Hydrogen sulfide production does not affect antibiotic resistance in Pseudomonas aeruginosa.

Hydrogen sulfide (H2S) has been proposed to protect bacteria from antibiotics, pointing to H2S-producing enzymes as possible targets for the development of antibiotic adjuvants. Here, MIC assays performed with Pseudomonas aeruginosa mutants producing altered H2S levels demonstrate that H2S does not affect antibiotic resistance in this bacterium. Moreover, correlation analyses in a large collection of P. aeruginosa cystic fibrosis isolates argue against the protective role of H2S from antibiotic activity during chronic lung infection.

State of the Art of Pharmacological Activators of p53 in Ocular Malignancies.

The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival and corneal tumors, retinoblastoma, uveal melanoma, and intraocular melanoma. As non-selective cancer chemotherapies as well as ionizing radiation can be associated with either poor efficacy or dose-limiting toxicities in the eye, reconstitution of the p53 signaling pathway currently represents an attractive target for cancer therapy. The present review discusses the role of p53 in the pathogenesis of these ocular tumors and outlines the various pharmacological activators of p53 that are currently under investigation for the treatment of ocular malignancies.

Nutrients, herbal bioactive derivatives and commensal microbiota as tools to lower the risk of SARS-CoV-2 infection.

The SARS-CoV-2 outbreak has infected a vast population across the world, causing more than 664 million cases and 6.7 million deaths by January 2023. Vaccination has been effective in reducing the most critical aftermath of this infection, but some issues are still present regarding re-infection prevention, effectiveness against variants, vaccine hesitancy and worldwide accessibility. Moreover, although several old and new antiviral drugs have been tested, we still lack robust and specific treatment modalities. It appears of utmost importance, facing this continuously growing pandemic, to focus on alternative practices grounded on firm scientific bases. In this article, we aim to outline a rigorous scientific background and propose complementary nutritional tools useful toward containment, and ultimately control, of SARS-CoV-2 infection. In particular, we review the mechanisms of viral entry and discuss the role of polyunsaturated fatty acids derived from α-linolenic acid and other nutrients in preventing the interaction of SARS-CoV-2 with its entry gateways. In a similar way, we analyze in detail the role of herbal-derived pharmacological compounds and specific microbial strains or microbial-derived polypeptides in the prevention of SARS-CoV-2 entry. In addition, we highlight the role of probiotics, nutrients and herbal-derived compounds in stimulating the immunity response.

Ten-year outcomes of microkeratome-assisted lamellar keratoplasty for keratoconus.

BACKGROUND/AIMS: To report the 10-year outcomes of modified microkeratome-assisted lamellar keratoplasty (LK) for keratoconus. METHODS: In this single-centre interventional case series, 151 consecutive eyes with keratoconus underwent modified microkeratome-assisted LK. Eyes with scars extending beyond the posterior half of the corneal stroma and preoperative thinnest-point pachymetry value of less than 300 µm were excluded. Outcome measures were best spectacle-corrected visual acuity (BSCVA), refractive astigmatism (RA), endothelial cell density, immunological rejection, ectasia recurrence and graft failure rates. RESULTS: Baseline BSCVA (0.89±0.31 logarithm of the minimum angle of resolution (logMAR)) significantly improved to 0.10±0.12 logMAR at year 3 (p<0.001), and remained stable up to 10 years. At 10 years, 94% of eyes saw ≥20/40, 61% saw ≥20/25 and 24% saw ≥20/20 Snellen BSCVA. At final follow-up, RA exceeding 4.5 dioptres was observed in 5 cases (4%). Endothelial cell loss was 25±17% at 1 year with an annual decline of 2% over 10 years. The 10-year cumulative risk for immunological rejection and graft failure was 8.5%, and 2.4%, respectively. No case developed recurrent ectasia at 10 years. CONCLUSION: Modified microkeratome-assisted LK results in stable visual and refractive outcomes with low rates of immunological rejection and graft failure in the absence of recurrence of ectasia for at least 10 years.

New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances.

Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematologic malignancies, and it is normally characterized by an aberrant proliferation of immature lymphoid cells. Moreover, dysregulation of multiple signaling pathways that normally regulate cellular transcription, growth, translation, and proliferation is frequently encountered in this malignancy. ALL is the most frequent tumor in childhood, and adult ALL patients still correlate with poor survival. This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies. Bi-specific T-cell Engagers (BiTE) antibodies, the chimeric antigen receptor (CAR)-T cells, or CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-associated nuclease 9) represent other new innovative approaches for this disease. Target and tailored therapy could make the difference in previously untreatable cases, i.e., precision and personalized medicine. Clinical trials will help to select the most efficient novel therapies in ALL management and to integrate them with existing treatments to achieve durable cures.

