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Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD). Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) α-FAPx4–1BB (MP0310) with FAP-dependent 4–1BB agonistic activity. The α-FAPx4–1BB DARPin simultaneously binds to FAP and 4–1BB overexpressed by activated FBs and immune cells, respectively. Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4–1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4–1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4–1BB overexpression allowed the engagement of α-FAPx4–1BB that acted as a bridge between FAP+FBs and 4–1BB+NK cells. Therefore, α-FAPx4–1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, α-FAPx4–1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs’ immunosuppressive effect. Overall, we speculate that treatment with α-FAPx4–1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.

Hypereosinophilic syndrome (HES) encompasses a heterogeneous and complex group of different subtypes within the wider group of hypereosinophilic disorders. Despite increasing research interest, several unmet needs in terms of disease identification, pathobiology, phenotyping, and personalized treatment remain to be addressed. Also, the prospective burden of non-malignant HES and, more in general, HE disorders is currently unknown. On a practical note, shortening the diagnostic delay and the time to an appropriate treatment approach probably represents the most urgent issue, even in light of the great impact of HES on the quality of life of affected patients. The present document represents the first action that the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC) has finalized within a wider project aiming to establish a collaborative national network on HES (InHES—Italian Network on HES) for patients and physicians. The first step of the project could not but focus on defining a common language as well as sharing with all of the medical community an update on the most recent advances in the field. In fact, the existing literature has been carefully reviewed in order to critically integrate the different views on the topic and derive practical recommendations on disease identification and treatment approaches.

Malignant melanoma (MM) is the “great mime” of dermatopathology, and it can present such rare variants that even the most experienced pathologist might miss or misdiagnose them. Naevoid melanoma (NM), which accounts for about 1% of all MM cases, is a constant challenge, and when it is not diagnosed in a timely manner, it can even lead to death. In recent years, artificial intelligence has revolutionised much of what has been achieved in the biomedical field, and what once seemed distant is now almost incorporated into the diagnostic therapeutic flow chart. In this paper, we present the results of a machine learning approach that applies a fast random forest (FRF) algorithm to a cohort of naevoid melanomas in an attempt to understand if and how this approach could be incorporated into the business process modelling and notation (BPMN) approach. The FRF algorithm provides an innovative approach to formulating a clinical protocol oriented toward reducing the risk of NM misdiagnosis. The work provides the methodology to integrate FRF into a mapped clinical process.

Introduction: Lung ultrasound (LUS) is widely used in clinical practice for identifying interstitial lung diseases (ILDs) and assessing their progression. Although high-resolution computed tomography (HRCT) remains the gold standard for evaluating the severity of ILDs, LUS can be performed as a screening method or as a follow-up tool post-HRCT. Minimum training is needed to better identify typical lesions, and the integration of innovative artificial intelligence (AI) automatic algorithms may enhance diagnostic efficiency. Aim: This study aims to assess the effectiveness of a novel AI algorithm in automatic ILD recognition and scoring in comparison to an expert LUS sonographer. The “SensUS Lung” device, equipped with an automatic algorithm, was employed for the automatic recognition of the typical ILD patterns and to calculate an index grading of the interstitial involvement. Methods: We selected 33 Caucasian patients in follow-up for ILDs exhibiting typical HRCT patterns (honeycombing, ground glass, fibrosis). An expert physician evaluated all patients with LUS on twelve segments (six per side). Next, blinded to the previous evaluation, an untrained operator, a non-expert in LUS, performed the exam with the SensUS device equipped with the automatic algorithm (“SensUS Lung”) using the same protocol. Pulmonary functional tests (PFT) and DLCO were conducted for all patients, categorizing them as having reduced or preserved DLCO. The SensUS device indicated different grades of interstitial involvement named Lung Staging that were scored from 0 (absent) to 4 (peak), which was compared to the Lung Ultrasound Score (LUS score) by dividing it by the number of segments evaluated. Statistical analyses were done with Wilcoxon tests for paired values or Mann–Whitney for unpaired samples, and correlations were performed using Spearman analysis; p < 0.05 was considered significant. Results: Lung Staging was non-inferior to LUS score in identifying the risk of ILDs (median SensUS 1 [0–2] vs. LUS 0.67 [0.25–1.54]; p = 0.84). Furthermore, the grade of interstitial pulmonary involvement detected with the SensUS device is directly related to the LUS score (r = 0.607, p = 0.002). Lung Staging values were inversely correlated with forced expiratory volume at first second (FEV1%, r = −0.40, p = 0.027), forced vital capacity (FVC%, r = −0.39, p = 0.03) and forced expiratory flow (FEF) at 25th percentile (FEF25%, r = −0.39, p = 0.02) while results directly correlated with FEF25–75% (r = 0.45, p = 0.04) and FEF75% (r = 0.43, p = 0.01). Finally, in patients with reduced DLCO, the Lung Staging was significantly higher, overlapping the LUS (reduced median 1 [1–2] vs. preserved 0 [0–1], p = 0.001), and overlapping the LUS (reduced median 18 [4–20] vs. preserved 5.5 [2–9], p = 0.035). Conclusions: Our data suggest that the considered AI automatic algorithm may assist non-expert physicians in LUS, resulting in non-inferior-to-expert LUS despite a tendency to overestimate ILD lesions. Therefore, the AI algorithm has the potential to support physicians, particularly non-expert LUS sonographers, in daily clinical practice to monitor patients with ILDs. The adopted device is user-friendly, offering a fully automatic real-time analysis. However, it needs proper training in basic skills.

