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The focus of precision medicine is providing the right treatment to each unique patient. This scientific movement has incited monumental advances in oncology including the approval of effective, targeted agnostic therapies. Yet, precision oncology has focused largely on genomics in the treatment decision making process, and several recent clinical trials demonstrate that genomics is not the only variable to be considered. Drug screening in three dimensional (3D) models, including patient derived organoids, organs on a chip, xenografts, and 3D-bioprinted models provide a functional medicine perspective and necessary complement to genomic testing. In this review, we discuss the practicality of various 3D drug screening models and each model’s ability to capture the patient’s tumor microenvironment. We highlight the potential for enhancing precision medicine that personalized functional drug testing holds in combination with genomic testing and emerging mathematical models.

As we move into the era of precision medicine, the growing relevance of genetic alterations to prostate cancer (PCa) development and treatment demonstrates the importance of characterizing preclinical models at the genomic level. Our study investigated the genomic characterization of eight PCa cell lines to understand which models are clinically relevant. We designed a custom AmpliSeq DNA gene panel that encompassed key molecular pathways targeting AR signaling, apoptosis, DNA damage repair, and PI3K/AKT/PTEN, in addition to tumor suppressor genes. We examined the relationship between cell line genomic alterations and therapeutic response. In addition, using DepMap’s Celligner tool, we identified which preclinical models are most representative of specific prostate cancer patient populations on cBioPortal. These data will help investigators understand the genetic differences in preclinical models of PCa and determine which ones are relevant for use in their translational research.

Amyotrophic lateral sclerosis (ALS) is a most frequently occurring and severe form of motor neuron disease, causing death within 3–5 years from diagnosis and with a worldwide incidence of about 2 per 100,000 person-years. Mutations in over twenty genes associated with familial forms of ALS have provided insights into the mechanisms leading to motor neuron death. Moreover, mutations in two RNA binding proteins, TAR DNA binding protein 43 and fused in sarcoma, have raised the intriguing possibility that perturbations of RNA metabolism, including that of the small endogenous RNA molecules that repress target genes at the posttranscriptional level, that is, microRNAs, may contribute to disease pathogenesis. At present, the mechanisms by which microglia actively participate to both toxic and neuroprotective actions in ALS constitute an important matter of research. Among the pathways involved in ALS-altered microglia responses, in previous works we have uncovered the hyperactivation of P2X7 receptor by extracellular ATP and the overexpression of miR-125b, both leading to uncontrolled toxic M1 reactions. In order to shed further light on the complexity of these processes, in this short review we will describe the M1/M2 functional imprinting of primary microglia and a role played by P2X7 and miR-125b in ALS microglia activation.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative autoimmune disorder of the central nervous system characterized by demyelination and neurodegeneration. Traditionally considered a T-cell-mediated disease, the crucial role of B lymphocytes in its pathogenesis, through different mechanisms contributing to inflammation and autoreactivity, is increasingly recognized. The risk of long-term disability in MS patients can be reduced by an early treatment initiation, in particular with high-efficacy therapies. The aim of this review is to provide an overview of the mechanisms of action of high-efficacy therapies for MS, with a focus on their impact on B cells and how this contributes to the drugs’ efficacy and safety profiles. Anti-CD20 monoclonal antibodies, Alemtuzumab, Cladribine and sequestering therapies encompassing Natalizumab and S1P receptors modulators will be discussed and emerging therapies, including Bruton’s Tyrosine Kinase inhibitors, will be presented.

Since the beginning of the COVID-19 pandemic, patients with Inborn Errors of Immunity have been infected by SARS-CoV-2 virus showing a spectrum of disease ranging from asymptomatic to severe COVID-19. A fair number of patients did not respond adequately to SARS-CoV-2 vaccinations, thus early therapeutic or prophylactic measures were needed to prevent severe or fatal course or COVID-19 and to reduce the burden of hospitalizations. Longitudinal, multicentric study on patients with Inborn Errors of Immunity immunized with mRNA vaccines treated with monoclonal antibodies and/or antiviral agents at the first infection and at reinfection by SARS-CoV-2. Analyses of efficacy were performed according to the different circulating SARS-CoV-2 strains. The analysis of the cohort of 192 SARS-CoV-2 infected patients, across 26 months, showed the efficacy of antivirals on the risk of hospitalization, while mabs offered a positive effect on hospitalization, and COVID-19 severity. This protection was consistent across the alpha, delta and early omicron waves, although the emergence of BA.2 reduced the effect of available mabs. Hospitalized patients treated with mabs and antivirals had a lower risk of ICU admission. We reported 16 re-infections with a length of SARS-CoV-2 positivity at second infection shorter among patients treated with mabs. Treatment with antivirals and mabs was safe. The widespread use of specific therapy, vaccination and better access to care might have contributed to mitigate risk of mortality, hospital admission, and severe disease. However, the rapid spread of new viral strains underlines that mabs and antiviral beneficial effects should be re- evaluated over time.

