Presentazione Alessandria

Author: Gianpiero Pescarmona
Date: 06/10/2017


Modeling life beyond Metabolomics. A comprehensive approach to metabolism in health and disease.

Papers Pescarmona GP

What models can predict

The role of Models in Clinical Practice


The EBM approach

  • Symptom/disease identification
  • "correct" therapy on the basis of the evidences (average choice based on thousand cases)

The biochemical approach

  • Identification of biochemical causal relationships leading to symptoms/disease in the single individual

A network neuroscience of neurofeedback for clinical translation, 2017

Patient is unique (read: anecdotal) so why he should be treated as similar to ....?

“Anecdotal Evidence”: Why Narratives Matter to Medical Practice, 2006

When anecdotes fit a deep biochemical model they are no longer anecdotes but evidences of biochemical model fitness.

Biochemical network are made by physical agents that are always linked by causal relationship, even if you don't know them.

When the network is very complex to test the predictive power of simple hypothesis on a large number of subjects usually fails because of the large number of factor involved but not recorded. ICT allows at acceptable costs collection of huge amount of data.
When an anecdotal info, collected by chance, lighten a new causal node, this node is added to the network and checked for other instances. And so one until the vast majority of the events become predictable.

Evidence is a record of the past, not a preview of the future.

The only correct experimental evidence is the never ended one, and evolutionary like life.

A Biochemical Method can allow Previews: if they are confirmed in the real patient the model is reinforced, otherwise we are forced to improve it (new nodes, new relationships, new polymorphysms)

Artificial Intelligence

‘Deep’ models and their relation to diagnosis, 1989

We provide a typology of different knowledge structures and reasoning processes that play a role in qualitative or functional reasoning and elaborate on functional representations as deep cognitive models for some aspects of causal reasoning in medicine.

The Failure of AI in Medicine depends on the fact that it is based on deep cognitive models and not on deep biochemical models

What is the Disease?

Disease: inadequacy of a living organism to cope with environmental requirements

To understand Disease we have to define the Living Organism and the Rules driving its life

Example 1: Pain

The First Rule: Dissipative

Pain (joints pain)

the higher the stimulus, the higher the spikes frequency...

but we get the same results when the intracellula ATP is low....

more details

which local conditions can affect ATP synthesis?

  1. Less oxygen transport
  2. Less CoQ
  3. Less Cyt C
  4. Less glucose
    • diet
    • hyperinsulinism

Pain, the First Rule and the Fourth Rule

Example 2: Regulation of proteins synthesis by Amino Acids Availability

Aminoacids supply to the tissues

livello di O2 e attivita' cognitive

Brain metabolite levels and language abilities in preschool children, 2015

viene fatta la rilevazione dei metaboli mediante la "Magnetic resonance spectroscopy" (MRS) e l'LCModel (Provencher, 2001) per calcolare la concentrazione (mmol/kg ww) per:

glutamate (Glu), glutamine (Gln), creatine + phosphocreatine (Cr/PCr), choline (glycerophosphocholine
+ phosphocholine), inositol, and NAA

in relazione alle abilità di lettura in bambini in età prescolare

L'articolo riporta:

"Our results show for the first time that brain metabolite concentrations and language abilities are related in preschool children.
Specifically, phonological processing ability was positively associated with glutamate, creatine, and inositol concentrations in the anterior cingulate"

A pag 6 dell'articolo ci sono i grafici relativi alla correlazione tra la concentrazione dei metaboliti e la velocità di lettura.

Alte concentrazioni di inositolo, creatina e glutammato nel giro cingolato anteriore sono correlati a buone abilità di lettura nei bambini.

La colina e la glutamina sembrano invece essere inversamente correlati con le abilità di lettura, in particolare la glutamina.

2017-11-25T16:52:28 - Gianpiero Pescarmona

In vivo metabolic flux profiling with stable isotopes discriminates sites and quantifies effects of mitochondrial dysfunction in C. elegans.2014