Abstract Background and objectives Lung Ultrasound Score (LUS) identifies and monitors pneumonia by assigning increasing scores. However, it does not include parameters, such as inferior vena cava (IVC) diameter and index of collapse, diaphragmatic excursions and search for pleural and pericardial effusions. Therefore, we propose a new improved scoring system, termed “integrated” lung ultrasound score (i-LUS) which incorporates previously mentioned parameters that can help in prediction of disease severity and survival, choice of oxygenation mode/ventilation and assignment to subsequent areas of care in patients with COVID-19 pneumonia. Methods Upon admission at the sub-intensive section of the emergency medical department (SEMD), 143 consecutively examined COVID-19 patients underwent i-LUS together with all other routine analysis. A database for anamnestic information, laboratory data, gas analysis and i-LUS parameters was created and analyzed. Results Of 143 enrolled patients, 59.4% were male (mean age 71 years) and 40.6% female. (mean age 79 years: p = 0.005). Patients that survived at 1 month had i-LUS score of 16, which was lower than that of non-survivors (median 20; p = 0.005). Survivors had a higher PaO2/FiO2 (median 321.5) compared to non-survivors (median 229, p

In recent years, an increasing enthusiasm has been observed towards artificial intelligence and machine learning, involving different areas of medicine. Among these, although still in the embryonic stage, the dermatopathological field has also been partially involved, with the attempt to develop and train algorithms that could assist the pathologist in the differential diagnosis of complex melanocytic lesions. In this article, we face this new challenge of the modern era, carry out a review of the literature regarding the state of the art and try to determine promising future perspectives.

Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM angiogenesis. We demonstrate that FBEVs’ cargo contains several angiogenic cytokines (i.e., VEGF, HGF, and ANG-1) that promote an early over-angiogenic effect independent from EVs uptake. Interestingly, co-culture of endothelial cells from MM patients (MMECs) with FBEVs for 1 or 6 h activates the VEGF/VEGFR2, HGF/HGFR, and ANG-1/Tie2 axis, as well as the mTORC2 and Wnt/β-catenin pathways, suggesting that the early over-angiogenic effect is a cytokine-mediated process. FBEVs internalization occurs after longer exposure of MMECs to FBEVs (24 h) and induces a late over-angiogenic effect by increasing MMECs migration, chemotaxis, metalloproteases release, and capillarogenesis. FBEVs uptake activates mTORC1, MAPK, SRC, and STAT pathways that promote the release of pro-angiogenic cytokines, further supporting the pro-angiogenic milieu. Overall, our results demonstrate that FBEVs foster MM angiogenesis through dual time-related uptake-independent and uptake-dependent mechanisms that activate different intracellular pathways and transcriptional programs, providing the rationale for designing novel anti-angiogenic strategies.

Aim. To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. Methods. All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (p = 0.034 and p = 0.028, respectively). Conclusions. Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.

Abstract Antibiotics that inhibit bacterial protein or nucleic acid synthesis and function can exert an off-target action on mitochondria (mitotoxic antibiotics), making actively dividing mammalian cells dependent on uridine and pyruvate supplementation. Based on this rationale, we carried out, for the first time, a randomized pilot study in 55 patients with asymptomatic bacteriuria or positive sperm culture, each treated with a single mitotoxic antibiotic with or without oral supplementation of uridine + pyruvate (Uripyr, Mitobiotix, Italy). The in vivo and ex vivo data show a a 3.4-fold higher value in the differential (before and after the antibiotic treatment) lymphocytes count and a 3.7-fold increase in the percentage of dividing T cells, respectively, in the Uripyr vs the control group. Our findings lay the groundwork to enhance the synergy between antibiotics and the immune system in order to optimize the administration protocols and widen the application potentials of antibiotic therapies as well as to re-evaluate old “forgotten” molecules to fight bacterial infections in the antibiotics resistance era.

The COVID-19 pandemic is an unprecedented event entailing long-term consequences on population health and welfare. Those who contracted the coronavirus may have suffered from both physical and mental health issues that unfold the need for tailored intervention strategies. Hence, our study aims to investigate the psychological and social consequences of COVID-19 on a sample of 86 participants, encompassing 43 patients (clinical group; 25 women; mean age = 50.4 ± 10.1 years) recruited from Bari University Hospital, 19 of whom were hospitalized due to the disease. The remaining 43 were individuals not fallen ill with COVID-19 to date (control group; 25 women; mean age = 50.4 ± 10.1 years). The investigation yielded significant gender differences in post-traumatic stress symptoms, depression, and representation of interpersonal distance (IPD), evaluated through the IES-R, the BDI-II, and the IVAS task, respectively. This pattern of results was not replicated in the control group. In general, participants who reported having experienced the most intense post-traumatic symptoms also presented a greater mood deflection and, more specifically, within the clinical group women obtained the highest scores on both scales. Women reported higher IES-R and BDI-II scores compared to men, that could indicate that women who have contracted COVID-19 are more exposed to post-traumatic and depressive symptoms. Our results also showed a significant effect of COVID-19 on IPD with a tendency of disease-experienced individuals to increase their preferred IPD from adults, children, and elderly people. Regarding gender differences in mood and proxemic behavior, a correlation between depressive symptoms and probable PTSD and a further correlation between probable PTSD and greater IPD were found in women from both clinical and control group. Overall, these findings might contribute to a better understanding of gender-based implications of the current pandemic on mental health, also leading to the development of integrated yet personalized intervention strategies.

Angiogenesis represents a pivotal hallmark of multiple myeloma (MM) that correlates to patients’ prognosis, overall survival, and drug resistance. Hence, several anti-angiogenic drugs that directly target angiogenic cytokines (i.e., monoclonal antibodies, recombinant molecules) or their cognate receptors (i.e., tyrosine kinase inhibitors) have been developed. Additionally, many standard antimyeloma drugs currently used in clinical practice (i.e., immunomodulatory drugs, bisphosphonates, proteasome inhibitors, alkylating agents, glucocorticoids) show anti-angiogenic effects further supporting the importance of inhibiting angiogenesis from potentiating the antimyeloma activity. Here, we review the most important anti-angiogenic therapies used for the management of MM patients with a particular focus on their pharmacological profile and on their anti-angiogenic effect in vitro and in vivo. Despite the promising perspective, the direct targeting of angiogenic cytokines/receptors did not show a great efficacy in MM patients, suggesting the need to a deeper knowledge of the BM angiogenic niche for the design of novel multi-targeting anti-angiogenic therapies.

