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Background: Since the beginning of the covid19 pandemic, clinical and demographic data showed that cancer patients are at high risk of developing severe consequences of Sars-Cov2 disease. For this reason, vaccination is strongly recommended, especially for patients on active treatment. Nevertheless, the efficacy of the Sars-Cov2 vaccine in cancer patients is not fully investigated. Our trial aim to explore the seroconversion in a large series of vaccinated cancer patients undergoing active treatment. Here we present a subgroup analysis concerning patients affected by breast cancer. Methods: The “VAX-on” is a single-center study that enrolled 366 cancer patients who underwent oncological treatment within the last six months. The study was approved by the ethics committee and all patients had to sign specific informed consent to be enrolled. Subjects were vaccinated against Sars-Cov2 with mRNA vaccine BNT162b2 (Comirnaty) - Pfizer BioNTech. Blood samples were obtained to quantify the production of specific anti-Spike IgG antibodies at day 21 from the first dose and at 6-8 weeks after the second dose. The antibody laboratory title cut-off of 50 U.A./mL defined the seroconversion. Results are shown as Mean and Standard Deviation for continuous variable, percentage (%) for categorical ones. The Mann-Whitney test or Chi-Square test were used to compare continuous or categorical groups, respectively. Results: A total of 100 patients with breast cancer were enrolled. Clinical and demographic data are summarized in Table 1. The median age was 60.5 years and the majority had an ECOG PS of 0 (75%). Almost all were women (97%), with advanced cancer in 60% of cases. In early or advanced setting 46% patients were treated with chemotherapy while 54% were on target therapy (also including monoclonal antibody and CDK4/6 inhibitors). The mean antibody title after the first dose of mRNA Comirnaty vaccine was 2185.03±9303.26 U.A./mL (M±SD), while after the second dose the mean antibody title rise to 6492.10±10425.95 (M±SD). After the first dose 61% of patients were considered as immunized, meanwhile after the second dose 86% of patients resulted immunized (defined as an antibody title >50 U.A./mL). In the 9 patients in treatment with steroids (prednisone > 10mg/die or equivalent), there was a trend to a decreased antibody development compared to patients without chronic use of steroids (p 0.06 and 0.05 after the first and second dose, respectively). Of interest, patients using G-CSF (12%) had a significant reduction in the production of Sars-Cov2 antibody after vaccination compared to patients who did not use them (p 0.02 and Table 1.Parameters *Gender (F) (%)97 (97.00)Age (yrs)60.55±11.94Advanced Stage (Yes) (%)60 (60.00)ECOGPS (%)075 (75.00)121 (21.00)24 (4.00)Setting (%)Other Therapy60 (60.00)Adjuvant & Neoadjuvant40 (40.00)Therapy (%)Other46 (46.00)Target54 (54.00)Last cycle 10 mg)/> 7 days9 (9.00)FANS last 7 days (Yes) (%)15 (15.00)G-CSF last 21 days (Yes) (%)12 (12.00)Previous Allergies (Yes) (%)19 (19.00)Antibody Title 1st Dose2185.03±9303.26Antibody Level 1st Dose (>50) (%)61 (62.89)Antibody Title 2nd Dose6492.10±10425.95Antibody Level 2nd Dose (>50) (%)86 (92.47) Citation Format: Agnese Fabbri, Eleonora Marrucci, Fabrizio Nelli, Marco Mazzotta, Angelo Onorato, Primi Francesca, Mario Giovanni Chilelli, Antonella Virtuoso, Carlo Signorelli, Julio R Giron Berrios, Marta Schirripa, Rossella Donghia, Enzo Maria Ruggeri. Evaluation of the effects of anticancer treatments in cancer patients undergoing SARS-COV2 vaccination (VAX-on study: Breast cancer subgroup analysis) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-11-02.

This figure shows the signal pathway of TLR1, TLR2, and TLR6. TLR1 and TLR6, each of which forms a heterodimer with TLR2, initiate MAPK or NFκB pathway through TAK1. MyD88: myeloid differentiation factor88, TRAF: TNF receptor-associated factor, IRAK: 　IL-1R associated kinase, TAK: TGFβ-activated kinase, TAB: TAK1-binding protein, MAPK: mitogen-activated protein kinase.