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease where activated glia release pro-inflammatory cytokines that trigger a vicious cycle of neurodegeneration in the absence of resolution of inflammation. Given the well-established role of histamine as a neuron-to-glia alarm signal implicated in brain disorders, the aim of this study was to investigate the expression and regulation of the histaminergic pathway in microglial activation in ALS mouse model and in humans. By examining the contribution of the histaminergic system to ALS, we found that particularly H1 and H4 receptors, histamine promoted an anti-inflammatory profile in microglia from SOD1-G93A mice by modulating their activation state. A decrease in NF-κB and NADPH oxidase 2 with an increase in arginase 1 and P2Y12 receptor was induced by histamine only in the ALS inflammatory environment, but not in the healthy microglia, together with an increase in IL-6, IL-10, CD163, and CD206 phenotypic markers in SOD1-G93A cells. Moreover, histaminergic H1, H2, H3, and H4 receptors, and histamine metabolizing enzymes histidine decarboxylase, histamine -methyltransferase, and diamine oxidase were found deregulated in spinal cord, cortex, and hypothalamus of SOD1-G93A mice during disease progression. Finally, by performing a meta-analysis study, we found a modulated expression of histamine-related genes in cortex and spinal cord from sporadic ALS patients. Our findings disclose that histamine acts as anti-inflammatory agent in ALS microglia and suggest a dysregulation of the histaminergic signaling in ALS.

Extracellular vesicles (EVs) provide a minimally invasive liquid biopsy source of tumor-specific markers for patients who have already undergone prostatectomies. Our laboratory has previously demonstrated enrichment of the cancer-type solute carrier organic anion transporter family 1B3 ( ) and the ATP Binding Cassette Subfamily Member C ( ) in castration-resistant cell lines (CRPC). However, their expression in EVs has yet to be explored. Our study demonstrated that ct-SLCO1B3 and ABCC3 are highly detectable in CRPC cell line-derived EVs. We also showed that and were detectable in a CRPC xenograft mouse model, both intratumorally and in plasma-derived EVs. Our results provide evidence for EV-contained and as novel, EV-based tumor markers for prostate cancer progression.

Objective This study investigated myostatin levels in SMA patients receiving disease‐modifying therapies (DMTs) to understand their relationship with treatment duration and functional status. Methods Our study includes both cross‐sectional and longitudinal analyses of myostatin levels in treated SMA patients. The longitudinal cohort included 46 treatment‐naive patients assessed at baseline and 12 months post‐treatment. Myostatin levels were measured using ELISA. Age‐matched controls (n = 89) were included for comparison. The cross‐sectional study included 128 patients with variable durations of treatment (from 0.4 to 7.2 years). In both cohorts, myostatin levels were correlated with SMA type, functional status, and clinical outcomes. Results Baseline myostatin levels were significantly lower than controls (p < 0.001), except during the neonatal period in presymptomatic patients. After 12 months of treatment, there were no significant changes compared to baseline levels (p = 0.1652). The only substantial changes were observed in presymptomatic neonates, who showed a reduction of myostatin despite treatment intervention. There was a significant correlation between myostatin levels, functional status, and SMA type both in the cross‐sectional and longitudinal groups. Interpretation This study demonstrates lower myostatin levels in SMA patients compared to controls. The association between myostatin levels, functional status, and SMA type suggests its possible role as a disease severity biomarker. The utility of myostatin as a biomarker for DMT response remains controversial; while we observed no significant increase in myostatin levels following treatment, we also did not observe the progressive reduction previously reported in untreated patients.

Assessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters. We performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells. We found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses. Thanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases.

Underrepresented populations’ participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3, *6, and *7). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve did not significantly differ between PMs (39,230 h*ng/mL) and IM/NMs (43,546 h*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.