Pediatric patients with inflammatory bowel disease exhibit increased serum levels of proinflammatory cytokines and chemokines, but decreased circulating levels of macrophage inhibitory protein-1ß, interleukin-2 and interleukin-17.

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition of the gastrointestinal tract. Although the causative events that lead to the onset of IBD are yet to be fully elucidated, deregulation of immune and inflammatory mechanisms are hypothesized to significantly contribute to this disorder. Since the onset of IBD is often during infancy, in the present study, the serum values of a large panel of cytokines and chemokines in pediatric patients (<18 years; n=26) were compared with age-matched controls (n=37). While elevations in the serum level of several proinflammatory and immune regulating cytokines were confirmed, such as interleukin (IL)-1ß, IL-5, IL-7, interferon (IFN)-γ-inducible protein-10, IL-16, cutaneous T-cell-attracting chemokine, leukemia inhibitory factor, monokine induced by γ-IFN, IFN-α2 and IFN-γ, notably decreased levels of IL-2, IL-17 and macrophage inhibitory protein-1ß were also observed. Therefore, while a number of proinflammatory cytokines exhibit increased levels in IBD patients, pediatric IBD patients may also exhibit certain aspects of a reduced immunological response.

Nanoparticles engineered with rituximab and loaded with Nutlin-3 show promising therapeutic activity in B-leukemic xenografts.

PURPOSE: Because the nongenotoxic inhibitor of the p53/MDM2 interactions Nutlin-3 has shown promising in vitro therapeutic activity against a variety of p53(wild-type) cancer cells, in this study we evaluated an innovative strategy able to specifically target Nutlin-3 toward CD20(+) malignant cells. EXPERIMENTAL DESIGN: The cytotoxic effects of Nutlin-3 encapsulated into poly(lactide-co-glycolide) nanoparticles (NP-Nut) and into rituximab (anti-CD20 antibody)-engineered NP (NP-Rt-Nut) as well as of NPs engineered with rituximab alone (NP-Rt) were initially analyzed in vitro in JVM-2 B-leukemic cells, by assessing both the functional activation of the p53 pathway (by Nutlin-3) and/or the activation of the complement cascade (by rituximab). Moreover, the potential therapeutic efficacy of NP-Nut, NP-Rt, and NP-Rt-Nut were comparatively assessed in vivo in CD20(+) JVM-2 leukemic xenograft SCID mice. RESULTS: Functional in vitro assays showed that NP-Nut and NP-Rt-Nut exhibited a comparable ability to activate the p53 pathway in the p53(wild-type) JVM-2 leukemic cells. On the other hand, NP-Rt and NP-Rt-Nut, but not NP nor NP-Nut, were able to promote activation of the complement cascade. Of note, the in vivo intratumoral injection in JVM-2 B-leukemic/xenograft mice showed that NP-Rt-Nut displayed the maximal therapeutic activity promoting a survival rate significantly higher not only with respect to control animals, treated either with vehicle or with empty NP, but also with respect to animals treated with NP-Nut or NP-Rt. CONCLUSIONS: Our data show for the first time the potential antileukemic activity of rituximab-engineered Nutlin-3-loaded NPs in xenograft SCID mice.

Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin's lymphoma xenografts.

BACKGROUND: Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL. METHODOLOGY/PRINCIPAL FINDINGS: The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV(-) Burkitt-type BJAB, median survival = 46 days) and an aggressive (EBV(+) B lymphoblastoid SKW6.4, median survival = 27 days) behavior in nude-SCID mice. Intra-peritoneal (i.p.) injection of MSC (4 days after i.p. injection of lymphoma cells) significantly increased the overall survival at an optimal MSC:lymphoma ratio of 1:10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days). Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i) MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii) MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL.

Baseline serum concentrations of TRAIL in early rheumatoid arthritis: relationship with response to disease-modifying antirheumatic drugs.

OBJECTIVE: To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) and the therapeutic response to disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA). METHODS: Circulating levels of TRAIL and its soluble receptor OPG were measured by ELISA in paired serum samples obtained from 66 patients with early RA at their first visit (baseline) and after 1 year of therapy. Levels of TRAIL and OPG were analyzed in relation to the clinical response, defined by the 28-joint count Disease Activity Score (DAS28). RESULTS: Both serum TRAIL and OPG increased after DMARD therapy. Baseline levels of TRAIL, but not OPG, were significantly higher (p < 0.05) in the patients that achieved a clinical response by DAS28 after 1 year of therapy, versus patients without clinical response to DMARD. Baseline serum levels of TRAIL were higher (p < 0.01) in rheumatoid factor-negative patients. CONCLUSION: Our data suggest that the basal level of circulating TRAIL is an important determinant in the therapeutic response to DMARD in patients with early RA.