A case of personalized and precision medicine: Pharmacometabolomic applications to rare cancer, microbiological investigation, and therapy.

RATIONALE: Advances in metabolomics, together with consolidated genetic approaches, have opened the way for investigating the health of patients using a large number of molecules simultaneously, thus providing firm scientific evidence for personalized medicine and consequent interventions. Metabolomics is an ideal approach for investigating specific biochemical alterations occurring in rare clinical situations, such as those caused by rare associations between comorbidities and immunosuppression. METHODS: Metabolomic database matching enables clear identification of molecular factors associated with a metabolic disorder and can provide a rationale for elaborating personalized therapeutic protocols. Mass spectrometry (MS) forms the basis of metabolomics and uses mass-to-charge ratios for metabolite identification. Here, we used an MS-based approach to diagnose and develop treatment options in the clinical case of a patient afflicted with a rare disease further complicated by immunosuppression. The patient's data were analyzed using proprietary databases, and a personalized and efficient therapeutic protocol was consequently elaborated. RESULTS: The patient exhibited significant alterations in homocysteine:methionine and homocysteine:thiodiglycol acid plasma concentration ratios, and these were associated with low immune system function. This led to cysteine concentration deficiency causing extreme oxidative stress. Plasmatic thioglycolic acid concentrations were initially altered and were used for therapeutic follow-up and to evaluate cysteine levels. CONCLUSIONS: An MS-based pharmacometabolomics approach was used to define a personalized protocol in a clinical case of rare peritoneal carcinosis with confounding immunosuppression. This personalized protocol reduced both oxidative stress and resistance to antibiotics and antiviral drugs.

SARS-CoV-2 Immunization Orchestrates the Amplification of IFNγ-Producing T Cell and NK Cell Persistence.

A successful vaccination would represent the most efficient means to control the pandemic of Coronavirus Disease-19 (COVID-19) that led to millions of deaths worldwide. Novel mRNA-based vaccines confer protective immunity against SARS-CoV-2, but whether immunity is immediately effective and how long it will remain in recipients are uncertain. We sought to assess the effectiveness of a two-dose regimen since the boosts are often delayed concerning the recommended intervals. Methods: A longitudinal cohort of healthcare workers (HCW, N = 46; 30.4% men; 69.6% women; mean age 36.05 ± 2.2 years) with no SARS-CoV-2 infection as documented by negative polymerase chain reaction was immunophenotyped in PBMC once a week for 4 weeks from the prime immunization (Pfizer mRNA BNT162b2) and had received 2 doses, to study the kinetic response. Results: We identified three risk groups to develop SARS-CoV-2 infection IgG+-based (late responders, R-; early responders, R+; pauci responders, PR). In all receipts, amplification of B cells and NK cells, including IL4-producing B cells and IL4-producing CD8+ T cells, is early stimulated by the vaccine. After the boost, we observed a growing increase of NK cells but a resistance of T cells, IFNγ-producing CD4+T cells, and IFNγ-producing NK cells. Also, hematologic parameters decline until the boost. The positive association of IFNγ-producing NK with IFNγ-producing CD4+T cells by the multiple mixed-effect model, adjusted for confounders (p = 0.036) as well as the correlation matrix (r = 0.6, p < 0.01), suggests a relationship between these two subsets of lymphocytes. Conclusions: These findings introduce several concerns about policy delay in vaccination: based on immunological protection, B cells and the persistent increase of NK cells during 2 doses of the mRNA-based vaccine could provide further immune protection against the virus, while CD8+ T cells increased slightly only in the R+ and PR groups.

Occupational Exposure in the Lombardy Region (Italy) to SARS-CoV-2 Infection: Results from the MUSTANG-OCCUPATION-COVID-19 Study.

Sero-epidemiological surveys are valuable attempts to estimate the circulation of SARS-CoV-2 in general or selected populations. Within this context, a prospective observational study was conducted to estimate the prevalence and persistence of SARS-CoV-2 antibodies in different categories of workers and factors associated with positivity, through the detection of virus-specific immunoglobulin G and M (IgG/IgM) in serum samples. Enrollees were divided in low exposure and medium-high groups on the basis of their work activity. Antibody responders were re-contacted after 3 months for the follow-up. Of 2255 sampled workers, 4.8% tested positive for SARS-CoV-2 IgG/IgM antibodies, with 81.7% to IgG only. Workers who continued to go to their place of work, were healthcare workers, or experienced at least one COVID-19-related symptom were more likely to test positive for SARS-CoV-2 antibodies. SARS-CoV-2 antibodies prevalence was significantly higher in the medium-high risk vs. low-risk group (7.2% vs. 3.0%, p < 0.0001). At 3-month follow-up, 81.3% of subjects still had antibody response. This study provided important information of SARS-CoV-2 infection prevalence among workers in northern Italy, where the impact of COVID-19 was particularly intense. The presented surveillance data give a contribution to refine current estimates of the disease burden expected from the SARS-CoV-2.

Increased Monoclonal Components: Prevalence in an Italian Population of 44 474 Outpatients Detected by Capillary Electrophoresis.

BACKGROUND: Identification, quantification and typing of M-Proteins (MP) play an important role in the diagnosis, classification and monitoring of monoclonal gammopathies both of malignant origin (eg. Multiple Myeloma) and of unknown origin. Previous evidence attests that MGUS (Monoclonal Gammopathy of Undetermined Significance) detected by agarose gel electrophoresis has a prevalence of 3.2% in the general population. Therefore, our study aimed to verify this data by means of capillary zone electrophoresis (CZE). METHODS: CZE was performed to evaluate the prevalence of M-Protein (MP) in 44.474 consecutive outpatients of all ages with a prescription for serum protein electrophoresis over a 2-year period (2008 and 2009). All MPs that were identified were then typed by immunofixation electrophoresis on agarose gel (IFE). RESULTS: In subjects aged over 50 (23.408, i.e., 52.6% of the whole cohort) MP ≤30 g/L (MGUS) was identified in 6.0% of cases, with a frequency nearly double than that previously reported. The population was then divided into ten-year age groups: the 71-80 age group had the highest percentage of MP (29%), followed by 61-70 (27%), 51-60 (18%), 81-90 (12%), 41-50 (8%), 31-40 (3%), >90 (2%) and <30 (1%). The frequency of MP types (IFE) was the same in each age group, with IgG Kappa being the most represented class. CONCLUSIONS: According to the high MGUS prevalence observed in this study, these results may be useful especially for general practitioners, because the identification even of small MP (analytical sensitivity: 0.5 g/L) may help optimize clinical management.