Blood-Based Multiomics-Guided Detection of a Precancerous Pancreatic Tumor.

Over a decade ago, longitudinal multiomics analysis was pioneered for early disease detection and individually tailored precision health interventions. However, high sample processing costs, expansive multiomics measurements along with complex data analysis have made this approach to precision/personalized medicine impractical. Here we describe in a case report, a more practical approach that uses fewer measurements, annual sampling, and faster decision making. We also show how this approach offers promise to detect an exceedingly rare and potentially fatal condition before it fully manifests. Specifically, we describe in the present case report how longitudinal multiomics monitoring (LMOM) helped detect a precancerous pancreatic tumor and led to a successful surgical intervention. The patient, enrolled in an annual blood-based LMOM since 2018, had dramatic changes in the June 2021 and 2022 annual metabolomics and proteomics results that prompted further clinical diagnostic testing for pancreatic cancer. Using abdominal magnetic resonance imaging, a 2.6 cm lesion in the tail of the patient's pancreas was detected. The tumor fluid from an aspiration biopsy had 10,000 times that of normal carcinoembryonic antigen levels. After the tumor was surgically resected, histopathological findings confirmed it was a precancerous pancreatic tumor. Postoperative omics testing indicated that most metabolite and protein levels returned to patient's 2018 levels. This case report illustrates the potentials of blood LMOM for precision/personalized medicine, and new ways of thinking medical innovation for a potentially life-saving early diagnosis of pancreatic cancer. Blood LMOM warrants future programmatic translational research with the goals of precision medicine, and individually tailored cancer diagnoses and treatments.

Sildenafil reverses the hypertrophy of mice right ventricle caused by hypoxia but does not reverse the changes in the myosin heavy chain isoforms.

In this study, we investigated the effect of hypoxia and concomitant sildenafil treatment on MHC isoforms in hypoxia-induced hypertrophied right ventricles. Right ventricular hypertrophy was induced in mice by exposing them to hypoxic stimulus (11% ambient oxygen) in a normobaric chamber for 20 days. 45 mice were used in this study, distributed randomly into three groups: the first group served as a control (CO), the second group was exposed to hypoxia for 20 days without sildenafil treatment (HY), and the third group was given sildenafil orally at a dose of 30 mg.kg-1.day-1 plus exposure to hypoxia for 20 days (HS). Relative amounts of MHC isoforms were calculated using two ELISA kits containing antibodies against α and ß MHC, and by SDS-PAGE. Compared with the CO group, the HY group showed a significant increase in right ventricle weight/left ventricle plus septum ratio (Fulton's ratio). The HS group showed a significant decrease in Fulton's ratio compared with the HY group, but not with the CO group. Expression of the MHC-ß isoform was significantly increased in the HY group compared with the CO group. There was no significant difference in MHC-ß between the HY group and the HS group. Plasma atrial natriuretic peptide level was significantly higher in HY group than HS group and did not return to normal after sildenafil treatment. Conclusion: sildenafil reversed the right ventricular hypertrophy induced by hypoxia but did not decrease the expression of MHC-ß to normal levels.

Value-based healthcare delivery through metabolomics-based personalized health platform.

Type 2 diabetes is routinely identified in clinical practice by tests that rely on a hyperglycemic index. However, people at risk for developing type 2 diabetes may not present with hyperglycemia. We identified several underlying risks for type 2 diabetes, insulin resistance, and associated co-morbidities, using a liquid chromatography mass spectrometry-based analysis of blood metabolites, in participants with normoglycemia and no clinical symptoms. Personalized lifestyle recommendations, including diet, exercise, and nutritional supplement recommendations, were conveyed to these participants by a web-based platform, and after 100 days of following their recommendations, these participants reported reductions in the health risks associated with type 2 diabetes and associated diseases. Our comprehensive metabolite-based assay can be used for type 2 diabetes risk stratification, and our personalized lifestyle recommendation system could be deployed as a preventative treatment option to improve health outcomes, reduce the incidence of chronic disease, and live healthier lives in an evidence-based way.

Multiplexed LC-ESI-MRM-MS-based Assay for Identification of Coronary Artery Disease Biomarkers in Human Plasma.

PURPOSE: A highly-multiplexed LC-ESI-multiple reaction monitoring-MS-based assay is developed for the identification of coronary artery disease (CAD) biomarkers in human plasma. EXPERIMENTAL DESIGN: The assay is used to measure 107 stable isotope labeled peptide standards and native peptides from 64 putative biomarkers of cardiovascular diseases in tryptic digests of plasma from subjects with (n = 70) and without (n = 45) angiographic evidence of CAD and no subsequent cardiovascular mortality during follow-up. RESULTS: Extensive computational and statistical analysis reveals six plasma proteins associated with CAD, namely apolipoprotein CII, C reactive protein, CD5 antigen-like, fibronectin, inter alpha trypsin inhibitor heavy chain H1, and protein S. The identified proteins are combined into a LASSO-logistic score with high classification performance (cross-validated area under the curve = 0.74). When combined with a separate score computed from markers currently used in the clinic with similar performance, the area under the receiver operating curve increases to 0.84. Similar results are observed in an independent set of subjects (n = 87). CONCLUSIONS AND CLINICAL RELEVANCE: If externally validated, the assay and identified biomarkers can improve CAD risk stratification.

Rhus coriaria L. (Sumac) Evokes Endothelium-Dependent Vasorelaxation of Rat Aorta: Involvement of the cAMP and cGMP Pathways.