  • Abstract
    Mitochondrial respiratory chain (RC) disease diagnosis is complicated both by an absence of biomarkers that sufficiently divulge all cases and limited capacity to quantify adverse effects across intermediary metabolism. We applied high performance liquid chromatography (HPLC) and mass spectrometry (MS) studies of stable-isotope based precursor-product relationships in the nematode, C. elegans, to interrogate in vivo differences in metabolic flux among distinct genetic models of primary RC defects and closely related metabolic disorders.
    C. elegans strains studied harbor single nuclear gene defects in complex I, II, or III RC subunits (gas-1, mev-1, isp-1); enzymes involved in coenzyme Q biosynthesis (clk-1), the tricarboxylic acid cycle (TCA, idh-1), or pyruvate metabolism (pdha-1); and central nodes of the nutrient-sensing signaling network that involve insulin response (daf-2) or the sirtuin homologue (sir-2.1). Synchronous populations of 2000 early larval stage worms were fed standard Escherichia coli on nematode growth media plates containing 1,6-(13)C2-glucose throughout their developmental period, with samples extracted on the first day of adult life in 4% perchloric acid with an internal standard. Quantitation of whole animal free amino acid concentrations and isotopic incorporation into amino and organic acids throughout development was performed in all strains by HPLC and isotope ratio MS, respectively. GC/MS analysis was also performed to quantify absolute isotopic incorporation in all molecular species of key TCA cycle intermediates in gas-1 and N2 adult worms.
    Genetic mutations within different metabolic pathways displayed distinct metabolic profiles. RC complex I (gas-1) and III (isp-1) subunit mutants, together with the coenzyme Q biosynthetic mutant (clk-1), shared a similar amino acid profile of elevated alanine and decreased glutamate. The metabolic signature of the complex II mutant (mev-1) was distinct from that of the other RC mutants but resembled that of the TCA cycle mutant (idh-1) and both signaling mutants (daf-2 and sir-2.1). All branched chain amino acid levels were significantly increased in the complex I and III mutants but decreased in the PDH mutant (pdha-1). The RC complex I, coenzyme Q, TCA cycle, and PDH mutants shared significantly increased relative enrichment of lactate+1 and absolute concentration of alanine+1, while glutamate+1 enrichment was significantly decreased uniquely in the RC mutants. Relative intermediary flux analyses were suggestive of proximal TCA cycle disruption in idh-1, completely reduced TCA cycle flux in sir-2.1, and apparent distal TCA cycle alteration in daf-2. GC/MS analysis with universally-labeled (13)C-glucose in adult worms further showed significantly increased isotopic enrichment in lactate, citrate, and malate species in the complex I (gas-1) mutant.
    Stable isotopic/mass spectrometric analysis can sensitively discriminate primary RC dysfunction from genetic deficiencies affecting either the TCA cycle or pyruvate metabolism. These data are further suggestive that metabolic flux analysis using stable isotopes may offer a robust means to discriminate and quantify the secondary effects of primary RC dysfunction across intermediary metabolism.

A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome, 2017

    A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism. It is also associated with common age-associated diseases and the aging process. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD+ biosynthesis (kynurenine and 3-hydroxyanthranilic acid). Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases.

High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity. 2017

  • Abstract
    Tumors develop numerous strategies to fine-tune inflammation and avoid detection and eradication by the immune system. The identification of mechanisms leading to local immune dysregulation is critical to improve cancer therapy. We here demonstrate that Interleukin-1 receptor 8 (IL-1R8 - previously known as SIGIRR/TIR8), a negative regulator of Toll-Like and Interleukin-1 Receptor family signaling, is up-regulated during breast epithelial cell transformation and in primary breast tumors. IL-1R8 expression in transformed breast epithelial cells reduced IL-1-dependent NF-κB activation and production of pro-inflammatory cytokines, inhibited NK cell activation and favored M2-like macrophage polarization. In a murine breast cancer model (MMTV-neu), IL-1R8-deficiency reduced tumor growth and metastasis and was associated with increased mobilization and activation of immune cells, such as NK cells and CD8+ T cells. Finally, immune-gene signature analysis in clinical specimens revealed that high IL-1R8 expression is associated with impaired innate immune sensing and T-cell exclusion from the tumor microenvironment. Our results indicate that high IL-1R8 expression acts as a novel immunomodulatory mechanism leading to dysregulated immunity with important implications for breast cancer immunotherapy.
2017-10-17T15:39:03 - Gianpiero Pescarmona

Francesca Silvagno suggestions:

  • cardiolipina,
  • Q10,
  • 25(OH)VitD3,
  • desaturasi,
  • rapporto aa,
    • e' dimostrato che nelle malattie mitocondriali il metabolismo degli aa che danno intermedi del TCA cambia, in particolare sale il rapporto Ala/Glu, Gly/Glu, Val/Glu, Leu/Glu, Ileu/Glu
  • trigliceridi,
  • acido lattico,
  • TGFbeta

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