ACE2 expression is related to the interferon response in airway epithelial cells but is that functional for SARS-CoV-2 entry?

In vitro interferon (IFN)α treatment of primary human upper airway basal cells has been shown to drive ACE2 expression, the receptor of SARS-CoV-2. The protease furin is also involved in mediating SARS‐CoV‐2 and other viral infections, although its association with early IFN response has not been evaluated yet. In order to assess the in vivo relationship between ACE2 and furin expression and the IFN response in nasopharyngeal cells, we first examined ACE2 and furin levels and their correlation with the well-known marker of IFNs’ activation, ISG15, in children (n = 59) and adults (n = 48), during respiratory diseases not caused by SARS-CoV-2. A strong positive correlation was found between ACE2 expression, but not of furin, and ISG15 in all patients analyzed. In addition, type I and III IFN stimulation experiments were performed to examine the IFN-mediated activation of ACE2 isoforms (full-length and truncated) and furin in epithelial cell lines. Following all the IFNs treatments, only the truncated ACE2 levels, were upregulated significantly in the A549 and Calu3 cells, in particular by type I IFNs. If confirmed in vivo following IFNs’ activation, the induction of the truncated ACE2 isoform only would not enhance the risk of SARS‐CoV‐2 infection in the respiratory tract

A case of long-term survival after repeated response to oxaliplatin-based chemotherapy and repeated thermoablation of liver metastases from colorectal cancer. Should we introduce the concept of oxaliplatin-resistant tumors?

Background. The management of advanced colorectal cancer patients differs among cancer centers. International guidelines recommend offering all the recognized active regimens in order to obtain survival advantage, but little information is given about the sequence and combination in which such regimens should be administered. Case report.We report the case of a man with multiple liver metastasis from colorectal cancer followed for more than 78 months at our Institution. Repeated response to the same oxaliplatin, 5-fluorouracil and folinic acid chemotherapy schedule was achieved, and repeated radiofrequency ablation of liver metastases was performed until progression of lung and brain disease at 50 and 72 months, respectively, after the diagnosis of advanced disease. Although the tumor became oxaliplatin and chemoresistant after the onset of extra-hepatic disease, a more aggressive chemotherapy regimen, including a doublet with a biological, halted tumor growth. Conclusions. The patient survived for more than 78 months without experiencing a major impact on his quality of life. This case reflects the importance of following tumor biology in the therapeutic decision-making process, reintroducing oxaliplatin whenever possible, and adopting a more aggressive strategy when the tumor becomes oxaliplatin-resistant

Differential interferon gene expression in bronchiolitis caused by respiratory syncytial virus-A genotype ON1

Bronchiolitis severity is determined by a complex interaction among viral replication and antiviral immunity. The current respiratory syncytial virus (RSV)-A, genotype ON1 demonstrated a high replicative capacity but seemed to be clinically less severe than the previously circulating RSV-A, NA1. To learn insights about ON1 innate immune response, we analyzed expression levels of type I/III interferon (IFN)-related genes in the respiratory mucosa of infants with RSV bronchiolitis. We enrolled RSV-positive bronchiolitis patients over 12 epidemic seasons at a university hospital in Rome. From nasopharyngeal washings' cells (46 positive to NA1, 47 to ON1 and 28 to RSV-B, genotype BA), the mRNA copy number of the type III IFN receptor (IFNLR1 and IL10RB subunits), and of the type I/III IFN-stimulated genes, MxA and ISG56, was calculated using the threshold cycle relative quantification method with respect to an invariant gene. Expression levels of type III IFN receptor subunits genes positively correlated to each other and did not differ in infants infected with different RSV genotypes. The ISGs levels also positively correlated between them but differed among groups. MxA levels were significantly higher in NA1-infected infants than in those with ON1 and BA; ISG56 expression was slightly higher in NA1 than in the other strains. Interestingly, a moderate negative correlation existed between viral load and both ISGs values in ON1-infected infants only. The reduced ISG levels elicited during infections with ON1 (and BA) may cause a weaker control of RSV replication and/or an inadequate host immune response which may impact the risk of respiratory sequelae

THE ROLE OF HEMOGLOBIN LEVEL IN PREDICTING THE RESPONSE TO FIRST-LINE CHEMOTHERAPY IN ADVANCED COLORECTAL CANCER (ACC) PATIENTS

