Immune checkpoint inhibitors (ICIs) have revolutionised treatment of advanced non-small cell lung cancer (aNSCLC), but a proportion of patients had no clinical benefit and even experienced ...detrimental effects. This study aims to characterise patients experiencing hyperprogression (HPD) and early death (ED) by longitudinal liquid biopsy.
aNSCLC receiving ICIs were prospectively enrolled. Plasma was collected at baseline (T1) and after 3/4 weeks of treatment, according to the treatment schedule (T2). Cell-free DNA (cfDNA) was quantified and analysed by NGS. cfDNA quantification and variant allele fraction (VAF) of tumour-associated genetic alterations were evaluated for their potential impact on outcome. The genetic alteration with the highest VAF (maxVAF) at baseline was considered as a reference.
From March 2017 to August 2019, 171 patients were enrolled. Five cases matched criteria for HPD and 31 ED were recorded; one overlapped. Quantification of cfDNA at T2 and its absolute and relative variation (T2-T1) were significantly associated with the risk of ED (P = 0.012, P = 0.005, P = 0.009). MaxVAF relative change (T2-T1/T1) was significantly associated with the risk of HPD (P = 0.02). After identifying optimal cut-off values, a two-step risk assessment model was proposed.
Liquid biopsy performed early during treatment has the potential to identify patients at high risk of ED and HPD.
Quantitative and qualitative alterations in the sense of smell are well established symptoms of COVID-19. Some reports have shown that non-neuronal supporting (also named sustentacular) cells of the ...human olfactory epithelium co-express ACE2 and TMPRSS2 necessary for SARS-CoV-2 infection. In COVID-19, syncytia were found in many tissues but were not investigated in the olfactory epithelium. Some studies have shown that syncytia in some tissues are formed when SARS-CoV-2 Spike expressed at the surface of an infected cell binds to ACE2 on another cell, followed by activation of the scramblase TMEM16F (also named ANO6) which exposes phosphatidylserine to the external side of the membrane. Furthermore, niclosamide, an approved antihelminthic drug, inhibits Spike-induced syncytia by blocking TMEM16F activity. The aim of this study was to investigate if proteins involved in Spike-induced syncytia formation, i.e., ACE2 and TMEM16F, are expressed in the human olfactory epithelium.
We analysed a publicly available single-cell RNA-seq dataset from human nasal epithelium and performed immunohistochemistry in human nasal tissues from biopsies.
We found that ACE2 and TMEM16F are co-expressed both at RNA and protein levels in non-neuronal supporting cells of the human olfactory epithelium.
Our results provide the first evidence that TMEM16F is expressed in human olfactory supporting cells and indicate that syncytia formation, that could be blocked by niclosamide, is one of the pathogenic mechanisms worth investigating in COVID-19 smell loss.
Objectives
Genetic drift and admixture are driving forces in human evolution, but their concerted impact to population evolution in historical times and at a micro‐geographic scale is poorly ...assessed. In this study we test a demographic model encompassing both admixture and drift to the case of social‐cultural isolates such as the so‐called “Commons.”
Materials and methods
Commons are peculiar institutions of medieval origins whose key feature is the tight relationship between population and territory, mediated by the collective property of shared resources. Here, we analyze the Y‐chromosomal genetic structure of four Commons (for a total of 366 samples) from the Central and Eastern Padana plain in Northern Italy.
Results
Our results reveal that all these groups exhibit patterns of significant diversity reduction, peripheral/outlier position within the Italian/European genetic space and high frequency of Common‐specific haplogroups. By explicitly testing different drift‐admixture models, we show that a drift‐only model is more probable for Central Padana Commons, while additional admixture (~20%) from external population around the same time of their foundation cannot be excluded for the Eastern ones.
Discussion
Building on these results, we suggest central Middle Ages as the most probable age of foundation for three of the considered Commons, the remaining one pointing to late antiquity. We conclude that an admixture‐drift model is particularly useful for interpreting the genetic structure and recent demographic history of small‐scale populations in which social‐cultural features play a significant role.
The innate immune system is crucial in fighting SARS-CoV-2 infection, which is responsible for coronavirus disease 2019 (COVID-19). Therefore, deepening our understanding of the underlying immune ...response mechanisms is fundamental for the development of novel therapeutic strategies. The role of extra-oral bitter (TAS2Rs) and sweet (TAS1Rs) taste receptors in immune response regulation has yet to be fully understood. However, a few studies have investigated the association between taste receptor genes and COVID-19 symptom severity, with controversial results. Therefore, this study aims to deepen the relationship between COVID-19 symptom presence/severity and
and
(
member) genetic variations in a cohort of 196 COVID-19 patients. Statistical analyses detected significant associations between rs307355 of the
gene and the following COVID-19-related symptoms: chest pain and shortness of breath. Specifically, homozygous C/C patients are exposed to an increased risk of manifesting severe forms of chest pain (OR 8.11, 95% CI 2.26-51.99) and shortness of breath (OR 4.83, 95% CI 1.71-17.32) in comparison with T/C carriers. Finally, no significant associations between the
haplotype and the presence/severity of COVID-19 symptoms were detected. This study, taking advantage of a clinically and genetically characterised cohort of COVID-19 patients, revealed
gene involvement in determining COVID-19 symptom severity independently of
activity, thus providing novel insights into the role of TAS1Rs in regulating the immune response to viral infections.
