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Cancer Immunology, Immunotherapy : CII Jul 2024Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these...
Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4 and CD8 T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.
Topics: Animals; Mice; Vaccines, DNA; Brain Neoplasms; Immune Checkpoint Inhibitors; Humans; Programmed Cell Death 1 Receptor; Cancer Vaccines; Mice, Inbred C57BL; Female; B7-H1 Antigen; Immunotherapy; Glioblastoma; Cell Line, Tumor; Intramolecular Oxidoreductases
PubMed: 38954031
DOI: 10.1007/s00262-024-03770-x -
Cancer Immunology, Immunotherapy : CII Jul 2024Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal...
BACKGROUND
Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear.
METHODS
Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry.
RESULTS
In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects.
CONCLUSION
We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.
Topics: Colorectal Neoplasms; Integrin alpha Chains; Animals; Humans; CD8-Positive T-Lymphocytes; Mice; Liver Neoplasms; Antigens, CD; Prognosis; Female; Male; Immunologic Memory; Biomarkers, Tumor; Memory T Cells; Lymphocytes, Tumor-Infiltrating; Middle Aged
PubMed: 38954030
DOI: 10.1007/s00262-024-03709-2 -
Cancer Immunology, Immunotherapy : CII Jul 2024Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors,...
Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1β, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1β were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1β between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.
Topics: Humans; Colorectal Neoplasms; Female; Male; Cytokines; Middle Aged; Aged; Intercellular Signaling Peptides and Proteins; Chemokines; Treatment Outcome; Biomarkers, Tumor; Adult; Prognosis; Case-Control Studies
PubMed: 38954024
DOI: 10.1007/s00262-024-03746-x -
Abdominal Radiology (New York) Jul 2024Hepatic ductopenia is a pathologic diagnosis characterized by a decrease in the number of intrahepatic bile ducts as a consequence of various underlying etiologies. Some... (Review)
Review
Hepatic ductopenia is a pathologic diagnosis characterized by a decrease in the number of intrahepatic bile ducts as a consequence of various underlying etiologies. Some etiologies, such as primary sclerosing cholangitis, primary biliary cholangitis, and ischemic cholangitis, often have distinctive imaging findings. In contrast, other causes such as chronic rejection following liver transplantation, drug-induced biliary injury, infection, malignancy such as lymphoma, and graft-versus-host disease may only have ancillary or non-specific imaging findings. Thus, diagnosing ductopenia in conditions with nonspecific imaging findings requires a multidimensional approach, including clinical evaluation, serological testing, imaging, and liver histology to identify the underlying cause. These etiologies lead to impaired bile flow, resulting in cholestasis, liver dysfunction, and, ultimately, cirrhosis and liver failure if the underlying cause remains untreated or undetected. In the majority of instances, individuals diagnosed with ductopenia exhibit a positive response to treatment addressing the root cause or cessation of the causative agent. This article focuses on acquired causes of ductopenia, its clinical manifestation, histopathology, imaging diagnosis, and management.
PubMed: 38954003
DOI: 10.1007/s00261-024-04462-x -
Time to improve the management of patients with suspected acute appendicitis: a retrospective study.Abdominal Radiology (New York) Jul 2024Preoperative imaging is now recommended in patients with suspected acute appendicitis (AA) by the World Society of Emergency Surgery. Our aims were (i) to describe our...
PURPOSE
Preoperative imaging is now recommended in patients with suspected acute appendicitis (AA) by the World Society of Emergency Surgery. Our aims were (i) to describe our local practice and (ii) to evaluate the efficiency of performing ultrasound (US) and/or computed tomography (CT) by assessing management failure, specificity and sensitivity, and length of stay in the emergency department (ED).
METHODS
This single-center retrospective study included all patients who underwent US or CT for the management of suspected AA. Patients were included if they were admitted to the ED in February or June between 2012 and 2021.
RESULTS
The study included 339 patients. US was performed in 278 patients (82%), of whom 91 also had a second-line CT (31.3%). There was a significant increase in the rate of CT over the inclusion period. Three percent (3%) of the patients had management failure and a higher age and CT or US + CT were significantly associated with the risk of management failure. Length of stay in the ED increased significantly when a second-line CT was performed. The sensitivity and specificity of US were 84.8% and 93.2%, respectively. Sensitivity was significantly different from CT (100%, p = 0.03) but not specificity (87.9%, p = 0.29). Both US and CT results were more likely to be considered for further management if positive. The vast majority of patients with negative or inconclusive results were admitted in surgical wards or underwent a second-line examination.
CONCLUSION
If available in the hospital together with CT, US should probably be performed systematically and as a first-line examination in patients with suspected acute appendicitis.