This table shows the association of each SNP and clinical outcome in TRIBE. The association between SNP and clinical outcome in FIRE-3 is also demonstrated when there are statistically significant associations in TRIBE.

Supplementary Table

Supplementary Figure S2

Purpose:BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1–V600E) or as dimers (class 2–codons 597/601), and RAS-dependent with impaired kinase activity (class 3–codons 594/596). Although clinical, pathologic, and molecular features of V600EBRAF-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.Experimental Design:Data from 117 patients with BRAF (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan–Meier and log-rank test.Results:Class 3 BRAF-mutated mCRC was more frequently left sided (P = 0.0028), pN0 (P = 0.0159), and without peritoneal metastases (P = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61–3.54] for class 1, 1.90 (95% CI, 0.85–4.26) for class 2, and 0.93 (95% CI, 0.51–1.69) for class 3 (P < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated class 2 (P = 0.033) compared with class 3 cases.Conclusions:For the first time, different clinical and pathologic features and outcome data were reported according to the three BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab.Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed.Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D–binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046).Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784–93. ©2017 AACR.

SNPs and clinical outcomes among patients with mCRC treated with first-line FOLFIRI/bevacizumab in FIRE-3 (discovery cohort)

Single particle tracking (SPT) combined with total internal reflection fluorescence (TIRF) microscopy is an outstanding approach to decipher crucial molecular mechanisms on the cell membrane at the nanometric scale. In multicolor configurations it can even be the ideal tool to investigate interactions, but this is hindered by a number of experimental challenges. We systematically and quantitatively analyze the impact of all the necessary sub-elements of any SPT-TIRF setup on signal-to-noise ratio, especially in dynamic studies using minimally-invasive dyes for biomolecule labeling. We show that the dominant limiting factor is the autofluorescence originating from the commonly-used optical glass. We identify and test a different material and show a significant improvement of signal-to-noise ratio in a multichannel TIRF configuration employing the new glass covers. We also address the problem of photobleaching of fluorescent probes by presenting effective approaches suited to a multicolor implementation that requires simultaneous stabilization of multiple dyes. We apply the developed protocol to the analysis of p75 receptors labeled by two fluorophores on the membrane of living cells. Our strategy yields reliable, simultaneous two-color SPT, even for fast-diffusing receptors, enabling this study under conditions not accessible with standard experimental configurations. We argue that the present protocol can pave the way for multicolor super-resolved localization and tracking of single molecules by TIRF microscopy, much expanding the potential of SPT.

How does Classical Extensional Mereology (CEM) interact with time and modality? In its first-order logical setting, CEM does not have the formal tools to deal with these dimensions. Nonetheless, it is often charged with endorsing controversial metaphysical theses like mereological essentialism and mereological constantism. Allowing CEM to interact with quantified modal logic (QML) without adding any further mereological commitment clarifies which modal theorems CEM actually implies and eventually undercuts wrong-headed allegations against it. From the logical side, I endorse system KTB of modal logic with constant domain semantics, but several theorems are also provable with the adoption of weaker logics (like KT and even the simplest K). We will also be able to successfully simulate variable domain semantics via the procedure of existential relativisation. From the mereological side, I necessitate the ordering axioms and the strong-supplementation axiom, leaving the door open for four different alternatives to deal with the axiom of unrestricted composition. The mereological results emerging from this setting include the necessity of extensionality principles – which does not lead to mereological essentialism – and the existence of possible fusions even when an actualist version of unrestricted composition is adopted. In the final part of the thesis, I apply the main findings of modal extensional mereology to group membership. After showing why some standard objections are misguided, I argue that the standard account of social groups based on CEM fails to be satisfactory because it conceives group membership as just parthood. My proposal is to regard group membership as φ-parthood instead. Under this new account, social groups are not just mereological wholes, but mereological wholes with a specified understanding of the parthood relation. Endorsing this novel account allows us to retain an account of social groups based on CEM while avoiding the knockdown objections faced by the standard one.