This study evaluates the efficacy of two advanced Large Language Models (LLMs), OpenAI's ChatGPT 4 and Google's Gemini Advanced, in providing treatment recommendations for head and neck oncology ...cases. The aim is to assess their utility in supporting multidisciplinary oncological evaluations and decision-making processes.
This comparative analysis examined the responses of ChatGPT 4 and Gemini Advanced to five hypothetical cases of head and neck cancer, each representing a different anatomical subsite. The responses were evaluated against the latest National Comprehensive Cancer Network (NCCN) guidelines by two blinded panels using the total disagreement score (TDS) and the artificial intelligence performance instrument (AIPI). Statistical assessments were performed using the Wilcoxon signed-rank test and the Friedman test.
Both LLMs produced relevant treatment recommendations with ChatGPT 4 generally outperforming Gemini Advanced regarding adherence to guidelines and comprehensive treatment planning. ChatGPT 4 showed higher AIPI scores (median 3 2-4) compared to Gemini Advanced (median 2 2-3), indicating better overall performance. Notably, inconsistencies were observed in the management of induction chemotherapy and surgical decisions, such as neck dissection.
While both LLMs demonstrated the potential to aid in the multidisciplinary management of head and neck oncology, discrepancies in certain critical areas highlight the need for further refinement. The study supports the growing role of AI in enhancing clinical decision-making but also emphasizes the necessity for continuous updates and validation against current clinical standards to integrate AI into healthcare practices fully.
The COVID-19 pandemic brought attention to our limited understanding of human olfactory physiology. While the cellular composition of the human olfactory epithelium is similar to that of other ...vertebrates, its functional properties are largely unknown. We prepared acute slices of human olfactory epithelium from nasal biopsies and used the whole-cell patch-clamp technique to record electrical properties of cells. We measured voltage-gated currents in human olfactory sensory neurons and supporting cells, and action potentials in neurons. Additionally, neuronal inward current and action potentials responses to a phosphodiesterase inhibitor suggested a transduction cascade involving cAMP as a second messenger. Furthermore, responses to odorant mixtures demonstrated that the transduction cascade was intact in this preparation. This study provides the first electrophysiological characterization of olfactory sensory neurons in acute slices of the human olfactory epithelium, paving the way for future research to expand our knowledge of human olfactory physiology.
Display omitted
•Acute slices of human olfactory epithelium are viable for patch-clamp recordings•Supporting cells (non-neuronal) exhibit outward voltage-gated currents•Olfactory sensory neurons display diverse patterns of action potentials•Olfactory sensory neurons respond to odorants and other stimuli
Neuroscience; Sensory neuroscience
The innate immune system is crucial in fighting SARS-CoV-2 infection, which is responsible for coronavirus disease 2019 (COVID-19). Therefore, deepening our understanding of the underlying immune ...response mechanisms is fundamental for the development of novel therapeutic strategies. The role of extra-oral bitter (TAS2Rs) and sweet (TAS1Rs) taste receptors in immune response regulation has yet to be fully understood. However, a few studies have investigated the association between taste receptor genes and COVID-19 symptom severity, with controversial results. Therefore, this study aims to deepen the relationship between COVID-19 symptom presence/severity and TAS1R and TAS2R38 (TAS2Rs member) genetic variations in a cohort of 196 COVID-19 patients. Statistical analyses detected significant associations between rs307355 of the TAS1R3 gene and the following COVID-19-related symptoms: chest pain and shortness of breath. Specifically, homozygous C/C patients are exposed to an increased risk of manifesting severe forms of chest pain (OR 8.11, 95% CI 2.26–51.99) and shortness of breath (OR 4.83, 95% CI 1.71–17.32) in comparison with T/C carriers. Finally, no significant associations between the TAS2R38 haplotype and the presence/severity of COVID-19 symptoms were detected. This study, taking advantage of a clinically and genetically characterised cohort of COVID-19 patients, revealed TAS1R3 gene involvement in determining COVID-19 symptom severity independently of TAS2R38 activity, thus providing novel insights into the role of TAS1Rs in regulating the immune response to viral infections.
