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Molecular Oncology Aug 2023Snail1 is a transcriptional factor required for cancer-associated fibroblast (CAF) activation, and mainly detected in CAFs in human tumors. In the mouse mammary tumor...
Snail1 is a transcriptional factor required for cancer-associated fibroblast (CAF) activation, and mainly detected in CAFs in human tumors. In the mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) model of murine mammary gland tumors, Snai1 gene deletion, besides increasing tumor-free lifespan, altered macrophage differentiation, with fewer expressing low levels of MHC class II. Snail1 was not expressed in macrophages, and in vitro polarization with interleukin-4 (IL4) or interferon-γ (IFNγ) was not altered by Snai1 gene depletion. We verified that CAF activation modified polarization of naïve bone-marrow-derived macrophages (BMDMΦs). When BMDMΦs were incubated with Snail1-expressing (active) CAFs or with conditioned medium derived from these cells, they exhibited a lower cytotoxic capability than when incubated with Snail1-deleted (inactive) CAFs. Gene expression analysis of BMDMΦs polarized by conditioned medium from wild-type or Snai1-deleted CAFs revealed that active CAFs differentially stimulated a complex combination of genes comprising genes that are normally induced by IL4, downregulated by IFNγ, or not altered during the two canonical differentiations. Levels of RNAs relating to this CAF-induced alternative polarization were sensitive to inhibitors of factors specifically released by active CAFs, such as prostaglandin E and TGFβ. Finally, CAF-polarized macrophages promoted the activation of the immunosuppressive regulatory T cells (T-regs). Our results imply that an active CAF-rich tumor microenvironment induces the polarization of macrophages to an immunosuppressive phenotype, preventing the macrophage cytotoxic activity on tumor cells and enhancing the activation of T-reg cells.
Topics: Humans; Mice; Animals; Cancer-Associated Fibroblasts; Interleukin-4; Culture Media, Conditioned; Cell Differentiation; Macrophages; Tumor Microenvironment; Cell Line, Tumor; Neoplasms
PubMed: 37199012
DOI: 10.1002/1878-0261.13454 -
Journal of Neurovirology Oct 2023Our study aims to report on the demographic, incidence rate (IR), clinical, and microbiological characteristics of PML patients diagnosed in our tertiary-care hospital... (Review)
Review
Our study aims to report on the demographic, incidence rate (IR), clinical, and microbiological characteristics of PML patients diagnosed in our tertiary-care hospital over the past 12 years. In this retrospective observational study, we reviewed all requests for JCPyV PCR in CSF from patients with suspected PML. We collected demographic, clinical, and microbiological data of patients diagnosed with PML. Since 2018, real-time quantitative PCR has been used, whereas prior to 2018, samples were sent to our National Reference Center for qualitative diagnosis. Thirteen patients were diagnosed with PML, with 10 of them having a definitive diagnosis and 3 classified as a possible diagnosis with negative PCR results. Eleven patients had advanced HIV, one had non-Hodgkin's lymphoma, and one had systemic lupus erythematosus. Most of the white matter lesions were located at the cerebral level, although the parenchyma and cerebellum were also affected. The most frequent symptoms were behavioral disorders and hemiparesis. The viral load of JCPyV in cerebrospinal fluid was < 1000 copies/mL in three patients. Six patients received compassionate treatment, and all six patients with definitive PML diagnosis died. Although advanced HIV patients were the most affected by PML in our study, it should also be considered in patients with other underlying diseases. While current PCR tests offer high sensitivity and specificity, false negatives can occur. The prognosis of the disease remains poor, and early multidisciplinary diagnosis-including clinical, microbiological, and neuroimaging assessments-remains crucial for improving neurological damage and prognosis.
Topics: Humans; Leukoencephalopathy, Progressive Multifocal; Retrospective Studies; JC Virus; HIV Infections; Tertiary Care Centers; Real-Time Polymerase Chain Reaction; Observational Studies as Topic
PubMed: 37470903
DOI: 10.1007/s13365-023-01158-8 -
Multiple Sclerosis and Related Disorders Sep 2023Progressive multifocal leukoencephalopathy (PML) is a rare viral central nervous system (CNS) demyelinating disease primarily associated with a compromised immune... (Review)
Review
Radiological abnormalities in progressive multifocal leukoencephalopathy: Identifying typical and atypical imaging patterns for early diagnosis and differential considerations.
Progressive multifocal leukoencephalopathy (PML) is a rare viral central nervous system (CNS) demyelinating disease primarily associated with a compromised immune system. PML is seen mainly in individuals with human immunodeficiency virus, lymphoproliferative disease, and multiple sclerosis. Patients on immunomodulators, chemotherapy, and solid organ or bone marrow transplants are predisposed to PML. Recognition of various PML-associated typical and atypical imaging abnormalities is critical for early diagnosis and differentiating it from other conditions, especially in high-risk populations. Early PML recognition should expedite efforts at immune-system restoration, allowing for a favorable outcome. This review aims to provide a practical overview of radiological abnormalities in PML patients and address differential considerations.
Topics: Humans; Leukoencephalopathy, Progressive Multifocal; Natalizumab; Immune Reconstitution Inflammatory Syndrome; Multiple Sclerosis; Early Diagnosis; JC Virus
PubMed: 37418930
DOI: 10.1016/j.msard.2023.104830 -
JCI Insight Nov 2023Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role...
Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.
Topics: Humans; Kidney Transplantation; Immunologic Memory; CD8-Positive T-Lymphocytes; Receptors, Antigen, T-Cell; Viruses
PubMed: 37751288
DOI: 10.1172/jci.insight.172681 -
Pathologie (Heidelberg, Germany) Jul 2024Infections can affect the kidney via different pathways. Urinary tract infections can directly involve the renal tissue by spreading along pre-existing canalicular... (Review)
Review
Infections can affect the kidney via different pathways. Urinary tract infections can directly involve the renal tissue by spreading along pre-existing canalicular structures. Such an ascending infection can manifest as a highly active and purulent or even abscessing interstitial nephritis or as a chronic-fibrosing process in recurrent pyelonephritis. Viral infections can also use the canalicular route as in polyomavirus nephropathy or spread via the blood stream in a hematogenous manner as in the case of cytomegalovirus or hantavirus infections. Likewise, bacterial infections can reach the kidney via the blood in the case of systemic infection. Another large group of nephropathies taking place as a sequel of infections includes infection-related glomerulonephritides (IRGN), which are mediated by a series of immunological mechanisms. These IRGN can be subdivided according to their temporal association with the infectious process, occurring either after the infection has healed (postinfectious) or accompanying the ongoing infectious process (parainfectious). The latter, in particular, is of increasing importance in the daily practice of nephropathologists, especially in older patients. A number of other glomerulonephritis forms, i.e., membranous or membranoproliferative forms, can occur as a consequence of infection. In addition, infections can trigger nephropathies, such as thrombotic microangiopathy. The present article gives an overview of morphologic changes in renal parenchyma that take place as a consequence of infectious processes, with particular focus on IRGN.
Topics: Humans; Glomerulonephritis; Urinary Tract Infections; Kidney; Kidney Diseases; Nephritis, Interstitial; Bacterial Infections
PubMed: 38598098
DOI: 10.1007/s00292-024-01322-9 -
Experimental and Clinical... Sep 2023This study aimed to determine the predictive factors of BK virus viremia/nephropathy in kidney transplant recipients and to evaluate the effects of low-dose tacrolimus...
OBJECTIVES
This study aimed to determine the predictive factors of BK virus viremia/nephropathy in kidney transplant recipients and to evaluate the effects of low-dose tacrolimus plus everolimus.
MATERIALS AND METHODS
This study included 3654 kidney transplant recipients. The patients were divided into 2 groups: group 1 were BK virus negative (n = 3525, 96.5%) and group 2 were BK virus positive (n = 129, viremia 3.5%, nephropathy 1%). Predictive factors were determined by receiver operating characteristic curve analysis and logistic regression models.We also divided and analyzed patients with BK virus viremia/nephropathy into 2 groups according to immunosuppressive changes. Group 2a had been switched to low-dose tacrolimus plus everolimus (n = 54, 41.9%), and group 2b had been switched to other immunosuppressive protocols (n = 75, 58.1%).
RESULTS
We found that use of anti-T-cell lymphocyte globulin and tacrolimus, deceased donor transplant, and rejection were predictive factors for BK virus viremia/nephropathy. In addition, patients who had low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor regimens showed a low rate of BK virus development(only 6.2% of all cases). In Group 2a, both the BK polyomavirus-associated nephropathy rate (n = 23 [42.6%] vs n = 12 [16%] in group 2b; P = .001) and viral load (DNA > 104 copies/mL) (n = 49 [90.7%] vs n = 27 [36%] in group 2b; P = .001) were increased versus group 2b. Graft function, graft survival, viral clearance, and rejection rate were similar between the groups after protocol change.