PubMed: 38954002
DOI: 10.1007/s00261-024-04471-w -
Cancer Immunology, Immunotherapy : CII Jul 2024Tumor immunotherapies targeting PD-(L)1 exhibit anti-tumor efficacy in only 10-30% of patients with various cancers. Literature has demonstrated that a "hot tumor" which...
Tumor immunotherapies targeting PD-(L)1 exhibit anti-tumor efficacy in only 10-30% of patients with various cancers. Literature has demonstrated that a "hot tumor" which contains high T lymphocytes in the tumor microenvironment exhibits a better response to immunotherapies than a "cold tumor." This study aimed to investigate whether tumor-intrinsic IFNα and CXCL10 determine the recruitment and activation of CD8 T cells to become "hot tumor." In this study, we found that CXCL10 overexpressed in a variety of tumors including lung, colon, and liver tumors with a correlation with PD-L1. High PD-L1 and CXCL10 are associated with better survival rates in tumor patients receiving immunotherapies. IFNs-downstream transcriptional factor IRF-1 and STAT1 were correlated with PD-L1 and CXCL10 expression. We demonstrated that IRF-1 and STAT1 were both bound with the promoters of PD-L1 and CXCL10, sharing the same signaling pathway and determining IFNs-mediated PD-L1 and CXCL10 expression. In addition, IFNα significantly increased activation marker IFNγ in PBMCs, promoting M1 type monocyte differentiation, CD4 T, and CD8 T cell activation. Particularly, we found that CD8 T lymphocytes abundantly expressed CXCR3, a receptor of CXCL10, by flow cytometry, indicating that tumor-intrinsic CXCL10 potentially recruited CD8 T in tumor microenvironment. To demonstrate the hypothesis, immunotherapy-sensitive CT26 and immunotherapy-resistant LL/2 were used and we found that CT26 cells exhibited higher IFNα, IFNγ, CXCL10, and PD-L1 levels compared to LL/2, leading to higher IFNγ expression in mouse splenocytes. Moreover, we found that CD8 T cells were recruited by CXCL10 in vitro, whereas SCH546738, an inhibitor of CXCR3, inhibited T cell migration and splenocytes-mediated anti-tumor effect. We then confirmed that CT26-derived tumor was sensitive to αPD-L1 immunotherapy and LL/2-tumor was resistant, whereas αPD-L1 significantly increased T lymphocyte activation marker CD107a in CT26-derived BALB/c mice. In conclusion, this study revealed that CXCL10 expression is correlated with PD-L1 in tumors, sharing the same signaling pathway and associating with better immunotherapeutic efficacy. Further evidence in the syngeneic tumor models demonstrated that immunotherapy-sensitive CT26 intrinsically exhibited higher IFNα and CXCL10 compared to immunotherapy-resistant LL/2 to recruit and activate CD8 T cells in the tumor microenvironment, exhibiting "hot tumor" characteristic of sensitizing αPD-L1 immunotherapies.
Topics: Chemokine CXCL10; Tumor Microenvironment; Animals; Mice; Humans; Interferon-alpha; Immunotherapy; Neoplasms; Lymphocyte Activation; Cell Line, Tumor; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Female; STAT1 Transcription Factor
PubMed: 38953994
DOI: 10.1007/s00262-024-03761-y -
Neuroradiology Jul 2024To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy...
PURPOSE
To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months.
METHODS
CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders.
RESULTS
125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07-8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%).
CONCLUSION
Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization.
PubMed: 38953988
DOI: 10.1007/s00234-024-03411-1 -
Cell and Tissue Research Jul 2024The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19, may lead to multiple organ dysfunctions and long-term complications. The...
SARS-CoV-2-related peptides induce endothelial-to-mesenchymal transition in endothelial capillary cells derived from different body districts: focus on membrane (M) protein.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19, may lead to multiple organ dysfunctions and long-term complications. The induction of microvascular dysfunction is regarded as a main player in these pathological processes. To investigate the possible impact of SARS-CoV-2-induced endothelial-to-mesenchymal transition (EndMT) on fibrosis in "long-COVID" syndrome, we used primary cultures of human microvascular cells derived from the lungs, as the main infection target, compared to cells derived from different organs (dermis, heart, kidney, liver, brain) and to the HUVEC cell line. To mimic the virus action, we used mixed SARS-CoV-2 peptide fragments (PepTivator) of spike (S), nucleocapsid (N), and membrane (M) proteins. TGFβ2 and cytokine mix (IL-1β, IL-6, TNFα) were used as positive controls. The percentage of cells positive to mesenchymal and endothelial markers was quantified by high content screening. We demonstrated that S+N+M mix induces irreversible EndMT in all analyzed endothelial cells via the TGFβ pathway, as demonstrated by ApoA1 treatment. We then tested the contribution of single peptides in lung and brain cells, demonstrating that EndMT is triggered by M peptide. This was confirmed by transfection experiment, inducing the endogenous expression of the glycoprotein M in lung-derived cells. In conclusion, we demonstrated that SARS-CoV-2 peptides induce EndMT in microvascular endothelial cells from multiple body districts. The different peptides play different roles in the induction and maintenance of the virus-mediated effects, which are organ-specific. These results corroborate the hypothesis of the SARS-CoV-2-mediated microvascular damage underlying the multiple organ dysfunctions and the long-COVID syndrome.
