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The Journal of Dermatological Treatment Dec 2024Response rates of approved systemic therapies for cutaneous T-cell lymphoma (CTCL) hover near 30%, suggesting unmet need. This study describes real-world treatment...
BACKGROUND
Response rates of approved systemic therapies for cutaneous T-cell lymphoma (CTCL) hover near 30%, suggesting unmet need. This study describes real-world treatment patterns and response rates of extracorporeal photopheresis (ECP) in CTCL patients.
METHODS
A chart review was conducted in the United States of adults with CTCL who initiated ECP between January 1, 2017, and February 28, 2019, and received at least three months of ECP treatment as monotherapy or concomitant therapy. Clinical outcomes were collected quarterly for up to 18 months.
RESULTS
The 52 patients were predominantly Caucasian. Half were male; median age was 69 years. Most patients had Sézary syndrome (50%) or mycosis fungoides (36.5%). Nearly 40% of patients had stage IV disease; 33% had lymph node involvement. Nineteen patients (36.5%) achieved response (>50% reduction in BSA affected); median time to response was 6.5 months. The percentage of patients rated as at least minimally improved was 59.5% at 6 months ( = 22), 75.0% at 9 months ( = 24), and 60.0% at 12 months ( = 15) after ECP initiation.
CONCLUSIONS
Despite the ECP treated population in this study being older and having more advanced-stage disease than recent trials, response rates were comparable. These real-world findings support ECP as an effective treatment option for CTCL patients.
Topics: Humans; Photopheresis; Male; Female; Aged; Middle Aged; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms; United States; Treatment Outcome; Retrospective Studies; Adult; Aged, 80 and over; Sezary Syndrome; Mycosis Fungoides; Neoplasm Staging
PubMed: 38852942
DOI: 10.1080/09546634.2024.2360568 -
Communications Biology Jun 2024Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates....
Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus A. fumigatus remains unclear. This study constructs six single knockout strains of A. fumigatus and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins' involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of sirE attenuates virulence in murine and Galleria mellonella infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat A. fumigatus infections or in combination therapy with available antifungals.
Topics: Aspergillus fumigatus; Sirtuins; Virulence; Animals; Mice; Aspergillosis; Acetylation; Fungal Proteins; Gene Expression Regulation, Fungal; Virulence Factors; Moths
PubMed: 38851817
DOI: 10.1038/s42003-024-06383-3 -
The Brazilian Journal of Infectious... 2024We report an autochthonous case of mild unifocal chronic pulmonary paracoccidioidomycosis in a 48-year-old previously healthy woman with no history of possible...
We report an autochthonous case of mild unifocal chronic pulmonary paracoccidioidomycosis in a 48-year-old previously healthy woman with no history of possible environmental exposures in endemic rural areas, supposedly resulting from reactivation of a latent pulmonary focus secondary to the use of methotrexate for the control of Chikungunya arthropathy. Laboratory investigation ruled out other immunosuppression. Her only symptoms were a dry cough and chest pain. Diagnosis confirmed by needle lung biopsy. There were no abnormalities on physical examination nor evidence of central nervous system involvement. MRI of the total abdomen showed no involvement of other organs. Computed chest tomography showed a favorable evolution under the use of itraconazole (200 mg/day). Different tomographic presentations findings are highlighted when performed before and after treatment. CONCLUSIONS: PCM should be considered even in a woman without a history of consistent environmental exposure and in a non-endemic geographic area.
Topics: Humans; Female; Paracoccidioidomycosis; Middle Aged; Methotrexate; Lung Diseases, Fungal; Chronic Disease; Itraconazole; Tomography, X-Ray Computed; Antifungal Agents; Immunosuppressive Agents
PubMed: 38851212
DOI: 10.1016/j.bjid.2024.103768 -
Archives of Dermatological Research Jun 2024Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) with its etiology not yet fully understood. Interleukin (IL)-35 is an inhibitory...
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) with its etiology not yet fully understood. Interleukin (IL)-35 is an inhibitory cytokine that belongs to the IL-12 family. Elevated IL-35 in the plasma and the tumor microenvironment increases tumorigenesis and indicates poor prognosis in different types of malignancies. The objective of this study is to estimate the expression levels of IL-35 in tissue and serum of MF patients versus healthy controls. This case-control study included 35 patients with patch, plaque, and tumor MF as well as 30 healthy controls. Patients were fully assessed, and serum samples and lesional skin biopsies were taken prior to starting treatment. The IL-35 levels were measured in both serum and tissue biopsies by ELISA technique. Both tissue and serum IL-35 levels were significantly higher in MF patients than in controls (P < 0.001) and tissue IL-35 was significantly higher than serum IL-35 in MF patients (P < 0.001). Tissue IL-35 was significantly higher in female patients and patients with recurrent MF compared to male patients and those without recurrent disease (P < 0.001). Since both tissue and serum IL-35 levels are increased in MF, IL-35 is suggested to have a possible role in MF pathogenesis. IL-35 can be a useful diagnostic marker for MF. Tissue IL-35 can also be an indicator of disease recurrence.