The pathophysiology of atrial fibrillation (AF) may involve atrial fibrosis/remodeling and dysfunctional endothelial activities. Despite the currently available treatment approaches, the progression of AF, its recurrence rate, and the high mortality risk of related complications underlay the need for more advanced prognostic and therapeutic strategies. There is increasing attention on the molecular mechanisms controlling AF onset and progression points to the complex cell to cell interplay that triggers fibroblasts, immune cells and myofibroblasts, enhancing atrial fibrosis. In this scenario, endothelial cell dysfunction (ED) might play an unexpected but significant role. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level. In the cardiovascular compartment, both free circulating and exosomal miRNAs entail the control of plaque formation, lipid metabolism, inflammation and angiogenesis, cardiomyocyte growth and contractility, and even the maintenance of cardiac rhythm. Abnormal miRNAs levels may indicate the activation state of circulating cells, and thus represent a specific read-out of cardiac tissue changes. Although several unresolved questions still limit their clinical use, the ease of accessibility in biofluids and their prognostic and diagnostic properties make them novel and attractive biomarker candidates in AF. This article summarizes the most recent features of AF associated with miRNAs and relates them to potentially underlying mechanisms.

Background and Objectives: COVID-19 induces massive systemic inflammation. Researchers have spent much time and effort finding an excellent and rapid image tool to evaluate COVID-19 patients. Since the pandemic’s beginning, lung ultrasound (LUS) has been identified for this purpose. Monoclonal antibodies (mAb) were used to treat mild patients and prevent respiratory disease worsening. Materials and Methods: We evaluated 15 Caucasian patients with mild COVID-19 who did not require home oxygen, treated with Bamlanivimab and Etesevimab (Group 1). A molecular nose–throat swab test confirmed the diagnosis. All were office patients, and nobody was affected by respiratory failure. They were admitted to receive the single-day infusion of mAb treatment in agreement with the Italian Drug Agency (AIFA) rules for approval. LUS was performed before the drug administration (T0) and after three months (T1). We compared LUS at T1 in other outpatients who came for follow-up and were overlapping at the time of diagnosis for admittance criteria to receive mAb (Group 2). Results: Our COVID-19 outpatients reported no hospitalization in a follow-up visit after recovery. All patients became SARS-CoV-2 negative within one month since T0. LUS score at T0 was 8.23 ± 6.46. At T1 we found a significant decrease in Group 1 LUS score (5.18 ± 4.74; p < 0.05). We also found a significant decrease in the LUS score of Group 1 T1 compared to Group2 T1 (5.18 ± 4.74 vs 7.82 ± 5.21; p < 0.05). Conclusion: Early treatment of the SARS-CoV-2 virus effectively achieves a better recovery from disease and reduces lung involvement after three months as evaluated with LUS. Despite extrapolation to the general population may be done with caution, based on our data this ultrasound method is also effective for evaluating and following lung involvement in COVID-19 patients.

Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy.

The SARS-CoV-2 pandemic has disrupted global health systems and brought the entire globe to its knees. Although born as a disease of the respiratory system, COVID-19 can affect different parts of the body, including the skin. Reports of ongoing skin manifestations of COVID-19 have gradually multiplied, pushing researchers to investigate the etiopathogenic mechanisms underlying these phenomena in more depth. In an attempt to investigate the possible association between SARS-CoV-2, ACE2, TMPRSS2 and skin manifestations, we performed immunohistochemical investigations of the ACE2 receptor and TMPRSS2 in nine skin samples from SARS-CoV-2-positive patients compared to a cohort of healthy controls. Furthermore, after consulting public databases regarding ACE2 mRNA expression in various cell populations resident in the skin, we conducted a literature review aimed at outlining the current state of this topic. We did not find statistically different immuno-expression of ACE2 and TMPRSS2 between the group of SARS-CoV-2-positive patients (nine skin biopsies) and the control group. Regarding ACE2, major immunolabeling was present in the epidermal keratinocytes and, rarely, in the fibroblasts and in the adenomeres of the eccrine sweat glands. Regarding the immune expression of TMPRSS2, we found no significant differences between the two groups, with a weak immune staining only in some skin cytotypes. From the review of the literature, we isolated 35 relevant articles according to the inclusion criteria adopted. ACE2 appears to be a target of SARS-CoV-2, although, other receptor molecules may potentially be implicated, such as TMPRSS2. Future studies with large cases and different molecular investigative methods are needed to further elucidate the mechanisms underlying the skin manifestations of SARS-CoV-2.

The application of artificial intelligence (AI) algorithms in medicine could support diagnostic and prognostic analyses and decision making. In the field of dermatopathology, there have been various papers that have trained algorithms for the recognition of different types of skin lesions, such as basal cell carcinoma (BCC), seborrheic keratosis (SK) and dermal nevus. Furthermore, the difficulty in diagnosing particular melanocytic lesions, such as Spitz nevi and melanoma, considering the grade of interobserver variability among dermatopathologists, has led to an objective difficulty in training machine learning (ML) algorithms to a totally reliable, reportable and repeatable level. In this work we tried to train a fast random forest (FRF) algorithm, typically used for the classification of clusters of pixels in images, to highlight anomalous areas classified as melanoma “defects” following the Allen–Spitz criteria. The adopted image vision diagnostic protocol was structured in the following steps: image acquisition by selecting the best zoom level of the microscope; preliminary selection of an image with a good resolution; preliminary identification of macro-areas of defect in each preselected image; identification of a class of a defect in the selected macro-area; training of the supervised machine learning FRF algorithm by selecting the micro-defect in the macro-area; execution of the FRF algorithm to find an image vision performance indicator; and analysis of the output images by enhancing lesion defects. The precision achieved by the FRF algorithm proved to be appropriate with a discordance of 17% with respect to the dermatopathologist, allowing this type of supervised algorithm to be nominated as a help to the dermatopathologist in the challenging diagnosis of malignant melanoma.

