The impact of impaired insulin regulation on severity of SARS-CoV-2 infection: a 2-year retrospective single-center analysis.

Background: The COVID-19 pandemic has caused an international healthcare crisis and produced a large healthcare burden. Diabetes mellitus (DM) is a common disease that can be controlled via pharmacologic agents; however, many patients have poor glycemic control, leading to disease-related complications. DM has been reported in the literature to be associated with increasing morbidity and mortality in COVID-19 patients. The authors aim to assess the associations between glucose homoeostasis and COVID-19 disease severity and mortality. Methods: A retrospective chart review of patients ages 18-100 years of age admitted with COVID-19 between January 2020 and December 2021 was performed. The primary outcome was COVID-19 mortality with respect to haemoglobin A1C levels of less than 5.7%, 5.7-6.4%, and 6.5% and greater. Disease severity was determined by degree of supplemental oxygen requirements (ambient air, low-flow nasal cannula, high-flow nasal cannula, non-invasive mechanical ventilation, and invasive mechanical ventilation). COVID-19 mortality and severity were also compared to blood glucose levels on admission as grouped by less than 200 mg/dl and greater than or equal to 200 mg/dl. Results: A total of 1156 patients were included in the final analysis. There was a statistically significant association between diabetic status and mortality (P=0.0002). Statistical significance was also noted between admission blood glucose ≥200 mg/dl and mortality (P=0.0058) and respiratory disease severity (P=0.0381). A multivariate logistic regression for predicting mortality showed increasing haemoglobin A1C was associated with increased mortality (odds ratio 1.72 with 95% CI of 1.122-2.635). Conclusions: In our 2-year retrospective analysis, there was an association between a diagnosis of DM and COVID-19-related mortality. Hyperglycaemia on admission was found to be statistically significant with mortality in patients diagnosed with COVID-19. Glucose homoeostasis and insulin dysregulation likely play a contributing factor to COVID-19 disease severity and mortality.

Geometric tumor embolic budding characterizes inflammatory breast cancer.

PURPOSE: Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery. METHODS: This study combines experimental studies with two different IBC xenografts with image algorithmic studies utilizing human tissue microarrays (TMAs) of IBC vs non-IBC cases to support a novel hypothesis to explain IBC's sina qua non signature of florid lymphovascular emboli. RESULTS: In the human TMAs, compared to tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which show that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really sets IBC apart is the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers indicate geometric or exponential differences between IBC and non-IBC. In the experimental xenograft studies, Mary-X gives rise to tight spheroids in vitro which exhibit dynamic budding into smaller daughter spheroids whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into smaller daughter emboli in vivo. The mechanism that regulates this involves the generation of E-cad/NTF1, a calpain-mediated cleavage 100 kDa product of 120 kDa full length membrane E-cadherin. Inhibiting this calpain-mediated cleavage of E-cadherin by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides that both penetrate the cell membrane and mimic either the cleavage site or the binding site on E-cadherin, inhibits the generation of E-cad/NTF1 in a dose-dependent manner, reduces spheroid compactness and decreases budding. CONCLUSION: Since E-cad/NFT1 retains the p120ctn binding site but loses the α-and ß-catenin sites, promoting its 360° distribution around the cell's membrane, the vacilating levels of this molecule trigger budding of both the spheroids as well as the emboli. Recurrent and geometric budding of parental emboli into daughter emboli then would account for the plethora of emboli seen in IBC.

The cell of cancer origin provides the most reliable roadmap to its diagnosis, prognosis (biology) and therapy.

Cancers arise from single transformed cells from virtually every organ of the body, divide in a relatively uncontrolled manner, and metastasize widely. A search for a "magic bullet" to precisely diagnose, characterize, and ultimately treat cancer has largely failed because cancer cells do not differ significantly from their organ-specific cells of origin. Instead of searching for genomic, epigenetic, transcriptional, and translational differences between cancers and their cells of origin, we should paradoxically focus on what cancer cells have in common with their untransformed cells of origin. This redirected search will lead to improved diagnostic and therapeutic strategies where therapeutic index considerations and drug-limiting toxicities can largely be circumvented. We cite three cancer examples that illustrate this paradigm-shifting strategy: pseudomyxoma peritonei (PP), metastasis of unknown origin (cancers of unknown primary) (MUO), and cancers that arise from potentially dispensable organs (CAD). In each of these examples, the cell of cancer origin still provides the most reliable road map to its diagnosis, prognosis (biology), and therapy.

Use of constitutive and inducible oncogene-containing iPSCs as surrogates for transgenic mice to study breast oncogenesis.

BACKGROUND: Powerful constitutive and inducible transgenic / bitransgenic / tritransgenic murine models of breast cancer have been used over the past two decades to shed light on the molecular mechanisms by which the given transgenic oncogenes have interacted with other cellular genes and set in motion breast cancer initiation and progression. However, these transgenic models, as in vivo models only, are expensive and restrictive in the opportunities they provide to manipulate the experimental variables that would enable a better understanding of the molecular events related to initial transformation and the target cell being transformed. METHODS: To overcome some of these limitations, we derived oncogene-containing induced pluripotent stem cell (iPSC) clones from tail vein fibroblasts of these transgenic mice and manipulated them both in vitro and in vivo in non-transgenic background mice. We created the iPSC clones with a relatively low M.O.I, producing retroviral integrations which averaged only 1 to 2 sites per retroviral plasmid construct used. RESULTS: Most iPSC clones derived from each group displayed an essentially normal murine karyotype, strong expression of the exogenous reprogrammable genes and significant expression of characteristic endogenous murine surface stem cell markers including SSEA-1 (CD15), PECAM-1 (CD31), Ep-Cam (CD326), and Nectin (CD112), but no expression of their transgene. A majority (75%) of iPSC clones displayed a normal murine karyotype but 25% exhibited a genomically unstable karyotype. However, even these later clones exhibited stable and characteristic iPSC properties. When injected orthotopically, select iPSC clones, either constitutive or inducible, no longer expressed their exogenous pluripotency reprogramming factors but expressed their oncogenic transgene (PyVT or ErbB2) and participated in both breast ontogenesis and subsequent oncogenesis. When injected non-orthotopically or when differentiated in vitro along several different non-mammary lineages of differentiation, the iPSC clones failed to do so. Although many clones developed anticipated teratomas, select iPSC clones under the appropriate constitutive or inducible conditions exhibited both breast ontogenesis and oncogenesis through the same stages as exhibited by their transgenic murine parents and, as such, represent transgenic surrogates. CONCLUSIONS: The iPSC clones offer a number of advantages over transgenic mice including cost, the ability to manipulate and tag in vitro, and create an in vitro model of breast ontogeny and oncogenesis that can be used to gain additional insights into the differentiated status of the target cell which is susceptible to transformation. In addition, the use of these oncogene-containing iPSC clones can be used in chemopreventive studies of breast cancer.