PubMed: 38953987
DOI: 10.1007/s00441-024-03900-y -
European Archives of Psychiatry and... Jul 2024A rise in affective and anxiety disorders and in antidepressant (AD) treatment during the COVID-19 pandemic has been extensively described, but few studies were provided...
PURPOSE
A rise in affective and anxiety disorders and in antidepressant (AD) treatment during the COVID-19 pandemic has been extensively described, but few studies were provided at the individual level, further considering COVID-19 severity and vaccination status.
METHODS
Case-control study evaluating the association between the new use of ADs and a previous COVID-19 infection, in Friuli Venezia Giulia Region, Italy, from March 1, 2020, to July 19, 2022. Multiple conditional logistic regressions assess the association between a new AD use and a COVID-19 infection previous to the index date, stratified by gender, age and anti-COVID-19 vaccination status. Odds Ratios (OR) and 95% confidence intervals were reported.
RESULTS
COVID-19 was associated with AD treatment after the infection. The disease severity was positively associated with a growing risk of being dispensed an AD, with the highest risk in unvaccinated subjects previously hospitalised in ICU (OR = 28.77). The risk of using ADs after COVID-19 infection was higher in unvaccinated subjects aged 65 years and older, both females and males. The association between COVID-19 infection and AD dispensation in vaccinated subjects was not significant, with the exception of females aged 65 years and over.
CONCLUSIONS
Anti-COVID-19 vaccination, especially among the elderly, might prevent post-COVID AD treatment. Clinicians should be aware that COVID-19 patients requiring hospitalisation are more likely to experience these symptoms, given their higher risk of being dispensed ADs. Future studies may benefit by analysing the incidence of both mental disorders and psychotropic treatment in post-COVID patients, considering socioeconomic factors and vaccination status.
PubMed: 38953980
DOI: 10.1007/s00406-024-01846-4 -
Pediatric Cardiology Jul 2024The role of preoperative cardiac computed tomography (CT) in neonates with pulmonary atresia and intact ventricular septum (PA-IVS) remains unclear. This study was aimed...
Pulmonary Atresia with Intact Ventricular Septum: Correlation of Preoperative Computed Tomography-Derived Parameters with Echocardiographic Tricuspid Valve Z-Score and Surgical Outcomes.
The role of preoperative cardiac computed tomography (CT) in neonates with pulmonary atresia and intact ventricular septum (PA-IVS) remains unclear. This study was aimed to elaborate the role of preoperative CT-derived anatomical and functional findings in planning treatment strategies in neonates with PA-IVS. The presence of ventriculocoronary arterial connections was evaluated by CT. CT-derived ventricular volumetric parameters were compared and correlated with echocardiographic tricuspid valve (TV) z-score in 12 neonates with PA-IVS. Cardiac CT and echocardiographic findings were compared between definite surgical types (median follow-up, 4 years). Ventriculocoronary arterial connections were identified with CT in 58.3% of cases (7/12) and associated with higher incidence of Fontan procedure (42.9%, 3/7) and high mortality (28.6%, 2/7). The CT-derived and echocardiographic TV z-scores exhibited a high correlation (R = 0.924, p < 0.001). The CT-derived right ventricle (RV) volume and RV-left ventricle volume ratio also displayed high correlations (R = 0.875 and 0.867, respectively; p < 0.001) with echocardiographic TV z-score. More positive echocardiographic TV z-score, high CT-derived RV end-diastolic volume and RV-left ventricle volume ratio, and low CT-derived left ventricular end-diastolic volume were observed in biventricular surgery group (N = 2), compared to Fontan operation (N = 3) and 1.5 ventricular surgery (N = 3) groups, and mortality cases (N = 3). Preoperative CT-derived coronary artery anatomy and ventricular volumetric parameters may supplement treatment planning in neonates with PA-IVS especially when multifactorial decision including echocardiographic TV z-score is in a gray zone.W.
PubMed: 38953951
DOI: 10.1007/s00246-024-03570-1