Abstract Background Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. Methods Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients’ characteristics and with a group of non-MM patients as controls. Results No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. Conclusion FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. Trial registration Clinical trial information can be found at the following link: NCT01063179

Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.

The term leishmaniasis includes multiple clinical syndromes: visceral, cutaneous, and mucosal leishmaniasis, resulting from an infection of macrophages throughout the reticuloendothelial system in the dermis and the naso-oropharyngeal mucosa, respectively. The clinical phenotype is mainly driven by the leishmania biologic characteristics and, ultimately, also by the host immune status. The disease is endemic in focal areas in the tropics, subtropics, and southern Europe, transmitted by the bite of female phlebotomine sandflies. Sandflies regurgitate the parasite’s flagellated promastigote stage into the host’s skin; promastigotes bind to receptors on macrophages are phagocytized and transformed within phagolysosomes into non-flagellated amastigotes which replicate and infect additional macrophages. Amastigotes ingested by sandflies transform back into infective promastigotes. Depending on the host’s innate and acquired immune status, systemic and visceral leishmaniasis can be characterized by irregular fever, weight loss, enlargement of the spleen and liver, and anaemia. We present a 42 year-old man with long-lasting type 1 autoimmune hepatitis under immunosuppressive treatment. In January 2017, the patient started to experience low-grade unresponsiveness to empiric antibiotic therapy. The patient developed severe anemia and progressive multilineage cytopenia accompanied by increased levels of inflammatory markers. FDG-PET revealed increased glucose uptake in the liver, spleen, and the whole bone marrow. The subsequently performed bone marrow biopsy evidenced Leishmania amastigotes inside macrophages, confirmed by serological positivity to anti-Leishmania antibody. Immunosuppressive therapy was suspended and replaced by treatment with amphotericin B at 4 mg/kg/day from day 1 to day 5, followed by a single infusion on days 10, 17, 24, 31, and 38. The bone marrow smear after treatment still evidenced few Leishmania amastigotes; in consideration of the patient’s immunosuppression status, two further doses of amphotericin B on days 45 and 52 were employed, leading to infection resolution. In real-life, as exemplified in this case, administering two additional doses of amphotericin B (concerning the guidelines) offered an additional therapeutic opportunity for a patient under long-term immunosuppressive treatment.

Ion channels are pore-forming proteins that allow ions to flow across plasma membranes and intracellular organelles in both excitable and non-excitable cells. They are involved in the regulation of several biological processes (i.e., proliferation, cell volume and shape, differentiation, migration, and apoptosis). Recently, the aberrant expression of ion channels has emerged as an important step of malignant transformation, tumor progression, and drug resistance, leading to the idea of “onco-channelopathy”. Here, we review the contribution of ion channels and transporters in multiple myeloma (MM), a hematological neoplasia characterized by the expansion of tumor plasma cells (MM cells) in the bone marrow (BM). Deregulation of ion channels sustains MM progression by modulating intracellular pathways that promote MM cells’ survival, proliferation, and drug resistance. Finally, we focus on the promising role of ion channels as therapeutic targets for the treatment of MM patients in a combination strategy with currently used anti-MM drugs to improve their cytotoxic activity and reduce adverse effects.

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role of lncRNAs in the pathogenesis of multiple myeloma (MM). We focus on their ability to regulate the biological processes identified as “hallmarks of cancer” that enable malignant cell transformation, early tumor onset and progression. The aberrant expression of lncRNAs in MM suggests their potential use as clinical biomarkers for diagnosis, patient stratification, and clinical management. Moreover, they represent ideal candidates for therapeutic targeting.

Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components’ immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients’ outcomes.

Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. In physiological condition, autophagy funnels cytoplasmic constituents to autophagolysosomes for degradation and is an alternative way for cell-death behavior. Here, we inspected autophagy as a prosurvival mechanism essential for drug resistance in multiple myeloma (MM). Accordingly, autophagy inhibitors used in association to conventional anti-MM drugs might enforce the effect against resistant MM plasma cells and render autophagy a new therapeutic target.

Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis.Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD.Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97).Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.

Background: Timely assessment of COVID-19 severity is crucial for the rapid provision of appropriate treatments. Definitive criteria for the early identification of severe COVID-19 cases that require intensive care unit admission are lacking.Methods: This was a single-center, retrospective case-control study of 95 consecutive adults admitted to the intensive care unit (cases) or a medical ward (controls) for laboratory-confirmed COVID-19. Clinical data were collected and changes in laboratory test results were calculated between presentation at the emergency department and admission. Univariate and multivariable logistic regression was performed to calculate odds ratios for intensive care unit admission according to changes in laboratory variables.Results: Of the 95 adults with COVID-19, 25 were admitted to intensive care and 70 to a medical ward after a median 6 h stay in the emergency department. During this interval, neutrophil counts increased in cases and decreased in controls (median, 934 vs. −295 × 106/L; P = 0.006), while lymphocyte counts decreased in cases and increased in controls (median, −184 vs. 109 × 106/L; P < 0.001). In cases, the neutrophil-to-lymphocyte ratio increased 6-fold and the urea-to-creatinine ratio increased 20-fold during the emergency department stay, but these ratios did not change in controls (P < 0.001 for both comparisons). By multivariable logistic regression, short-term increases in the neutrophil-to-lymphocyte ratio (OR = 1.43; 95% CI, 1.16–1.76) and urea-to-creatinine ratio (OR = 1.72; 95% CI, 1.20–2.66) were independent predictors of intensive care unit admission.Conclusion: Short-time changes in neutrophil-to-lymphocyte ratio and urea-to-creatinine ratio emerged as stand-alone parameters able to identify patients with aggressive disease at an early stage.