Background: Several in vitro studies showed that colorectal cancer cells responding to 5-fluorouracil (5-FU) become resistant under hypoxic conditions. Moreover, it has been demonstrated that tumoral tissues are hypoxic in anemic pts. We investigated the impact of hemoglobin levels in predicting response to first-line chemotherapy in ACC patients. Methods: We collected data from 394 consecutive patients treated and followed in two centers from 1994 to 2003. Two hundred and forty-five pts were men and 149 women. Median age: 61 years (29–80); WHO performance status (PS) 0/I/II: 279/90/25 pts; number of organs involved 1/2/3: 267/104/23 pts; metastases (mts) in liver were evident in 71% pts; mts in lung in 28% pts; mts in peritoneum in 19% pts; prior adjuvant chemotherapy was administered in 30% pts. All pts were submitted to 5-FU-based first-line chemotherapy. 184 pts received 5-FU ± folinic acid (FA); 195 pts received 5-FU + LOHP ± FA; 15 pts received 5-FU + CPT-11 ± FA. Hemoglobin levels were evaluated before chemotherapy start. Pts with hemoglobin < 12 g/dl were considered anemic. Response was evaluated every three cycles with CT scan. Results: Clinical response (CR + PR) was recorded in 136 pts 34.6%), stable disease in 155 (39.9%) and progression in 103 (26.5%). At baseline, 170 pts (43.1%) were anemic. 45/170 anemic pts (26.5%) and 91/224 non-anemic pts (40.6%) responded to chemotherapy (x2 = 8.57; P < 0.003). Anemia maintained its predictive role for disease response even after adjusting for PS, grading, T, or age in multivariate logistic analysis. Patients with normal hemoglobin levels showed a longer time to progression (13.0 months versus 10.1; P < 0.002) and a longer survival (27.6 months versus 17.8; P < 0.0001) than anemic ones. Cox’s multivariate survival analysis confirmed hemoglobin level as an independent predictor of time to progression and survival. Conclusions: Anemia is a strong predictive factor of activity and efficacy of 5-fluorouracil-based chemotherapy in advanced colorectal cancer patients

The role of lung metastasis resection in improving outcome of colorectal cancer patients: Results from a large retrospective study

BACKGROUND: The role of surgery for lung metastases (LM) secondary to colorectal cancer (CRC) remains controversial. The bulk of evidence is derived from single surgical series, hampering any definitive conclusions. The aim of this study was to compare the outcomes of CRC patients with LM submitted to surgery with those who were not. PATIENTS AND METHODS: Data from 409 patients with LM as the first evidence of advanced disease were extracted from a database of 1,411 patients. Patients were divided into three groups: G1, comprised of 155 patients with pulmonary and extrapulmonary metastases; G2, comprised of 104 patients with LM only and no surgery; G3, comprised of 50 patients with LM only and submitted to surgery. RESULTS: No difference in response rates emerged between G1 and G2. Median progression-free survival (PFS) times were: 10.3 months, 10.5 months, and 26.2 months for G1, G2, and G3, respectively. No difference in PFS times was observed between G1 and G2, whereas there was a statistically significant difference between G2 and G3. Median overall survival times were 24.2 months, 31.5 months, and 72.4 months, respectively. Survival times were longer in resected patients: 17 survived >5 years and three survived >10 years. In patients with LM only and no surgery, four survived for 5 years and none survived >10 years. CONCLUSIONS: Even though patients with resectable LM are more likely to be those with a better outcome, our study provides evidence suggesting an active role of surgery in improving survival outcomes in this patient subset

Development of the CMS detector for the CERN LHC Run 3

International audienceSince the initial data taking of the CERN LHC, the CMS experiment has undergone substantial upgrades and improvements. This paper discusses the CMS detector as it is configured for the third data-taking period of the CERN LHC, Run 3, which started in 2022. The entire silicon pixel tracking detector was replaced. A new powering system for the superconducting solenoid was installed. The electronics of the hadron calorimeter was upgraded. All the muon electronic systems were upgraded, and new muon detector stations were added, including a gas electron multiplier detector. The precision proton spectrometer was upgraded. The dedicated luminosity detectors and the beam loss monitor were refurbished. Substantial improvements to the trigger, data acquisition, software, and computing systems were also implemented, including a new hybrid CPU/GPU farm for the high-level trigger