Abstract only
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Background: ICIs revolutionized aNSCLC treatment. The next challenge lays on the search for predictive markers. Detection of multiple tumor-related genetic alterations through NGS ...in cell free DNA is a promising tool, provided the limited availability of tumor tissue in most cases. Methods: Between January 2017 and October 2019, aNSCLC pts consecutively referring to our Institution were prospectively screened with plasma NGS while included in two clinical trials: VISION (NCT02864992) and MAGIC trial, an observational study. In VISION trial NGS was performed in plasma (Guardant360 test) and tissue (Oncomine Focus Assay). In MAGIC Myriapod NGS-IL 56G Assay was used. Aim of the study was to evaluate the impact of STK11, KRAS and TP53 mutations (muts) on outcome of ICI-treated pts, with overall survival (OS) as primary endpoint. A control group of pts not receiving ICIs was also analyzed. Results: A total of 235 NSCLC pts were enrolled and received ICIs. 93 pts were analyzed in plasma at the time of beginning ICIs: median OS was 18.9 m (95% CI: 13.7-24.1) and median immune-related progression free disease (irPFS) 3.8 m (95% CI: 2.5-5.1). 49 (52.7%), 22 (23.7%) and 8 (8.6%) pts carried TP53, KRAS and STK11 pathogenic alterations, respectively. STK11 mutated pts showed a trend for worse OS compared with wildtype counterpart (14.9 m, 95% CI: 6.5-23.3, versus 20.3, 95% CI: 13.4-27.2, p = 0.192) KRAS muts had no impact on outcome. Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01). Number of muts negatively impacts pts’ OS (HR = 1.2, 95% CI: 1.1-1.3, p = 0.02) and was higher among TP53 mutated pts (p < 0.001, Mann-Whitney test). In multivariate analysis, TP53 and STK11/KRAS retained significance. A control group of pts not receiving ICIs was analyzed (n = 101): median OS was 16.8 m (95% CI: 13-20.6). Nor STK11 (n = 10), nor STK11/KRAS (n = 6) had impact on OS (HR = 1.8, 95% CI: 0.7-4.7, p = 0.267 and 1.4, 95% CI: 0.7-3.0, p = 0.293) while the presence of TP53 muts (n = 41) was associated with shorter OS (11.4 m, 95% CI: 7.3-15.5; HR = 2.2, 95% CI: 1.2-4.2, p = 0.009). Conclusions: NGS performed in plasma might be used to detect predictive markers. TP53 muts in plasma at baseline had prognostic value, while STK11/KRAS muts were associated with worse outcome to ICIs.
ctDNA is a useful tool for NGS molecular profiling in advanced NSCLC patients. Its clinical applicability in patients with gene rearrangements is still limited due to a lower detection rate of these ...types of alterations compared to single SNVs or small indels. To this purpose, we performed a study in two Italian centers to assess the concordance between tissue and plasma samples in the detection of genes fusions (ALK, ROS, RET) and METexon14 mutations in advanced NSCLC patients.
Patients with a histological diagnosis of oncogene addicted (ALK, ROS1, RET positive or METexon14 mutated) advanced NSCLC were enrolled at the time of first line of TKI treatment. Plasma samples were harvested before the start of TKI treatment and NGS analysis on ctDNA samples using the AVENIO ctDNA Expanded kit was performed. The Positive Percent Agreement (PPA) between tissue and plasma was calculated.
Fifty-eight rearranged or METexon14 mutated NSCLC patients were included and 57 ctDNA samples were successfully sequenced. An overall PPA of 37% (21/57) was obtained, with a best performance for RET fusion (80%), intermediate for METexon14 skipping mutations (40%) and ALK rearranged (36%) and a worst one for ROS1 rearranged samples (18%). We found TP53, APC and SMAD4 as most prevalent co-mutated genes (21%, 12% and 10% of patients, respectively). Among different factors considered, increased driver detection rate in patients with extra-thoracic metastases (p = 0.0049) was observed. Significantly shorter survival was observed in patients harboring co-occurring KRAS/NRAS mutations in ctDNA.
ctDNA testing to detect oncogenic fusions or METexon14 mutations in advanced NSCLC patients is useful, even if type of gene alterations and clinical characteristics could influence the driver detection rate. Liquid biopsy represents a complementary tool to tissue genotyping, however more sensitive approaches for gene fusions and METexon14 detection are needed to implement its strength and reliability.
In this diagram main results are condensed. PPA is depicted on the left, while summary of co-alteration status is graphed on the right. NGS, Next Generation Sequencing; AF, allele frequency Display omitted
•CtDNA NGS has a consolidated value for molecular profiling of NSCLC patients.•Assay sensitivity for fusions/METexon14 mutations is reduced compared to SNVs.•A variable detection rate according to mutation type was evidenced.•Extra-thoracic metastases correlated with gene alterations detection in cfDNA.•Co-mutations in KRAS or NRAS genes are associated with worse survival.
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