Effects of immunomodulatory drugs on TNF-α and IL-12 production by purified epidermal langerhans cells and peritoneal macrophages

<p>Abstract</p> <p>Background</p> <p>Langerhans cells constitute a special subset of immature dendritic cells localized in the epidermis that play a key role in the skin's immune response. The production of cytokines is a key event in both the initiation and the regulation of immune responses, and different drugs can be used to remove or modify their production by DC and, therefore, alter immune responses in a broad spectrum of diseases, mainly in human inflammatory and autoimmune diseases. In the present study, we examined the effects of prednisone, thalidomide, cyclosporine A, and amitriptyline, drugs used in a variety of clinical conditions, on the production of TNF-α, IL-10, and IL-12 by purified epidermal Langerhans cells and peritoneal macrophages in BALB/c mice.</p> <p>Findings</p> <p>All drugs inhibited TNF-α production by Langerhans cells after 36 hours of treatment at two different concentrations, while prednisone and thalidomide decreased IL-12 secretion significantly, amitriptyline caused a less pronounced reduction and cyclosporine A had no effect. Additionally, TNF-α and IL-12 production by macrophages decreased, but IL-10 levels were unchanged after all treatments.</p> <p>Conclusions</p> <p>Our results demonstrate that these drugs modulate the immune response by regulating pro-inflammatory cytokine production by purified epidermal Langerhans cells and peritoneal macrophages, indicating that these cells are important targets for immunosuppression in various clinical settings.</p

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Molecular Epidemiology of Agents of Human Chromoblastomycosis in Brazil with the Description of Two Novel Species

The human mutilating disease chromoblastomycosis is caused by melanized members of the order Chaetothyriales. To assess population diversity among 123 clinical strains of agents of the disease in Brazil we applied sequencing of the rDNA internal transcribed spacer region, and partial cell division cycle and β-tubulin genes. Strains studied were limited to three clusters divided over the single family Herpotrichiellaceae known to comprise agents of the disease. A Fonsecaea cluster contained the most important agents, among which F. pedrosoi was prevalent with 80% of the total set of strains, followed by 13% for F. monophora, 3% for F. nubica, and a single isolate of F. pugnacius. Additional agents, among which two novel species, were located among members of the genus Rhinocladiella and Cyphellophora, with frequencies of 3% and 1%, respectively

Multilocus tree of <i>Rhinocladiella</i> based on ITS and partial <i>BT2</i> sequences.

<p>Constructed with maximum likelihood implemented in MEGA 7. Bootstrap values of >80% from 100 resampled data sets are shown with branches. <i>Cladophialophora yegresii</i> and <i>C</i>. <i>carrionii</i> comprised the outgroup. Novel species causing chromoblastomycosis are indicated with red branches. Type strain in bold.</p

Phylogeny of a representative selection of species in Chaetothyriales, based on confidently aligned LSU sequences.

<p>Constructed with Maximum likelihood implemented in MEGA 7. Bootstrap values > 80% from 100 resampled datasets are shown with branches. Coloured boxes represent species complexes taken from de Hoog et al. [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005102#pntd.0005102.ref021" target="_blank">21</a>], Feng et al. [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005102#pntd.0005102.ref022" target="_blank">22</a>], and Vicente et al. [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005102#pntd.0005102.ref023" target="_blank">23</a>]. Clades with species causing chromoblastomycosis analysed in this study are indicated with arrows. Type strain in bold.</p

<i>Rhinocladiella tropicalis</i>, microscopic morphology.

<p>(A) Colonies on SGA; (B, C) twisted hyphae and conidia; (D-G) conidiophores with conidia produced in sympodial order; (H-O) conidial apparatus with conidia. Scale bars 10 μm.</p

Cardinal temperatures of strains described.

<p>(A) <i>Cyphellophora ludoviensis</i> with optimal growth temperature at 30°C and maximum at 37°C. (B) <i>Rhinocladiella tropicalis</i> with optimal development at 27°C and maximum at 37°C.</p

<i>Cyphellophora ludoviensis</i> microscopic morphology.

<p>(A) colonies on SGA; (B-E) hyphae with chlamydospores and lateral extensions; (F) anastomosis; (G-H) spirally twisted hyphae; (I) poorly differentiated phialide producing conidia; (J-P) chlamydospores and conidia. Scale bars 10 μm.</p

Strains analysed.

<p>Strains analysed.</p

Multilocus tree of <i>Cyphellophora</i> based on ITS and partial <i>BT2</i> sequences.

<p>Constructed with maximum likelihood implemented in MEGA 7. Bootstrap values of >80% from 100 resampled data sets are shown with branches. <i>Cladophialophora yegresii</i> and <i>C</i>. <i>carrionii</i> comprised the outgroup. Novel species causing chromoblastomycosis are indicated with red branches. Type strain in bold.</p