Topics: Humans; Mycosis Fungoides; Interleukins; Female; Male; Case-Control Studies; Middle Aged; Skin Neoplasms; Adult; Skin; Aged; Biopsy; Biomarkers, Tumor
PubMed: 38850434
DOI: 10.1007/s00403-024-03115-9 -
Investigative Ophthalmology & Visual... Jun 2024Fungal keratitis (FK) is an invasive corneal infection associated with significant risk to vision. Although the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon...
PURPOSE
Fungal keratitis (FK) is an invasive corneal infection associated with significant risk to vision. Although the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has been recognized for its role in defending against viral infections, its involvement in FK still remains largely unclear. This study sought to elucidate the contribution of the cGAS/STING signaling pathway to the pathogenesis of FK.
METHODS
The expression of cGAS/STING signaling components was assessed in a murine model of Candida albicans keratitis through RNA sequencing, western blot analysis, immunofluorescence staining, and real-time PCR. Both genetic (utilizing Sting1gt/gt mice) and pharmacological (using C176) interventions were employed to inhibit STING activity, allowing for the evaluation of resultant pathogenic alterations in FK using slit-lamp examination, clinical scoring, hematoxylin and eosin (H&E) staining, fungal culture, and RNA sequencing. Subconjunctival administration of the NOD-like receptor protein 3 (NLRP3) inflammasome inhibitor MCC950 was performed to evaluate FK manifestations following STING activity blockade. Furthermore, the impact of the STING agonist diABZI on FK progression was investigated.
RESULTS
Compared to uninfected corneas, those infected with C. albicans exhibited increased expression of cGAS/STING signaling components, as well as its elevated activity. Inhibiting cGAS/STING signaling exacerbated the advancement of FK, as evidenced by elevated clinical scores, augmented fungal load, and heightened inflammatory response, including NLRP3 inflammasome activation and pyroptosis. Pharmacological inhibition of the NLRP3 inflammasome effectively mitigated the exacerbated FK by suppressing STING activity. Conversely, pre-activation of STING exacerbated FK progression compared to the PBS control, characterized by increased fungal burden and reinforced inflammatory infiltration.
CONCLUSIONS
This study demonstrates the essential role of the cGAS/STING signaling pathway in FK pathogenesis and highlights the necessity of its proper activation for the host against FK.
Topics: Animals; Membrane Proteins; Signal Transduction; Nucleotidyltransferases; Eye Infections, Fungal; Mice; Candida albicans; Disease Models, Animal; Candidiasis; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Keratitis; Blotting, Western; NLR Family, Pyrin Domain-Containing 3 Protein; Female; Corneal Ulcer; Inflammasomes
PubMed: 38848078
DOI: 10.1167/iovs.65.6.13 -
Indian Journal of Public Health Jan 2024Invasive fungal sinusitis is a highly lethal infection in an immunocompromised population that can spread rapidly to involve the adjacent structures by direct invasion...
Invasive fungal sinusitis is a highly lethal infection in an immunocompromised population that can spread rapidly to involve the adjacent structures by direct invasion or through vascular invasion. Involvement of cerebral parenchyma by vascular invasion is a devastating complication in these patients which may lead to vasculitis, thrombus formation, cerebritis, or abscess formation. Here, we present a case of a young male with uncontrolled diabetes mellitus who initially presented with COVID-19 lung disease and later developed sinonasal mucormycosis complicated with left orbital cellulitis and pulmonary mucormycosis.
Topics: Humans; Mucormycosis; Male; COVID-19; SARS-CoV-2; Lung Diseases, Fungal; Adult; Diabetes Complications
PubMed: 38847641
DOI: 10.4103/ijph.ijph_237_23 -
Skin Health and Disease Jun 2024Brief description of a syringotropic mycosis fungoides.
Brief description of a syringotropic mycosis fungoides.
