Type 3 hypersensitivity in COVID-19 vasculitis

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels

Lactobacillus iners cell‐free supernatant enhances biofilm formation and hyphal/pseudohyphal growth by candida albicans vaginal isolates

Candida albicans is a commensal fungus of the vaginal mucosa and the principal etiological agent of vaginal candidiasis. Vaginal dysbiosis has been reported during vulvovaginal candidiasis (VVC), with a progressive decrease in Lactobacillus crispatus population and an increase in L. iners population. To date, the role of L. iners in VVC pathogenesis remains scarcely explored. Herein we investigated the in vitro effect of L. iners cell‐free supernatant (CFS) on the ability of C. albicans to form biofilms. Biomass and metabolic activity were measured by crystal violet and XTT assays. Further, light microscopy was performed to determine the effect of L. iners CFS on biofilm cellular morphology. We found that L. iners CFS induced a significant increase in biofilm formation by C. albicans clinical isolates which were categorized as moderate or weak biofilm producers. This effect was associated with an enhancement of hyphal/pseudohyphal growth, and the expression levels of HWP1 and ECE1, which are typical hyphae‐associated genes, were upregulated. Overall, these results suggest that L. iners contributes to the pathogenesis of VVC and highlight the complexity of the interaction between C. albicans and vaginal lactobacilli. Understanding these interactions could prove essential for the development of new strategies for treating VVC

Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients

Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66\u20130.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73\u201313.96; OR = 7.14, 95% CI: 2.06\u201324.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients

Neoantigen-specific T-cell immune responses: The paradigm of NPM1-mutated acute myeloid leukemia

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicat-ing persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients

Il trattamento del donatore d'organi: cure intensive orientate al procurement

Con la morte cerebrale (o meglio encefalica, ovvero cessazione irreversibile di tutte le funzioni del cervello e del tronco encefalico), attualmente definita pi\uf9 correttamente come morte diagnosticata con criteri neurologici, compare un peculiare e unico quadro clinico, neurologico e somatico che tende alla disgregazione funzionale organica e al decadimento perfusivo che, se non contrastato, conduce all\u2019 arresto cardiaco e quindi alla cessazione della perfusione stessa degli organi e della loro funzione. In tali condizioni viene intrapreso un percorso diagnostico (dettagliatamente normato da Leggi e Regolamento applicativo) finalizzato a rendere possibile l\u2019accertamento della morte, e, qualora ne sussistano tutti i requisiti, al suo termine il prelievo dal soggetto deceduto, a scopo di trapianto terapeutico, degli organi: questi mantengono la loro funzionalit\ue0 grazie alla persistenza della funzione cardiaca ed emodinamica (perfusione e metabolismo) e respiratoria (scambio gassoso) artificialmente mantenute. Il periodo di accertamento della avvenuta morte (non meno di sei ore nell\u2019 adulto) richiede un attivo e mirato intervento da parte dell\u2019 equipe intensivologica finalizzato a \u201cmantenere\u201d la biologia del soggetto correggendo o contrastando gli effetti della morte encefalica (assenza dei controlli regolatori per la venuta meno delle funzioni svolte fisiologicamente dall\u2019encefalo). Il prevenire o l\u2019 attenuare le disfunzioni degli organi del potenziale donatore a cuore battente richiede l\u2019 approfondita conoscenza delle conseguenze fisiopatologiche che seguono alla morte encefalica. Per trattamento (meglio che mantenimento) del donatore d\u2019organi si intende la gestione intensivologica di un organismo che ha perso l\u2019omeostasi corporea. Consiste nell\u2019 insieme delle attivit\ue0 diagnostico \u2013 terapeutiche, di monitoraggio, nursing e organizzative usualmente praticate nei reparti di Rianimazione, orientate al mantenimento e al miglioramento delle funzioni degli organi prelevabili e trapiantabili e occupa il periodo che va dal momento in cui \ue8 stata effettuata la diagnosi di morte ed iniziato il periodo di accertamento, fino al termine del periodo dell\u2019osservazione. Gli organi prelevabili e trapiantabili con successo sono quelli con alta vitalit\ue0 biologica e con prerogative funzionali conservate in quanto precedentemente normoperfusi e privi di potenziale lesivit\ue0 per il ricevente. Il trattamento del donatore \ue8, quindi, un\u2019 azione sanitaria complessa e multi-disciplinare da attuare in un concentrato periodo di tempo (tra comparsa dei segni clinici e strumentali di morte e completamento del periodo formale di accertamento di essa, ovvero pi\uf9 esattamente sino alla fine delle attivit\ue0 chirurgiche di prelievo degli organi). Si basa sui principi e gli strumenti della buona pratica clinica intensivologica orientata alla \u201crianimazione biologica\u201d del soggetto donatore in stato di morte a cuore battente (specificit\ue0 fisiopatologica) e alla protezione degli organi prelevabili e trapiantabili (finalit\ue0 terapeutica primaria). Il trattamento del donatore comprende inoltre l\u2019assistenza intensiva durante il trasporto dalla Rianimazione a sedi esterne di diagnosi (Imaging neuroradiologico e radiologico) e alla Sala operatoria e nel corso dell\u2019intervento chirurgico di prelievo

Triple approach strategy for patients with locally advanced pancreatic carcinoma.

Triple approach strategy for patients with locally advanced pancreatic carcinoma

A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection