Search

Abstract Identifying marker combinations for robust prognostic validation in primary tumour compartments remains challenging. We aimed to assess the prognostic significance of CSC markers (ALDH1, CD44, p75NTR, BMI-1) and E-cadherin biomarkers in OSCC. We analysed 94 primary OSCC and 67 metastatic lymph node samples, including central and invasive tumour fronts (ITF), along with clinicopathological data. We observed an increase in ALDH1+/CD44+/BMI-1- tumour cells in metastatic lesions compared to primary tumours. Multivariate analysis highlighted that elevated p75NTR levels (at ITF) and reduced E-cadherin expression (at the tumour centre) independently predicted metastasis, whilst ALDH1high exhibited independent predictive lower survival at the ITF, surpassing the efficacy of traditional tumour staging. Then, specifically at the ITF, profiles characterized by CSChighE-cadherinlow (ALDH1highp75NTRhighE-cadherinlow) and CSCintermediateE-cadherinlow (ALDH1 or p75NTRhighE-cadherinlow) were significantly associated with worsened overall survival and increased likelihood of metastasis in OSCC patients. In summary, our study revealed diverse tumour cell profiles in OSCC tissues, with varying CSC and E-cadherin marker patterns across primary tumours and metastatic sites. Given the pivotal role of reduced survival rates as an indicator of unfavourable prognosis, the immunohistochemistry profile identified as CSChighE-cadherinlow at the ITF of primary tumours, emerges as a preferred prognostic marker closely linked to adverse outcomes in OSCC.

Backgrounds: Ganoderma lucidum polysaccharides have been shown several anti-cancer, anti-inflammatory, and immunomodulatory properties among studies with different tumor models and its use with advanced and conventional combination therapies is a world trend. The administration of 5-Fluorouracil is already used as chemotherapy for many tumors and works on tumor remission; however, its adverse effects are still severe, impoverishing treatment and quality of life for patients. Cancer stem cells represent a subpopulation of cells with defense mechanisms against chemotherapy agents and are the main cause of relapses and metastases in cancer treatments. Also, the Epithelial-Mesenchymal Transition program increases properties related to tumor malignancy and mortality. In this scenario, the aim of the study is to evaluate the effects of Ganoderma lucidum polysaccharides in combination with 5-Fluorouracil on the subpopulation of cancer stem cells present in the human oral squamous carcinoma cell line SCC-9. Methods: SCC-9 cells were treated in vitro for 72 h with different 5-Fluorouracil low doses, associated or not with Ganoderma lucidum polysaccharides. Cells maintained with culture media or cisplatin were used as control. All the cells were evaluated for cytotoxicity, cancer stem cells, and Epithelial-Mesenchymal Transition properties. Results: The associated treatment avoided proliferation, delayed migration, slightly modified morphology of cells, increased apoptosis, decreased colony and blocked spheres formation, and downregulated cancer stem cells, Epithelial-Mesenchymal Transition, and ABC drug transporters expression. In addition, Ganoderma lucidum polysaccharides + 5-Fluorouracil changed the treated cells into a non-cancer stem cell phenotype, a characteristically not resistant and less proliferative population. The 5-Fluorouracil treatment alone showed remarkable modification in cellular morphology, apoptosis, and absence of holoclones; however, it upregulated the molecular expression of cancer stem cells' hallmarks. Conclusions: These findings demonstrate that combining Ganoderma lucidum polysaccharides with a low dose of 5-Fluorouracil is effective against oral squamous cell carcinoma in vitro by enhancing the cells' sensitivity to drugs and reducing the characteristics associated with cancer stem cells (CSCs). This suggests the possibility of reducing conventional chemotherapy doses and improving oral squamous cell carcinoma treatment. It also highlights the potential for this combination to be used as an adjunct in Complementary Alternative Medicine (CAM).

Louis Cantor,1 Dan Lindfield,2 Federico Ghinelli,3 Anna W Świder,3 Francesca Torelli,3 Carolyn Steeds,3 Jaime E Dickerson Jr,4,5 Dan Q Nguyen6 1Eugene and Marilyn Glick Eye Institute, Indiana School of Medicine, Indianapolis, IN, USA; 2Royal Surrey County Hospital, Guildford, England, UK; 3Valid Insight, Macclesfield, England, UK; 4Sight Sciences, Menlo Park, CA, USA; 5North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA; 6Mid-Cheshire Hospitals NHS Foundation Trust, Crewe, UKCorrespondence: Francesca Torelli, Valid Insight, Ropewalks, Newton St, Macclesfield, SK11 6QJ, UK, Tel +44 203 750 9833 Ext 703, Email ftorelli@validinsight.comIntroduction: Selective laser trabeculoplasty (SLT) and minimally invasive glaucoma surgery (MIGS) are increasingly used options for mild-to-moderate open-angle glaucoma (OAG) care. While most MIGS devices are indicated for use in combination with cataract surgery only, with phacoemulsification playing a role in lowering IOP, newer technologies can also be used as standalone glaucoma surgery.Methods: This systematic literature review (SLR) aimed to assess the clinical, economic, and humanistic outcomes of MIGS and SLT for the treatment of OAG and was conducted according to PRISMA guidelines. Studies that assessed MIGS or SLT in at least one treatment arm versus any other glaucoma treatment in adults with mild-to-moderate OAG were included. Clinical, humanistic (health-related quality of life [HRQoL] and patient burden), and economic data were extracted, and the methodological quality of included studies was evaluated.Results: A total of 2720 articles were screened, and 81 publications were included. Fifty-eight reported clinical outcomes. The majority assessed iStent or iStent inject (n=41), followed by OMNI (n=9), gonioscopy-assisted transluminal trabeculotomy (GATT) or the Kahook Dual Blade (KDB) (n=7), Hydrus (n=6), SLT (n=5), Xen Gel Stent (n=2), PreserFlo (n=1), and iTrack (n=1). IOP reduction was observed across prospective studies, varying from − 31% to − 13.7% at month 6 and from − 39% to − 11.4% at year 1 versus baseline. Most adverse events were transient and non-serious. Limited humanistic and economic data were identified.Conclusion: Given their established efficacy and safety, there is a rationale for wider use of MIGS in mild-to-moderate OAG. Of the MIGS devices, iStent and OMNI have the largest clinical evidence base supporting their sustained effectiveness.Keywords: intraocular pressure, IOP, iStent, MIGS, OMNI, SLT

Abstract Objective Neutrophils are key effector cells of the innate immune system. They recognize antigens through membrane receptors, which are expressed during their maturation and activation. Neutrophils express FcγRII (CD32), FcγRIII (CD16), and FcγRI (CD64) after being activated by different factors such as cytokines and bacterial products. These receptors are involved with phagocytosis of IgG-opsonized microbes and enhance defense mechanisms. Based on that, our study seeks to compare the expression of FcγRII, FcγRIII, FcγRI, and CD11b on neutrophils from elderly and young subjects and their expression after in vitro activation with cytokines and LPS. Methodology Neutrophils were isolated from human peripheral blood and from mice bone marrow by density gradient. After isolation, FCγRs expression was immediately analyzed by flow cytometry or after in vitro stimulation. Results In freshly isolated cells, the percentage of FcγRIIIb+ and CD11b+ neutrophils were higher in samples from young individuals; FcγRIIIa expression was more prominent on aged neutrophils; FcγRIA expression was similar in all samples analyzed. Exposure to CXCL8 and LPS resulted in a higher percentage of FcγRIa+ neutrophils on elderly individuals’ samples but lower when compared with neutrophils from young donors. We observed that LPS caused an increase in FcγRIIa expression on aging human neutrophils. In contrast, FcγRIIIb expression in response to CXCL8 and LPS stimulation was not altered in the four groups. CD11b expression was lower in neutrophils from elderly individuals even in response to LPS and CXCL8. In mice, we observed differences only regarding CD11b expression, which was increased on aged neutrophils. LPS exposure caused an increase in all FcγRs. Conclusions Our results suggest that, in humans, the overall pattern of FcγR expression and integrin CD11b are altered during aging and immunosenescence might contribute to age-related infection.

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

BACKGROUND Although Mycobacterium leprae (ML) is well characterised as the causative agent of leprosy, the pathophysiological mechanisms underlying peripheral nerve damage still need further understanding. In vitro and in vivo studies have yielded insights into molecular mechanisms of ML interaction with Schwann cells (SC), indicating the regulation of genes and proteins crucial to neural plasticity. OBJECTIVES We aimed to investigate the effect of ML on neurotrophins expression in human SC (hSC) and mice sciatic nerves to better understand their role in leprosy neuropathy, and aiming to contribute to future therapeutic approaches. METHODS We evaluated mRNA and protein expression of BDNF, NGF, NT-3, NT-4 in hSC from amputation nerve fragments, as well as in athymic nude mice, infected by ML for eight months. FINDINGS and MAIN CONCLUSIONS Our in vitro results showed a trend to decline in NGF and BDNF mRNA in ML-treated hSC, compared to controls. The immunodetection of BDNF and NT-4 was significantly downregulated in ML-treated hSC. Conversely, ML-infected mice demonstrated upregulation of NT-3, compared to non-infected animals. Our findings indicate that ML may be involved in neurotrophins regulation, suggesting that a pathogen-related imbalance of these growth factors may have a role in the neural impairment of leprosy.

AimsThe aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia.MethodsThis was an observational prospective study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients' medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO2/FiO2 ratio ResultsA total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth "boosted mixed model" included 20 variables was selected from the model 3, achieved the best predictive performance (AUC = 0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example.ConclusionThis study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.

Narrative developments often stem from images in Dany Laferrière’s work. On the other hand, some of the narration in Laferrière’s fiction and nonfiction is synthesized in narrative snapshots that resemble descriptions. Temporal dimension plays a key role in this constant shift between image and imagination, because, as Didi-Huberman has shown, images carry an anachronistic element. This element also allows Laferrière and his narrators to use mainly simple present tense, even when the content of the narration is set in the past. Nevertheless, images are never explained or rationalized in Laferrière’s work, which keeps the mystery and ambiguity that characterize visual representations.

Let Π be a finite projective plane admitting a large abelian collineation group. It is well known that this situation may be studied by algebraic means (via a representation by suitable types of difference sets), namely using group rings and algebraic number theory and leading to rather strong nonexistence results. What is less well-known is the fact that the abelian group (and sometimes its group ring) can also be used in a much more geometric way; this will be the topic of the present survey. In one direction, abelian collineation groups may be applied for the construction of interesting geometric objects such as unitals, arcs and (hyper-)ovals, (Baer) subplanes, and projective triangles. On the other hand, this approach makes it sometimes possible to provide simple geometric proofs for non-trivial structural restrictions on the given collineation group, avoiding algebraic machinery.

UnlabelledAlthough HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis.Trial registrationClinicalTrials.gov NCT00751595.

This study reports the echocardiographic reference intervals in the American Staffordshire Terrier (AST). The echocardiographic variables obtained in 57 healthy adult AST were compared with published data from the general canine population and other breeds. In the AST, the left ventricular volumes were lower than values reported in Boxers and Dobermans (P<0.0001), but higher than in small breeds (P<0.0001). The left ventricular ejection fraction was higher than Boxers and Dobermans (P<0.0001), but lower than small breed dogs (P=0.027). The aortic peak velocity values were similar to Boxers (P=0.55) but higher than the general canine population (P<0.0001). The reference intervals presented in this study are clinically useful for an accurate echocardiographic interpretation and screening in the AST. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence of invasive cervical cancer in HIV-positive women is higher than in the general population. There is evidence that HIV-positive women do not participate sufficiently in cervical cancer screening in Italy, where cervical cancer is more than 10-fold higher in women with AIDS than in the general population. The aim of the present study was to evaluate the history of Pap-smear in HIV-positive women in Italy in recent years. We also examined the sociodemographic, clinical, and organizational factors associated with adherence to cervical cancer screening. Methods A cross-sectional study was conducted between July 2006 and June 2007 in Emilia-Romagna region (Northern Italy). All HIV-positive women who received a follow-up visit in one of the 10 regional infectivology units were invited to participate. History of Pap-smear, including abnormal smears and subsequent treatment, was investigated through a self-administered anonymous questionnaire. The association between lack of Pap-smear in the year preceding the interview and selected characteristics was assessed by means of odds ratios (OR) and 95% confidence intervals adjusted for study centre and age. Results A total of 1,002 HIV-positive women were interviewed. Nine percent reported no history of Pap-smear, and 39% had no Pap-smear in the year prior to the date of questionnaire (last year). The lack of Pap-smear in the last year was significantly associated with age Three hundred five (34%) women reported a previous abnormal Pap-smear, and of the 178 (58%) referred for treatment, 97% complied. Conclusions In recent years the self-reported history of Pap-smear in HIV-positive women, in some public clinics in Italy, is higher than previously reported, but further efforts are required to make sure cervical cancer screening is accessible to all HIV-positive women.

Abstract Background By persisting in infected cells for a long period of time, proviral HIV-1 DNA can represent an alternative viral marker to RNA viral load during the follow-up of HIV-1 infected individuals. In the present study sequential blood samples of 10 patients under antiretroviral treatment from 1997 with two NRTIs, who refused to continue any antiviral regimen, were analyzed for 16 – 24 weeks to study the possible relationship between DNA and RNA viral load. Methods The amount of proviral DNA was quantified by SYBR green real-time PCR in peripheral blood mononuclear cells from a selected group of ten patients with different levels of plasmatic viremia (RNA viral load). Results Variable levels of proviral DNA were found without any significant correlation between proviral load and plasma HIV-1 RNA levels. Results obtained showed an increase or a rebound in viral DNA in most patients, suggesting that the absence of therapy reflects an increase and/or a persistence of cells containing viral DNA. Conclusion Even though plasma HIV RNA levels remain the basic parameter to monitor the intensity of viral replication, the results obtained seem to indicate that DNA levels could represent an adjunct prognostic marker in monitoring HIV-1 infected subjects.

ABSTRACT Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants used in traditional medicine for the treatment of inflammatory diseases and other ailments. Objective In this study, we evaluated whether budlein A modulates the activation of innate and adaptive immune cells such as neutrophils and lymphocytes. Material and Methods Our research group has investigated several plant species and several compounds have been isolated, identified, and their medical potential evaluated. Budlein A is a SL isolated from the species Aldama buddlejiformis and A. robusta (Asteraceae) and shows anti-inflammatory and anti-nociceptive activities. Advances in understanding how plant-derived substances modulate the activation of innate and adaptive immune cells have led to the development of new therapies for human diseases. Results Budlein A inhibited MPO activity, IL-6, CXCL8, IL-10, and IL-12 production and induces neutrophil apoptosis. In contrast, budlein A inhibited lymphocyte proliferation and IL-2, IL-10, TGF-β, and IFN-γ production, but it did not lead to cell death. Conclusions Collectively, our results indicate that budlein A shows distinct immunomodulatory effects on immune cells.