PubMed: 38846681
DOI: 10.1002/ski2.353 -
PLoS Biology Jun 2024In exploring the evolutionary trajectories of both pathogenesis and karyotype dynamics in fungi, we conducted a large-scale comparative genomic analysis spanning the... (Comparative Study)
Comparative Study
In exploring the evolutionary trajectories of both pathogenesis and karyotype dynamics in fungi, we conducted a large-scale comparative genomic analysis spanning the Cryptococcus genus, encompassing both global human fungal pathogens and nonpathogenic species, and related species from the sister genus Kwoniella. Chromosome-level genome assemblies were generated for multiple species, covering virtually all known diversity within these genera. Although Cryptococcus and Kwoniella have comparable genome sizes (about 19.2 and 22.9 Mb) and similar gene content, hinting at preadaptive pathogenic potential, our analysis found evidence of gene gain (via horizontal gene transfer) and gene loss in pathogenic Cryptococcus species, which might represent evolutionary signatures of pathogenic development. Genome analysis also revealed a significant variation in chromosome number and structure between the 2 genera. By combining synteny analysis and experimental centromere validation, we found that most Cryptococcus species have 14 chromosomes, whereas most Kwoniella species have fewer (11, 8, 5, or even as few as 3). Reduced chromosome number in Kwoniella is associated with formation of giant chromosomes (up to 18 Mb) through repeated chromosome fusion events, each marked by a pericentric inversion and centromere loss. While similar chromosome inversion-fusion patterns were observed in all Kwoniella species with fewer than 14 chromosomes, no such pattern was detected in Cryptococcus. Instead, Cryptococcus species with less than 14 chromosomes showed reductions primarily through rearrangements associated with the loss of repeat-rich centromeres. Additionally, Cryptococcus genomes exhibited frequent interchromosomal translocations, including intercentromeric recombination facilitated by transposons shared between centromeres. Overall, our findings advance our understanding of genetic changes possibly associated with pathogenicity in Cryptococcus and provide a foundation to elucidate mechanisms of centromere loss and chromosome fusion driving distinct karyotypes in closely related fungal species, including prominent global human pathogens.
Topics: Cryptococcus; Chromosomes, Fungal; Genome, Fungal; Karyotype; Genomics; Evolution, Molecular; Phylogeny; Synteny; Centromere; Cryptococcosis; Humans
PubMed: 38843310
DOI: 10.1371/journal.pbio.3002682 -
Frontiers in Cellular and Infection... 2024Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for and a promising therapeutic target. This study reveals previously unknown roles of TPS1...
Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for and a promising therapeutic target. This study reveals previously unknown roles of TPS1 in evasion of host defenses during pulmonary and disseminated phases of infection. In the pulmonary infection model, TPS1-deleted () are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (:) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance of mutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified by but not H99 inhibition in a coculture with dispersed lung cells and its rapid clearance coinciding with innate leukocyte infiltration. In the disseminated model of infection, which bypasses initial lung-fungus interactions, strain remains highly attenuated. Specifically, mutant is unable to colonize the lungs from the bloodstream or expand in spleens but is capable of crossing into the brain, where it remains controlled even in the absence of T cells. In contrast, strains H99 and rapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance of mutant resembles a response to acapsular strains, the effect of deletion on capsule formation and was examined. cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowing evasion of resident pulmonary and innate defense mechanisms, most likely its role in cryptococcal capsule formation.
Topics: Animals; Cryptococcus neoformans; Cryptococcosis; Mice; Glucosyltransferases; Lung; Virulence; Virulence Factors; Disease Models, Animal; Host-Pathogen Interactions; Brain; Spleen; Female; Mice, Inbred C57BL; Immunity, Innate; Immune Evasion; Gene Deletion
PubMed: 38841113
DOI: 10.3389/fcimb.2024.1392015 -
Southern African Journal of HIV Medicine 2024The high burden of cryptococcal meningitis (CM) among people living with HIV persists despite widespread access to antiretroviral therapy. Efforts to prevent CM among...
BACKGROUND
The high burden of cryptococcal meningitis (CM) among people living with HIV persists despite widespread access to antiretroviral therapy. Efforts to prevent CM among people living with HIV could be hindered by a limited understanding of their lived experiences of CM and its diagnosis.
OBJECTIVES
To explore and describe the experiences of people diagnosed with HIV-associated CM in routine care. Two public healthcare facilities in Johannesburg, South Africa.
METHOD
This was a qualitative-methods exploratory, descriptive, phenomenological study. We conducted semi-structured, individual in-depth interviews with nine purposively sampled participants (comprising 5 men and 4 women). Data were analysed using the Moustakas phenomenological approach.
RESULTS
Five themes and several sub-themes emerged from the data. Participants described their experiences of being diagnosed, which were marked by intense headaches. Diagnosis of CM led to reduced quality of life, fear of death, and loss of income. Participants described their CM treatment experience and health-seeking behaviour including self-medication, seeking help from traditional healers and general practitioners and utilising public health facilities as a last resort. Barriers to care included negative healthcare workers' attitudes, unhealthy lifestyles, and poor knowledge of CM.
CONCLUSION
People with HIV-associated CM face negative impacts prior to and after diagnosis. These patients struggled to access timely quality healthcare. Patients starting or restarting antiretroviral therapy, and thus at risk for CM, should receive CM education as part of HIV counselling.
PubMed: 38840713
DOI: 10.4102/sajhivmed.v25i1.1560