Two mechanisms are involved in the immune escape of cancer cells: the immunoediting of tumor cells and the suppression of the immune system. Both processes have been revealed in multiple myeloma (MM). Complex interactions between tumor plasma cells and the bone marrow (BM) microenvironment contribute to generate an immunosuppressive milieu characterized by high concentration of immunosuppressive factors, loss of effective antigen presentation, effector cell dysfunction, and expansion of immunosuppressive cell populations, such as myeloid-derived suppressor cells, regulatory T cells and T cells expressing checkpoint molecules such as programmed cell death 1. Considering the great immunosuppressive impact of BM myeloma microenvironment, many strategies to overcome it and restore myeloma immunosurveillance have been elaborated. The most successful ones are combined approaches such as checkpoint inhibitors in combination with immunomodulatory drugs, anti-monoclonal antibodies, and proteasome inhibitors as well as chimeric antigen receptor (CAR) T cell therapy. How best to combine anti-MM therapies and what is the optimal timing to treat the patient are important questions to be addressed in future trials. Moreover, intratumor MM heterogeneity suggests the crucial importance of tailored therapies to identify patients who might benefit the most from immunotherapy, reaching deeper and more durable responses.

Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.

We report on an observational, multicenter study of 345 adult CVID patients, designed to assess the diagnostic value and the clinical association of serum free light chain (sFLC) pattern in Common Variable Immunodeficiency disorders (CVID). Sixty CVID patients were tested twice in order to assess intraindividual variability of sFLC. As control groups we included 138 patients affected by undefined primary antibody defects (UAD), lymphoproliferative diseases (LPDs), and secondary antibody deficiencies not related to hematological malignancies (SID). CVID patients presented lower κ and λ chain concentration compared to controls, showing low intraindividual sFLC variability. On the basis of the sFLC pattern, patients were classified into four groups: κ−λ+, κ+λ−, κ−λ−, κ+λ+. The most common pattern in CVID patients was κ−λ− (51%), followed by κ−λ+, (25%), κ+λ+ (22%), and κ+λ− (3%). In UAD, LPD, and SID groups κ+λ+ was the most common pattern observed. By analyzing the possible association between sFLC patterns and disease-related complications of CVID, we observed that patients belonging to the κ−λ− group presented more commonly unexplained enteropathy compared to the κ+λ+ group and showed higher frequency of bronchiectasis and splenomegaly compared to both the κ−λ+ and κ+λ+ patients. When compared to the other groups, κ−λ− had also lower serum IgG, IgA, and IgM concentrations at diagnosis, lower frequency of CD27+IgD–IgM– switched memory B cells, and higher frequency of CD21low B cells, receiving earlier CVID diagnosis. Thus, lower levels of sFLC might be an epiphenomenon of impairment in B cell differentiation, possibly leading κ−λ− patients to a higher risk for bacterial infections and chronic lung damage. Based on these results, we suggest adding sFLC assay to the diagnostic work-up of hypogammaglobulinemia and during follow-up. The assay may be useful to differentiate CVID from other causes of hypogammaglobulinemia and to early detect monoclonal lymphoproliferation occurring over years. Moreover, since the sFLC pattern seems to be related to disease phenotypes and clinical manifestations of CVID and after confirmation by further studies, sFLC assay might be considered a promising prognostic tool for identifying patients at higher risk of developing enteropathy and chronic lung damage or splenomegaly. This will allow designing a tailored follow-up for CVID patients.

COVID-19 is a pandemic disease caused by the new coronavirus SARS-CoV-2 that mostly affects the respiratory system. The consequent inflammation is not able to clear viruses. The persistent excessive inflammatory response can build up a clinical picture that is very difficult to manage and potentially fatal. Modulating the immune response plays a key role in fighting the disease. One of the main defence systems is the activation of neutrophils that release neutrophil extracellular traps (NETs) under the stimulus of autophagy. Various molecules can induce NETosis and autophagy; some potent activators are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). This molecule is released by damaged lung cells and can induce a robust innate immunity response. The increase in HMGB1 and NETosis could lead to sustained inflammation due to SARS-CoV-2 infection. Therefore, blocking these molecules might be useful in COVID-19 treatment and should be further studied in the context of targeted therapy.

Considering that Aurora kinase inhibitors are currently under clinical investigation in hematologic cancers, the identification of molecular events that limit the response to such agents is essential for enhancing clinical outcomes. Here, we discover a NF-κB-inducing kinase (NIK)-c-Abl-STAT3 signaling-centered feedback loop that restrains the efficacy of Aurora inhibitors in multiple myeloma. Mechanistically, we demonstrate that Aurora inhibition promotes NIK protein stabilization via downregulation of its negative regulator TRAF2. Accumulated NIK converts c-Abl tyrosine kinase from a nuclear proapoptotic into a cytoplasmic antiapoptotic effector by inducing its phosphorylation at Thr735, Tyr245 and Tyr412 residues, and, by entering into a trimeric complex formation with c-Abl and STAT3, increases both the transcriptional activity of STAT3 and expression of the antiapoptotic STAT3 target genes PIM1 and PIM2. This consequently promotes cell survival and limits the response to Aurora inhibition. The functional disruption of any of the components of the trimer NIK-c-Abl-STAT3 or the PIM survival kinases consistently enhances the responsiveness of myeloma cells to Aurora inhibitors. Importantly, concurrent inhibition of NIK or c-Abl disrupts Aurora inhibitor-induced feedback activation of STAT3 and sensitizes myeloma cells to Aurora inhibitors, implicating a combined inhibition of Aurora and NIK or c-Abl kinases as potential therapies for multiple myeloma. Accordingly, pharmacological inhibition of c-Abl together with Aurora resulted in substantial cell death and tumor regression in vivo. The findings reveal an important functional interaction between NIK, Abl and Aurora kinases, and identify the NIK, c-Abl and PIM survival kinases as potential pharmacological targets for improving the efficacy of Aurora inhibitors in myeloma.

