biorepository. Breast tissue “controls” were collected via sampling of surrounding unaffected tissue of the same breast cancer patients. Samples were analyzed and glycomic profiles were obtained using MALDI-TOF Mass Spectroscopy by the Emory Glycomics and Molecular Interactions Core. One-way ANOVA statistical analysis was performed using JMP statistical software.
Ó 2023 American Medical Association. All rights reserved.
Results: Significantly elevated expression of a number of glycans from all three groups (high mannose, complex, and hybrid) was detected in stage I breast cancer tumor tissue when compared with the surrounding unaffected breast tissue (p<0.05). In total, we detected 5 high mannose glycans, 19 complex glycans, and 5 hybrid glycans with significantly elevated expression in stage I breast cancer tumor tissue. when compared to the surrounding unaffected tissue.
Conclusion: Our data supports and expands previous research in the area of glycomic profiling of cancers. High mannose glycans have been shown to be elevated in breast and other, and our findings support this data in specifically stage I breast cancer tissue. Elevated expression of complex and hybrid glycans are interesting findings that could be additional promising breast cancer biomarkers for diagnosis, screening, or treatment. Further research into the cellular function of these glycans in cancer could help better understand how cancer progresses and metastasizes.

Elevated glycan expression in stage I breast cancer tumors

Background: Cancer is a leading health concern and the second highest cause of death in the United States. When considering cancer from a genomic standpoint, genes can be divided into two main categories. One category includes oncogenes, which, when mutated, develop a gain of function. The second category consists of tumor suppressor genes, which in mutated state lose their ability to protect the cell. Both oncogenes and tumor suppressor genes are known as cancer-critical genes. This analysis evaluates 50 cancer-critical genes for presence of hotspot mutations affecting various signaling pathways. Specifically, we focused on nine pathways: RTK/RAS/MAP, TGFβ, PI3K, Wnt, GPCR, p53, JAK/STAT, Notch, and the cell cycle pathway. Our study aims to enhance understanding of the impact of hotspot mutations in these 50 cancer-critical genes. Additionally, the study will aim in integration of artificial intelligence (AI) to predict personalized treatments based on the identified mutations.

Methods: We conducted an analysis of previously identified mutations in 35 breast cancer patients and 39 lung cancer patients from the Prisma Health Cancer Institute. We utilized genomic databases, including ClinVar, to gather available information and published literature about these mutations. We analyzed and recorded characteristics of each mutation, including predicted changes in protein folding, clinical significance and associated pathological conditions, possible variations, and affected signaling pathways.

Results: Among the 50 cancer-critical genes previously sequenced for hotspot mutations, we identified a total of 79 different hotspot mutations in the studied group of 74 cancer patients. Notably, for 9 of these mutations we did not find any available information. Furthermore, one mutation (KDR p.Gln472His) exhibited a very high prevalence among cancer patients. We suggest further investigation of this group of mutations for potential clinical significance.

Conclusion: The identified unknown mutations in cancer-critical genes may have clinical significance and require further investigation. The information collected in this study will contribute to the development of a comprehensive cancer patient database accessible to clinicians and researchers. Moreover, the data will be further utilized in AI applications to predict personalized treatment approaches for cancer patients.


Next from AMA Research Challenge 2023

Role of MAP Kinase in IPMN and PDAC