The evolution of the Apennine wedge has seen the time-space migration of the forebulge, foredeep, thrust wedge, and back-arc extension phases in the wake of the Eastward rollback of the subducting Adria slab. In this framework, thrusting and post-orogenic extensional faulting have occurred in two parallel forelandward-migrating ribbons, with extensional deformation overprinting or partly exploiting anisotropies of the inherited thrust system. Here, we explore the tectonic framework and the timing of thrusting and subsequent negative inversion of the Circeo thrust, one of the major thrusts in the inner portion of the central Apennines, with the main aim to constrain the timing and mode of the compression to extension switch. Structural analysis, carbonate C and O and clumped isotopes analysis, X-ray diffraction of clay minerals, and U-Pb dating of calcite slickenfibers have been integrated with seismic interpretation, cross-section balancing, and 1D burial and thermal modeling. We show that the Circeo thrust developed during Langhian-Serravallian time. Its extensional reactivation is dated at the Serravallian, during the stacking of an underlying thrust slice, before the onset of Pliocene back-arc extension in the area. Combination of our data with the age of thrusts, extensional basins, and base of the foredeep infill of the central Apennines, demonstrates that forelandward migration of the foredeep-thrust system occurred at variable velocities. Accelerations and decelerations are synchronous, respectively, with the opening of the Liguro-Provençal and Tyrrhenian back-arc basins and with the interluding quiescent period., Tectonics, 42 (6), ISSN:1944-9194

Structural analysis coupled with geochemical study of syn-tectonic mineralizations unraveled the role of fluids during the polyphase tectonic evolution of the Val D’Agri, a seismically-active intermontane basin located in the Southern Apennines fold and thrust belt, hosting the largest onshore oil field in western Europe. In this basin, the structural control on present-day fluid circulation is still not well constrained. For this reason, the aim of this work is to reconstruct the Val d’Agri fault system (VAF) architecture and paleo-fluid circulation during the basin tectonic evolution. The VAF evolution was caused by non-coaxial polyphase stress regimes that can be summarized in: 1) Upper Miocene-Lower Pliocene compressional regime; 2) Upper Pliocene-Lower Pleistocene late orogenic strike-slip regime 3) Early Pleistocene-Present post-orogenic extensional regime. Based on new field work, mapping, and structural analysis, we recognized that the VAF is organized in different oriented faults sets. The main sets are N-S-, NE-SW-, and ESE-WNW-striking faults, where the last one has the higher degree of maturity. U-Pb dating of calcite slickenfibres highlighted the long-term tectonic history of these fault sets, with episodes of activation and reactivation of inherited faults. In particular, we recognize: N-S-striking normal faults that reactivated inherited Upper Miocene-Lower Pliocene thrusts; Upper Pleistocene NE-SW-striking normal-lateral faults; one Miocene ESE-WNW-striking normal-lateral fault, with also evidence of reactivation in more recent time. Clumped isotopes analysis together with optical and cathodoluminescence observations of about 50 syn-tectonic calcite mineralizations allowed us to link specific fluid pathways to the different stress regimes. Indeed, bed-parallel veins and mineralizations sampled along transpressive, transtensive, and normal fault sets show that: 1) during the Upper Miocene-Lower Pliocene compressive tectonic phase, fluid circulation occurred in a closed system, characterized by host-rock buffered fluids; 2) during Upper Pliocene-Lower Pleistocene late orogenic phase, fluid circulation occurred in an open system, characterized by meteoric water with low to moderate residence time; 3) during the Lower Pleistocene-Present extensional phase, fluid circulation occurred in an open system, characterized by the mixing of meteoric water and uprising deep high temperature fluids. We highlight that the reconstruction of paleo to present-day fluid circulation is a valid tool for assessing natural and induced seismic hazard in seismically active areas where hydrocarbons are exploited and fluids are injected into the crust, such as in the Val d'Agri basin.