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Third-generation tyrosine kinase inhibitors are the first-line gold standard in treating advanced non-small-cell lung cancer bearing common EGFR mutations, but data documenting clinical efficacy in uncommon mutations are currently limited. In this paper, we describe the case of a patient bearing uncommon compound EGFR mutations in exon 20, who experienced a near-complete response to third-line Osimertinib, with metabolic complete response of pulmonary, nodal and ostheolytic lesions. This radiological assessment corresponded to an ECOG PS improvement (from three to one) and a substantial clinical benefit for the patients. Out of two mutations, S768I was associated with poor response to third-generation TKI and V774M had unknown clinical significance, highlighting the complexity of the correct management of these kinds of mutations. We reviewed the literature to document the up-to-date preclinical and clinical data concerning third-generation tyrosine kinase inhibitors for the treatment of patients bearing uncommon EGFR mutations. [ABSTRACT FROM AUTHOR]

The remarkable variability of response to vaccines against SARS‐CoV‐2 is apparent. The present study aims to estimate the extent to which the host genetic background contributes to this variability in terms of immune response and side effects following the administration of the BNT162b2 vaccine. We carried out a genome wide association study (GWAS) by genotyping 873 Italian healthcare workers who underwent anti‐SARS‐CoV‐2 vaccination with the BNT162b2 vaccine and for whom information about anti‐SARS‐CoV‐2 spike antibodies titers and vaccine side effects were available. The GWAS revealed a significant association between the HLA locus and the anti‐SARS‐CoV‐2 Spike antibodies level at 2 months following the first dose of vaccine (SNP: rs1737060; p = 9.80 × 10−11). In particular, we observed a positive association between the antibody levels and the presence of the HLA‐A*03:01 allele. The same allele was found associated with a 2–2.4‐fold increased risk of experiencing specific side effects such as fever, chills and myalgia and a 1.5–1.8‐fold increased risk of joint pain, nausea, fatigue, headache and asthenia, independently of age and sex. This study confirms that the heterogeneity in the immune response to the BNT162b2 vaccine and in its side effects are at least partially influenced by genetic variants. This information, integrated with individual biological and lifestyle‐related correlates, could be of use in the definition of algorithms aimed at the identification of subjects in which the administration of additional vaccine doses would be particularly beneficial to maintain immunity against the virus. [ABSTRACT FROM AUTHOR]

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most pivotal phase III studies; this precludes the generalization of ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common "special" NSCLC subpopulations. [ABSTRACT FROM AUTHOR]

Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia–neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h—while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress. [ABSTRACT FROM AUTHOR]

Intracerebral accumulation of amyloid-β in the extracellular plaques of Alzheimer's disease (AD) brains represents the main cause of reactive astrogliosis and neuroinflammatory response. Of relevance, leucine-rich repeat kinase 2 (LRRK2), a kinase linked to genetic and sporadic Parkinson's disease (PD), has been identified as a positive mediator of neuroinflammation upon different inflammatory stimuli, however its pathogenicity in AD remains mainly unexplored. In this study, by using pharmacological inhibition of LRRK2 and murine primary astrocytes, we explored whether LRRK2 regulates astrocytic activation in response to amyloid-β1-42 (Aβ1-42). Our results showed that murine primary astrocytes become reactive and recruit serine 935 phosphorylated LRRK2 upon Aβ1-42 fibril exposure. Moreover, we found that pharmacological inhibition of LRRK2, with two different kinase inhibitors, can attenuate Aβ1-42-mediated inflammation and favor the clearance of Aβ1-42 fibrils in astrocytes. Overall, our findings report that LRRK2 kinase activity modulates astrocytic reactivity and functions in the presence of Aβ1-42 deposits and indicate that PD-linked LRRK2 might contribute to AD-related neuroinflammation and pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Oral potentially malignant disorders (OPMDs) represent a heterogeneous set of different histological lesions, characterized by the capacity to transform in oral squamous cell carcinoma (OSCC). Despite optimal surgical treatment, approximately 20%–30% of OPMDs may evolve into OSCC. No clear clinical/histological factors are able to identify OPMDs at higher risk of malignant transformation. Materials and Methods: We considered surgically treated patients with a diagnosis of OPMDs, enrolled from 1996 to 2019 at ASST Spedali Civili of Brescia without a diagnosis of OSCC within the previous 2 years. Clinical and histological characteristics were recorded. Outcomes of interest were recurrence-free survival (RFS), defined as the time from surgery for primary OPMD to any relapse of OPMD or malignant transformation, whichever occurred first, and carcinoma-free survival (CFS), defined as the time from surgery for OPMD to malignant transformation. Results: We retrospectively reviewed 106 OPMDs cases. Median age at first diagnosis was 64 years old (IQR = 18.75); female patients comprise 51.9% of the cases. During a median follow-up of 30.5 months (IQR = 44), in 23.5% of patients, malignant transformation occurred. RFS at 1, 5, and 10 years was 92.4%, 60.9%, and 43.2%, respectively. Female sex and history of previous OSCC were independent risk factors for RFS. CFS at 1, 5, and 10 years of follow-up was 97.1%, 75.9%, and 64.4%, respectively. Previous OSCC was an independent risk factor for CFS. Conclusions: In this large series of OPMDs, only previous diagnosis of OSCC was a prognostic factor for further OSCC occurrence. Given the lack of additional clinical/pathological prognostic factors, we advocate further studies into molecular characterization of OPMDs to better stratify the risk of malignant transformation. [ABSTRACT FROM AUTHOR]

Abstract Background The volume of data available on genetic variations has increased considerably with the recent development of high-density, single-nucleotide polymorphism (SNP) arrays. Several software programs have been developed to assist researchers in the analysis of this huge amount of data, but few can rely upon a whole genome variability visualisation system that could help data interpretation. Results We have developed GenotypeColour™ as a rapid user-friendly tool able to upload, visualise and compare the huge amounts of data produced by Affymetrix Human Mapping GeneChips without losing the overall view of the data. Some features of GenotypeColour™ include visualising the entire genome variability in a single screenshot for one or more samples, the simultaneous display of the genotype and Copy Number state for thousands of SNPs, and the comparison of large amounts of samples by producing "consensus" images displaying regions of complete or partial identity. The software is also useful for genotype analysis of trios and to show regions of potential uniparental disomy (UPD). All information can then be exported in a tabular format for analysis with dedicated software. At present, the software can handle data from 10 K, 100 K, 250 K, 5.0 and 6.0 Affymetrix chips. Conclusion We have created a software that offers a new way of displaying and comparing SNP and CNV genomic data. The software is available free at http://www.med.unibs.it/~barlati/GenotypeColour and is especially useful for the analysis of multiple samples.

Background. Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3ß (GSK3ß), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3ß, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods. To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3ß expression. Results. We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion. Our findings suggest that, like GSK3ß, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3ß pathway for NSs of SCZ. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long‐term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2‐week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome. [ABSTRACT FROM AUTHOR]

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome‐wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome‐wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy‐one patients with treatment‐resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR‐corrected p = 2.4 × 10−5) and in patients with major depressive disorder (best SNP: FDR‐corrected p = 2.6 × 10–3). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p =.01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy. [ABSTRACT FROM AUTHOR]