CONCLUSIONS
BK virus viremia/nephropathy rate was lower in patients who received low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor protocols; the low-dose tacrolimus plus everolimus switch protocol after BK virus was more effective and safe than other protocols.
Topics: Humans; Tacrolimus; Everolimus; BK Virus; Kidney Transplantation; Calcineurin Inhibitors; Viremia; Immunosuppressive Agents; Sirolimus; Nephritis, Interstitial; Polyomavirus Infections; Tumor Virus Infections; Transplant Recipients; TOR Serine-Threonine Kinases
PubMed: 37885288
DOI: 10.6002/ect.2023.0065 -
Journal of the American Society of... May 2024Posoleucel was generally safe, well tolerated, and associated with a greater reduction of BK viremia compared with placebo. BK viremia reduction occurred coincident with... (Randomized Controlled Trial)
Randomized Controlled Trial
KEY POINTS
Posoleucel was generally safe, well tolerated, and associated with a greater reduction of BK viremia compared with placebo. BK viremia reduction occurred coincident with an increase in the circulating frequency of BK virus–specific T cells in posoleucel recipients. The presence and persistence of posoleucel was confirmed by T-cell receptor variable sequencing.
BACKGROUND
Kidney transplant recipients with BK virus infection are at risk of developing BK virus–associated nephropathy, allograft rejection, and subsequent graft loss. There are no approved treatments for BK virus infection. Posoleucel is an off-the-shelf, allogeneic, multivirus-specific T-cell investigational therapy targeting BK virus, as well as five other opportunistic viruses: adenovirus, cytomegalovirus, Epstein–Barr virus, human herpesvirus 6, and John Cunningham virus.
METHODS
In this phase 2, double-blind study, kidney transplant recipients with BK viremia were randomized 1:1:1 to receive posoleucel weekly for 3 weeks and then every 14 days (bi-weekly dosing) or every 28 days (monthly dosing) or placebo for 12 weeks. Participants were followed for 12 weeks after completing treatment. The primary objective was safety; the secondary objective was plasma BK viral load reduction.
RESULTS
Sixty-one participants were randomized and dosed. Baseline characteristics were similar across groups. No deaths, graft-versus-host disease, or cytokine release syndrome occurred. The proportion of patients who had adverse events (AEs) judged by the investigators to be treatment-related was slightly lower in recipients of posoleucel: 20% (4 of 20 patients) and 18% (4 of 22) in those infused on a bi-weekly and monthly schedule, respectively, and 26% (5 of 19) in placebo recipients. None of the grade 3–4 AEs or serious AEs in any group were deemed treatment-related. No deaths, graft-versus-host disease, or cytokine release syndrome occurred. Three participants had allograft rejection, but none were deemed treatment-related by investigators. In posoleucel recipients, BK viremia reduction was associated with an increase in the circulating frequency of BK virus–specific T cells, and the presence and persistence of posoleucel was confirmed by T-cell receptor sequencing.
CONCLUSIONS
Posoleucel was generally safe, well tolerated, and associated with a larger reduction of BK viremia compared with placebo. Limitations of this study include the relatively short duration of follow-up and lack of power to detect significant differences in clinical outcomes.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:
Study of Posoleucel (Formerly Known as ALVR105; Viralym-M) in Kidney Transplant Patients With BK Viremia, NCT04605484.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; BK Virus; Double-Blind Method; Kidney Transplantation; Polyomavirus Infections; Transplant Recipients; Tumor Virus Infections; Viremia
PubMed: 38470444
DOI: 10.1681/ASN.0000000000000329 -
Infectious Agents and Cancer Nov 2023Cancer, as a complex, heterogeneous disease, is currently affecting millions of people worldwide. Even if the most common traditional treatments, namely, chemotherapy... (Review)
Review
BACKGROUND
Cancer, as a complex, heterogeneous disease, is currently affecting millions of people worldwide. Even if the most common traditional treatments, namely, chemotherapy (CTx) and radiotherapy (RTx), have been so far effective in some conditions, there is still a dire need for novel, innovative approaches to treat types of cancer. In this context, oncoviruses are responsible for 12% of all malignancies, such as human papillomavirus (HPV), Merkel cell polyomavirus (MCPyV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), as well as hepatitis B virus (HBV) and hepatitis C virus (HCV), and the poorest in the world also account for 80% of all human cancer cases. Against this background, nanomedicine has developed nano-based drug delivery systems (DDS) to meet the demand for drug delivery vectors, e.g., extracellular vesicles (EVs). This review article aimed to explore the potential of engineered small EVs (sEVs) in suppressing human oncovirus-associated cancers.