Abstract Background Multiple myeloma (MM) is a cancer of terminally differentiated plasma that is part of a spectrum of blood diseases. The role of the micro-environment is crucial for MM clonal evolution. Methods This paper describes the analysis carried out on a limited number of genes automatically extracted by a nonnegative matrix factorization (NMF) based approach from gene expression profiles of bone marrow fibroblasts of patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results Automatic exploration through NMF, combined with a motivated post-processing procedure and a pathways analysis of extracted genes, allowed to infer that a functional switch is required to lead fibroblasts to acquire pro-tumorigenic activity in the progression of the disease from MGUS to MM. Conclusion The extracted biologically relevant genes may be representative of the considered clinical conditions and may contribute to a deeper understanding of tumor behavior.

Background/Aims: Hypoxia is a powerful stimulator of angiogenesis under physiological as well as pathological conditions. Normal endothelial cells (EC), such as human umbilical vein EC (HUVEC), are relatively affected by hypoxic insult in terms of cell survival. In contrast, EC from tumors are particularly resistant to hypoxia-induced cell death. Previous reports have shown that EC in bone marrow from multiple myeloma (MM) patients had a hypoxic phenotype, even under normoxic conditions. The aim of this study was to evaluate whether HUVEC and MMEC adapt differently to hypoxia. Methods: Cell proliferation was assessed by the CyQUANT assay. Cdc25A, p21, Bax, Bcl-xl, BNIP3, glucose transporter (GLUT)-1, monocarboxylate transporter (MCT)-4 and carbonic anhydrase (CA)IX mRNA expression was determined by qRT-PCR. HIF-1α, BNIP3, Beclin-1, LC3B, livin, Bax, Bcl-xl, p21, p62 and β-actin protein expression was analyzed by western blot. Apoptosis was determined by TUNEL assay. Silencing of BNIP3 was achieved by stealth RNA system technology. Results: While HUVEC survival was reduced after prolonged hypoxic exposure, MMEC were completely unaffected. This difference was also significant in terms of livin, cdc25A and p21 expression. Hypoxia induced apoptosis and inhibited autophagy in HUVEC, but not in MMEC, where hypoxic treatment resulted in a more sustained adaptive response. In fact, MMEC showed a more significant increase in the expression of genes regulated transcriptionally by hypoxia-inducible factor (HIF)-1α. Interestingly, they showed higher expression of BNIP3 than did HUVEC, indicating a more pronounced autophagic (and pro-survival) phenotype. The potential role of BNIP3 in EC survival was confirmed by BNIP3 siRNA experiments in HUVEC, where BNIP3 inhibition resulted in reduced cell survival and increased apoptosis. Conclusion: These findings provide further information on how hypoxia may affect EC survival and could be important for a better understanding of EC physiology under normal and pathological conditions, such as in multiple myeloma.

Systemic sclerosis (SSc) is a rare autoimmune inflammatory rheumatic disease. The prevalence of SSc ranges from 7 to 700 cases per million worldwide. Due to multiple organ involvement and constant inflammatory state, this group of patients presents an increased risk of infectious diseases. This paper aimed to gather the up-to-date evidence on vaccination strategies for patients with SSc and to be a useful tool for the prevention and management of infectious diseases. The authors conducted a scoping review in which each paragraph presents data on a specific vaccine’s safety, immunogenicity, and efficacy. The work deals with the following topics: SARS-CoV-2, seasonal influenza, S. pneumoniae, HAV, HBV, HZV, N. meningitidis, H. influenzae, HPV, and diphtheria-tetanus-pertussis.

Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring.

Introduction : Oxidative stress is a result of an imbalance between endogenous production of free reactive oxygen species and reduced effectiveness of antioxidant defence mechanisms. Advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) are compounds formed by transformation of macromolecules, including proteins which can serve as markers of oxidative stress and inflammation in several diseases. Aim : To investigate the role of AGEs and AOPPs as new markers of oxidative stress and inflammation in patients with chronic spontaneous urticaria (CSU). Material and methods : Advanced glycation end products and AOPP levels were determined in the sera of 85 patients with CSU and 64 healthy controls, using spectrofluorimetry and spectrophotometry, respectively. Results : Advanced oxidation protein products levels in patients were statistically higher than those in controls. These levels were not affected by the presence of positive autologous serum test results or autologous plasma test results. No statistically significant differences were found between AGE levels in patients and controls. Conclusions : Formation of AGEs and AOPPs may be accelerated in immunological and allergic disorders. Depending on the sites evaluated, the presence or absence of oxidative stress in chronic urticaria is controversial. To our knowledge, this is the first study showing the possible involvement of AOPPs in CSU. The different behaviour observed for these two biomarkers is very likely due to the activation of specific related biochemical pathways associated with the condition under study.

The Coronavirus disease 2019 (COVID-19) pandemic has represented an unprecedented challenge for humankind from health, economic, and social viewpoints. In February 2020, Italy was the first western country to be deeply hit by the pandemic and suffered the highest case/fatality rate among western countries. Brand new anti-COVID-19 vaccines have been developed and made available in

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions.

Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community’s effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target.

Background and aim. The review aimed to summarize advances in the topic of endocrine diseases and coronavirus disease 2019 (COVID-19). Methods. Scientific and institutional websites and databases were searched and data were collected and organized, when plausible, to angle the discussion toward the following clinical issues. (1) Are patients with COVID-19 at higher risk of developing acute or late-onset endocrine diseases or dysfunction? (2) May the underlying endocrine diseases or dysfunctions be considered risk factors for poor prognosis once the infection has occurred? (3) Are there defined strategies to manage endocrine diseases despite pandemic-related constraints? Herein, the authors considered only relevant and more frequently observed endocrine diseases and disorders related to the hypothalamic-pituitary region, thyroid and parathyroid glands, calcium-phosphorus homeostasis and osteoporosis, adrenal glands, and gonads. Main. Data highlight the basis of some pathophysiological mechanisms and anatomical alterations of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-induced endocrine dysfunctions. Some conditions, such as adrenal insufficiency and cortisol excess, may be risk factors of worse clinical progression once the infection has occurred. These at-risk populations may require adequate education to avoid the SARS-CoV-2 infection and adequately manage medical therapy during the pandemic, even in emergencies. Endocrine disease management underwent a palpable restraint, especially procedures requiring obligate access to healthcare facilities for diagnostic and therapeutic purposes. Strategies of clinical triage to prioritize medical consultations, laboratory, instrumental evaluations, and digital telehealth solutions should be implemented to better deal with this probably long-term situation.

The antimicrobial resistance (AMR) phenomenon is an emerging global problem and is induced by overuse and misuse of antibiotics in medical practice. In total, 10% of antibiotic prescriptions are from dentists, usually to manage oro-dental pains and avoid postsurgical complications. Recent research and clinical evaluations highlight new therapeutical approaches with a reduction in dosages and number of antibiotic prescriptions and recommend focusing on an accurate diagnosis and improvement of oral health before dental treatments and in patients’ daily lives. In this article, the most common clinical and operative situations in dental practice, such as endodontics, management of acute alveolar abscesses, extractive oral surgery, parodontology and implantology, are recognized and summarized, suggesting possible guidelines to reduce antibiotic prescription and consumption, maintaining high success rates and low complications rates. Additionally, the categories of patients requiring antibiotic administration for pre-existing conditions are recapitulated. To reduce AMR threat, it is important to establish protocols for treatment with antibiotics, to be used only in specific situations. Recent reviews demonstrate that, in dentistry, it is possible to minimize the use of antibiotics, thoroughly assessing patient’s conditions and type of intervention, thus improving their efficacy and reducing the adverse effects and enhancing the modern concept of personalized medicine.

Abstract Background The efficacy and safety of direct-acting antiviral agents (DAAs) were evaluated in a cohort of prospectively enrolled patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC), an immune complex-mediated vasculitis of small and medium vessels in which the pathogenetic role of HCV has been clearly established. Methods Twenty-two patients received DAAs. Clinical and laboratory features were recorded at baseline, every 4 weeks until the end of treatment (EoT), and 12 weeks afterwards. Primary efficacy endpoints were (a) sustained virological response 12 weeks after therapy completion (SVR12), (b) regression of symptomatology (clinical response) and (c) cryoglobulin disappearance or cryocrit reduction ≥50% (immunological response). Complete response (CR) was defined as the occurrence of all three primary endpoints; partial response (PR) was defined as the occurrence of SVR12, with or without either immunological or clinical response; and no response was defined as missing the achievement of all three endpoints. Results All patients reached SVR12. Compared with basal values, mean cryocrit values were significantly decreased at EoT and SVR12. A significant reduction of alanine transaminase and a parallel increase of complement component C4 levels were also detected. Rheumatoid factor activity was significantly reduced at EoT but not at SVR12. At SVR12, a CR was established in 14 patients (63.7%) and a PR in 8 patients (36.3%). In one patient with small lymphocytic lymphoma, the tumour progressed despite viral clearance. Mild adverse events were recorded in nine patients (40.9%). Conclusions The response rates induced by the use of DAAs in patients with MC were remarkably higher than those previously achieved with pegylated interferon-α/ribavirin, with or without rituximab. A much longer follow-up is desirable to achieve useful information in terms of persistent viral clearance and clinical response.

Angiogenesis is a crucial event for tumor progression and metastasis. It is the process through which new blood vessels are formed and has become a therapeutic target in many cancer therapies. However, current anti-angiogenic drugs such as Thalidomide still have detrimental teratogenic effects. This property could be caused by the presence of chiral carbons, intrinsic to such compounds. We synthesized four different phthalimide derivatives that lack chiral carbons in their chemical structure. We hypothesized that these achiral carbon compounds would retain similar levels of anti-angiogenic activity whilst reducing teratogenic effects. We tested for their anti-angiogenic functions using an in vitro 3D microfluidic assay with human endothelial cells. All four compounds caused a drastic inhibition of angiogenesis at lower effective concentrations compared to Thalidomide. Quantification of the blood vessel sprouting in each condition allowed us to classify compounds depending on their anti-angiogenic capabilities. The most effective identified compound (C4), was tested in vivo on a zebrafish embryo model. Blood vessel development was measured using number and lengths of the stalks visible in the fli1a:EGFP transgenic line. Potential teratogenic effects of C4 were monitored over zebrafish embryonic development. The in vivo results confirmed the increased potency of C4 compared to Thalidomide demonstrated by results in embryos exposed to concentrations as low as 0.02 μM. The teratogenic analysis further validated the advantages of using C4 over Thalidomide in zebrafish embryos. This study highlights how the use of in vitro 3D model can allow rapid screening and selection of new and safer drugs.