Rhus coriaria L. (sumac) is widely used in traditional remedies and cuisine of countries of the Mediterranean as well as Central and South-West Asia. Administration of sumac to experimental models and patients with diverse pathological conditions generates multi-faceted propitious effects, including the quality as a vasodilator. Together, the effects are concertedly channeled toward cardiovasobolic protection. However, there is paucity of data on the mechanism of action for sumac's vasodilatory effect, an attribute which is considered to be advantageous for unhealthy circulatory system. Accordingly, we sought to determine the mechanisms by which sumac elicits its vasorelaxatory effects. We deciphered the signaling networks by application of a range of pharmacological inhibitors, biochemical assays and including the quantification of cyclic nucleotide monophosphates. Herein, we provide evidence that an ethanolic extract of sumac fruit, dose-dependently, relaxes rat isolated aorta. The mechanistic effect is achieved via stimulation of multiple transducers namely PI3-K/Akt, eNOS, NO, guanylyl cyclase, cGMP, and PKG. Interestingly, the arachidonic acid pathway (cyclooxygenases), adenylyl cyclase/cAMP and ATP-dependent potassium channels appear to partake in this sumac-orchestrated attenuation of vascular tone. Clearly, our data support the favorable potential cardio-vasculoprotective action of sumac.

Determination of Vascular Reactivity of Middle Cerebral Arteries from Stroke and Spinal Cord Injury Animal Models Using Pressure Myography.

Stroke and other neurovascular derangements are main causes of global death. They, along with spinal cord injuries, are responsible for being the principal cause of disability due to neurological and cognitive problems. These problems then lead to a burden on scarce financial resources and societal care facilities as well as have a profound effect on patients' families. The mechanism of action in these debilitating diseases is complex and unclear. An important component of these problems arises from derangement of blood vessels, such as blockage due to clotting/embolism, endothelial dysfunction, and overreactivity to contractile agents, as well as alteration in endothelial permeability. Moreover, the cerebro-vasculature (large vessels and arterioles) is involved in regulating blood flow by facilitating auto-regulatory processes. Moreover, the anterior (middle cerebral artery and the surrounding region) and posterior (basilar artery and its immediate locality) regions of the brain play a significant role in triggering the pathological progression of ischemic stroke particularly due to inflammatory activity and oxidative stress. Interestingly, modifiable and non-modifiable cardiovascular risk factors are responsible for driving ischemic and hemorrhagic stroke and spinal cord injury. There are different stroke animal models to examine the pathophysiology of middle cerebral and basilar arteries. In this context, arterial myography offers an opportunity to determine the etiology of vascular dysfunction in these diseases. Herein, we describe the technique of pressure myography to examine the reactivity of cerebral vessels to contractile and vasodilator agents and a prelude to stroke and spinal cord injury.

Can a smaller than expected crown-rump length reliably predict the occurrence of subsequent miscarriage in a viable first trimester pregnancy?

AIM: To elicit the diagnostic value of smaller than expected crown-rump length (CRL) to predict the occurrence of subsequent miscarriage in women with a viable first trimester pregnancy. METHODS: A cohort study was conducted in the fetal special care unit of a tertiary care maternity hospital. The recruited participants were young pregnant women at 6-13 weeks of gestation. Transvaginal ultrasonography was performed to determine pregnancy viability and measure the embryonic CRL. To compare the differences in CRL between those pregnancies that remained viable and those that subsequently miscarried, the deviation of observed and expected CRL was calculated and expressed in standard deviations (SD) as Z score. The primary outcome measure was the percentage of pregnancies with antecedent growth delay that miscarried by the end of the first trimester. RESULTS: Of the pregnancies that subsequently miscarried, 79.3% (42/53) had smaller than expected CRL, and in 56.6% (30/53) the CRL was 2 SD or less from that expected for gestational age (GA). The mean Z score for CRL was significantly lower in pregnancies that subsequently miscarried compared to pregnancies that remained viable (-2.9 ± 2.6 vs -0.8 ± 2.1, respectively, P < 0.001). A CRL of 2 SD or less from that expected for GA as a cut-off point had a sensitivity of 56.6, specificity of 81.9, positive predictive value of 36.6, negative predictive value of 91.1, likelihood ratio positive of 3.1 and likelihood ratio negative of 0.5 in predicting subsequent miscarriage. CONCLUSION: Viable first trimester pregnancies with small for GA CRL were associated with a higher probability of a subsequent miscarriage.

SPARC regulates microgliosis and functional recovery following cortical ischemia.

Secreted protein acidic rich in cysteine (SPARC) is a matricellular protein that modulates the activity of growth factors, cytokines, and extracellular matrix to play multiple roles in tissue development and repair, such as cellular adhesion, migration, and proliferation. Throughout the CNS, SPARC is highly localized in mature ramified microglia, but its role in microglia--in development or during response to disease or injury--is not understood. In the postnatal brain, immature amoeboid myeloid precursors only induce SPARC expression after they cease proliferation and migration, and transform into mature, ramified resting microglia. SPARC null/CX3CR1-GFP reporter mice reveal that SPARC regulates the distribution and branching of mature microglia, with significant differences between cortical gray and white matter in both controls and SPARC nulls. Following ischemic and excitotoxic lesion, reactive, hypertrophic microglia rapidly downregulate and release SPARC at the lesion, concomitant with reactive, hypertrophic perilesion astrocytes upregulating SPARC. After photothrombotic stroke in the forelimb sensorimotor cortex, SPARC nulls demonstrate enhanced microgliosis in and around the lesion site, which accompanies significantly enhanced functional recovery by 32 d after lesion. Microglia from SPARC nulls also intrinsically proliferate at a greater rate in vitro--an enhanced effect that can be rescued by the addition of exogenous SPARC. SPARC is thus a novel regulator of microglial proliferation and structure, and, in addition to regulating glioma progression, may play an important role in differently regulating the gray and white matter microglial responses to CNS lesion--and modulating behavioral recovery--after injury.