METHODS
Our search was conducted for published research between 2000 and 2022 using several international databases, including Scopus, PubMed, Web of Science, and Google Scholar. We also reviewed additional evidence from relevant published articles.
RESULTS
In this line, the findings revealed that EV engineering as a new field is witnessing the development of novel sEV-based structures, and it is expected to be advanced in the future. EVs may be further exploited in specialized applications as therapeutic or diagnostic tools. The techniques of biotechnology have been additionally utilized to create synthetic bilayers based on the physical and chemical properties of parent molecules via a top-down strategy for downsizing complicated, big particles into nano-sized sEVs.
CONCLUSION
As the final point, EV-mediated treatments are less toxic to the body than the most conventional ones, making them a safer and even more effective option. Although many in vitro studies have so far tested the efficacy of sEVs, further research is still needed to develop their potential in animal and clinical trials to reap the therapeutic benefits of this promising platform.
PubMed: 37915098
DOI: 10.1186/s13027-023-00549-0 -
Transplant Immunology Oct 2023As a therapeutic method, kidney transplantation significantly improved the life quality and prognosis of patients with the end-stage renal disease. Since a key element... (Review)
Review
As a therapeutic method, kidney transplantation significantly improved the life quality and prognosis of patients with the end-stage renal disease. Since a key element in stable kidney transplantation is continuous therapy with immunosuppressive agents, an inhibited immune response makes patients vulnerable to opportunistic viral and bacterial infections. Polyomavirus (PyV), from the Polyomaviridae family, includes a well-known BK virus (BKPyV) and less publicized human polyomavirus 9 (HPyV9). Both these viruses may inflict significant damage to kidney transplants because of their high prevalence and pathogenesis. While a great body of knowledge was accumulated about the BKPyV-caused nephropathy, much less information is about the potential threat from the HPyV9-caused damage to kidney transplants. The current review provides a glimpse of general information about the PyV-associated nephropathy with a special focus on the role of the HPyV9 in pathogenesis of nephropathy in kidney transplants.
Topics: Humans; Kidney Transplantation; Polyomavirus Infections; Polyomaviridae; Kidney Diseases; BK Virus; Transplant Recipients; Tumor Virus Infections
PubMed: 37414266
DOI: 10.1016/j.trim.2023.101894 -
Medicine Sep 2023Progressive multifocal leukoencephalopathy (PML) is a central nervous system disease caused by the human polyomavirus 2 that usually occurs in a setting of...
Progressive multifocal leukoencephalopathy (PML) is a central nervous system disease caused by the human polyomavirus 2 that usually occurs in a setting of immunodeficiency. PML without overt immunosuppression is considered a rare occurrence but has been described in multiple previous case reports and series. Its prevalence, overall frequency, and prognosis are largely unknown. This is a single-center retrospective review of all University of Florida cases with the ICD10 PML diagnosis code (A81.2). PML without overt immunosuppression was defined as absence of human immunodeficiency virus (HIV) infection, hematological malignancy, immunomodulatory/-suppressive medications, autoimmune conditions with a propensity for PML (sarcoidosis, systemic lupus erythematosus). Cases that did not fulfill criteria for clinically or histologically definite PML were excluded. Of 52 patients with the ICD10 code A 81.2, 17 fulfilled definite diagnostic criteria for PML. Overt immunosuppression was identified in 15/17 (88.2%) cases (10/17 (58.8%): human immunodeficiency virus; 5/17 (29.4%): immunomodulatory/-suppressive medication). Two/seventeen (11.8%) cases were consistent with PML without overt immunosuppression. Possible contributing factors were a preceding dog bite and mild hypogammaglobulinemia M (39 mg/dL) in case 1 and significant alcohol use without evidence for liver disease in case 2. Both cases were fatal within 6 (case 1) and 2 (case 2) months. The results suggest that PML without overt immunosuppression may be more common than previously described. Therefore, PML should be considered even in the absence of overt immunosuppression if clinical and radiographic findings are suggestive of the diagnosis.
Topics: Animals; Dogs; Humans; Autoimmune Diseases; HIV Infections; Immune Tolerance; Leukoencephalopathy, Progressive Multifocal; Lupus Erythematosus, Systemic
PubMed: 37773871
DOI: 10.1097/MD.0000000000035265