Endothelial cells (EC) line the bone marrow microvasculature and are in close contact with CD8+ T cells that come and go across the permeable capillaries. Because of these intimate interactions, we investigated the capacity of EC to act as antigen-presenting cells (APC) and modulate CD8+ T cell activation and proliferation in bone marrow of patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance. We found that EC from MM patients show a phenotype of semi-professional APC given that they express low levels of the co-stimulatory molecules CD40, CD80 and CD86, and of the inducible co-stimulator ligand (ICOSL). In addition, they do not undergo the strong switch from immunoproteasome to standard proteasome subunit expression which is typical of mature professional APC such as dendritic cells. EC can trap and present antigen to CD8+ T cells, stimulating a central memory CD8+ T cell population that expresses Foxp3 and produces high amounts of IL-10 and TGF-β. Another CD8+ T cell population is stimulated by professional APC, produces IFN-γ, and exerts antitumor activity. Thus, two distinct CD8+ T cell populations coexist in the bone marrow of MM patients: the first population is sustained by EC, expresses Foxp3, produces IL-10 and TGF-β, and exerts pro-tumor activity by negatively regulating the second population. This study adds new insight into the role that EC play in MM biology and describes an additional immune regulatory mechanism that inhibits the development of antitumor immunity and may impair the success of cancer immunotherapy.

Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically.

Amyloidosis is due to deposition of an excessive amount of protein in many parenchymal tissues, including myocardium. The onset of cardiac Amyloidosis (CA) is an inauspicious prognostic factor, which can lead to sudden death. We retrospectively analyzed 135 patients with systemic amyloidosis, admitted to our ward between 1981 and 2019. Among them, 54 patients (46.30% F/53.70% M, aged 63.95 ± 12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. As a control group, we enrolled 81 patients (49.30% F/50.70% M, aged 58.33 ± 15.65) who did not meet the criteria for CA. In 44/54 of patients CA was associated with AL, 5/54 with AA and 3/54 of patients with ATTR, and in 1/54 AL was related to hemodialysis and in 1/54 to Gel-Amyloidosis. The most common AL type was IgG (28/44); less frequent forms were either IgA (7/44) or IgD (2/44), while seven patients had a λ free light chain form. The 32 AL with complete Ig were 31 λ-chain and just one k-chain. CA patients presented normal BP (SBP 118.0 ± 8.4 mmHg; DBP 73.8 ± 4.9 mmHg), while those with nCA had an increased proteinuria (p = 0.02). TnI and NT-proBNP were significantly increased compared to nCA (p = 0.031 and p = 0.047, respectively). In CA patients we found an increased LDH compared to nCA (p = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA (p = 0.002), a decreased Ejection Fraction % (p = 0.0018) and Doppler velocity E/e’ ratio (p = 0.0095). Moreover, CA patients had an enhanced right atrium area (p = 0.0179), right ventricle basal diameter (p = 0.0112) and wall thickness (p = 0.0471) compared to nCA, and an increased inferior cava vein diameter (p = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients (p = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; p = 0.031) as well as Gamma globulins (r = 0.43, p = 0.033), Monoclonal components (r = 0.72; p = 0.047) and IgG values (r = 0.62, p = 0.018). Conversely, a significant negative correlation with LDH (r = −0.57, p = 0.005), IVS (r = −0.51, p = 0.008) and diastolic function evaluated as E/e’ (r = −0.60, p = 0.003) were verified. CA patients had very poor survival rates compared to controls (30 vs. 66 months in CA vs. nCA, respectively, p = 0.15). Mean survival of CA individuals was worse also when stratified according to NT-proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, for patients with lower vs. higher values than the median, respectively p = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with lower values than 18 mm, p = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we analyzed the role of different cellular components of the tumor microenvironment, including mast cells, macrophages, and lymphocytes, in the tumor progression of DLBCL. We examined several approaches to confront the available pieces of evidence, whereby three key points emerged. DLBCL is a disease of malignant B cells spreading and accumulating both at nodal and at extranodal sites. In patients with both nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. The DLBCL cell interaction with mature stromal cells and vessels confers tumor protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL–milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.

The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway.

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

MicroRNAs (miRNAs, or miRs) are single-strand short non-coding RNAs with a pivotal role in the regulation of physiological- or disease-associated cellular processes. They bind to target miRs modulating gene expression at post-transcriptional levels. Here, we present an overview of miRs deregulation in the pathogenesis of multiple myeloma (MM), and discuss the potential use of miRs/nanocarriers association in clinic. Since miRs can act as oncogenes or tumor suppressors, strategies based on their inhibition and/or replacement represent the new opportunities in cancer therapy. The miRs delivery systems include liposomes, polymers, and exosomes that increase their physical stability and prevent nuclease degradation. Phase I/II clinical trials support the importance of miRs as an innovative therapeutic approach in nanomedicine to prevent cancer progression and drug resistance. Results in clinical practice are promising.

Immune checkpoint inhibitor (ICI)-related inflammatory diseases, including polymyositis (PM) and dermatomyositis (DM), in patients suffering from neoplastic disorders represent a medical challenge. The treatment of these conditions has taken on new urgency due to the successful and broad development of cancer-directed immunological-based therapeutic strategies. While primary and secondary PM/DM phenotypes have been pathophysiologically characterized, a rational, stepwise approach to the treatment of patients with ICI-related disease is lacking. In the absence of high-quality evidence to guide clinical judgment, the available data must be critically assessed. In this literature review, we examine partially neglected immunological and clinical findings to obtain insights into the biological profiles of ICI-related PM/DM and potential treatment options. We show that differential diagnosis is essential to stratifying patients according to prognosis and therapeutic impact. Finally, we provide a comprehensive assessment of druggable targets and suggest a stepwise patient-oriented approach for the treatment of ICI-related PM/DM.