New Frontiers about the Role of Human Microbiota in Immunotherapy: The Immune Checkpoint Inhibitors and CAR T-Cell Therapy Era

Microbiota is considered an independent organ with the capability to modulate tumor growth and response to therapies. In the chemo-free era, the use of new immunotherapies, more selective and effective and less toxic, led to the extension of overall survival of patients, subject to their ability to not stop treatment. This has focused scientists’ attention to optimize responses by understanding and changing microbiota composition. While we have obtained abundant data from studies in oncologic and hematologic patients receiving conventional chemotherapy, we have less data about alterations in intestinal flora in those undergoing immunotherapy, especially based on Chimeric Antigen Receptor (CAR) T-cells. Actually, we know that the efficacy of Programmed Cell Death 1 (PD-1), PD-1 ligand, and Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is improved by probiotics rich in Bifidobacterium spp., while compounds of Bacteroidales and Burkholderiales protect from the development of the anti-CTLA-4-induced colitis in mouse models. CAR T-cell therapy seems to not be interfering with microbiota; however, the numerous previous therapies may have caused permanent damage, thus obscuring the data we might have obtained. Therefore, this review opens a new chapter to transfer known acquisitions to a typology of patients destined to grow

Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies

Radiation therapy plays a critical role in the management of a wide range of hematologic malignancies. It is well known that the post-irradiation damages both in the bone marrow and in other organs are the main causes of post-irradiation morbidity and mortality. Tumor control without producing extensive damage to the surrounding normal cells, through the use of radioprotectors, is of special clinical relevance in radiotherapy. An increasing amount of data is helping to clarify the role of oxidative stress in toxicity and therapy response. Radioprotective agents are substances that moderate the oxidative effects of radiation on healthy normal tissues while preserving the sensitivity to radiation damage in tumor cells. As well as the substances capable of carrying out a protective action against the oxidative damage caused by radiotherapy, other substances have been identified as possible enhancers of the radiotherapy and cytotoxic activity via an oxidative effect. The purpose of this review was to examine the data in the literature on the possible use of old and new substances to increase the efficacy of radiation treatment in hematological diseases and to reduce the harmful effects of the treatment

Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma

Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs’ efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs

Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma

Multiple myeloma (MM) is typically exemplified by a desynchronized cytokine system with increased levels of inflammatory cytokines. We focused on the contrast between inflammatory and anti-inflammatory systems by assessing the role of cytokines and their influence on MM. The aim of this review is to summarize the available information to date concerning this equilibrium to provide an overview of the research exploring the roles of serum cytokines in MM. However, the association between MM and inflammatory cytokines appears to be inadequate, and other functions, such as pro-proliferative or antiproliferative effects, can assume the role of cytokines in the genesis and progression of MM. It is possible that inflammation, when guided by cancer-specific Th1 cells, may inhibit tumour onset and progression. In a Th1 microenvironment, proinflammatory cytokines (e.g., IL-6 and IL-1) may contribute to tumour eradication by attracting leucocytes from the circulation and by increasing CD4 + T cell activity. Hence, caution should be used when considering therapies that target factors with pro- or anti-inflammatory activity. Drugs that may reduce the tumour-suppressive Th1-driven inflammatory immune response should be avoided. A better understanding of the relationship between inflammation and myeloma will ensure more effective therapeutic interventions

Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs

Effects of Substrate and Cement Shade on the Translucency and Color of CAD/CAM Lithium-Disilicate and Zirconia Ceramic Materials

The aim of this in vitro study was to evaluate the effects of substrate and cement shades on the translucency and color of lithium-disilicate and zirconia CAD/CAM materials. Two light-cured resin cements (RelyX Veneer Cement; 3M; Choice 2 Veneer Cement; Bisco Dental) with a standardized thickness (0.1 mm) were tested in combination with two different monolithic CAD/CAM materials (E-Max CAD (LI2SI2O5); Ivoclar Vivadent; Katana (ZrO2); Kuraray-Noritake Dental) on two different colored composite substrates used as a dentin (Filtek Supreme XTE; 3M); for a total of 12 combinations (n = 10). The specimens’ color was measured with a spectrophotometer (Spectroshade; MHT). Measurements were taken using the CIELAB color coordinate system (L*a*b*) against black and white backgrounds. L*a*b* values were statistically analyzed for the variables Substrate, Ceramic, and Cement by applying a Three-Way ANOVA followed by the Tukey Test for post-hoc comparison (p E00 1.8 and 0.8) were used. Statistically significant influence was found for factors ceramic material, cement shade, and substrate color (p 2Si2O5. Opacity was significantly higher when white opaque cement shade was employed. Ceramic type and cement shade significantly influenced L*a*b* color coordinates. The final translucency and color of ceramic restorations can, therefore, be influenced by ceramic material, cement shade, and substrate color

Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw

Bisphosphonates (BPs) are inhibitors of osteoclast-mediated bone resorption used for the treatment of multiple myeloma (MM) patients with osteolytic lesions. Bisphosphonate-induced osteonecrosis of the jaw (BONJ) is an infrequent drug-caused adverse event of these agents. Long noncoding RNAs (lncRNAs) are a set of more than 200 base pairs, noncoding RNA molecules, which are critical posttranscriptional regulators of gene expression. Our study was aimed at evaluating 17 lncRNAs, whose targets were previously validated as key elements in MM, bone metabolism, and angiogenesis in MM subjects without BONJ (MM group), in MM subjects with BONJ (BONJ group), and a group of healthy controls (CTRL group). Our results demonstrated a different lncRNA profile in BONJ patients compared to MM patients and controls. Two lncRNAs (DANCR and MALAT1) were both downregulated compared to controls and MM, twelve (HOTAIR, MEG3, TP73-AS1, HOTTIP, HIF1A-AS2, MANTIS, CTD-2201E18, CTD1-2003C8, R-471B22, RP1-43E13, RP11-553L6.5, and RP1-286D6) were overexpressed in MM with BONJ, and one (H19) was upregulated compared with only MM. Two lncRNAs (JHDMD1 and MTMR9LP) had higher expression, but these differences were not statistically significant. The examined lncRNAs target several genes and metabolic pathways. An altered lncRNA signature could contribute to the onset of BONJ or have a protective action. Targeting these lncRNAs could offer a possibility for the prevention or therapy of BONJ

Evaluation of the AGE/sRAGE Axis in Patients with Multiple Myeloma

Glycative stress influences tumor progression. The aim of the present study was to evaluate the advanced glycation end products/soluble receptor of advanced glycation end products (AGE/sRAGE) axis in patients with multiple myeloma (MM). Blood samples were taken from 19 patients affected by MM and from 16 sex-matched and age-matched healthy subjects. AGE and sRAGE axis were dosed in patients with MM and matched with controls. AGEs were measured by spectrofluorimetric methods. Blood samples for the determination of sRAGE were analyzed by ELISA. AGE levels were significantly reduced in patients with respect to controls. Instead, sRAGE was significantly elevated in patients affected by MM compared to healthy subjects. Moreover, we showed that there was a statistically significant difference in sRAGE according to the heavy and light chain. IgA lambda had significantly higher sRAGE values than IgA kappa, IgG kappa, and IgG Lambda MM patients. From our data emerges the role of the sRAGE/AGE axis in MM. Since AGE is a positive regulator of the activity of RAGE, circulating sRAGE concentrations may reflect RAGE expression and may be raised in parallel with serum AGE concentrations as a counter-system against AGE-caused tissue damage. Serum concentrations of AGE and sRAGE could therefore become potential therapeutic targets

Post-Fatigue Fracture Resistance of Lithium Disilicate and Polymer-Infiltrated Ceramic Network Indirect Restorations over Endodontically-Treated Molars with Different Preparation Designs: An In-Vitro Study

The aim of the present study was to evaluate the fatigue to cyclic and static resistance of indirect restorations with different preparation designs made either of lithium disilicate (LS) or polymer-infiltrated ceramic network (PICN). Eighty-four (n = 84) molars were chosen, endodontically treated, and prepared with standardized MOD cavities. The molars were randomly divided into 6 study groups (n = 14) taking into account the “preparation design’’ (occlusal veneer with 1.2 mm occlusal thickness; overlay with 1.6 mm occlusal thickness; adhesive crown with 2 mm occlusal thickness) and the “CAD/CAM material’’ (E-max CAD, Ivoclar vivadent; Vita Enamic, Vita). A fatigue test was conducted with a chewing simulator set at 50 N for 1,500,000 cycles. Fracture resistance was assessed using a universal testing machine with a 6 mm diameter steel sphere applied to the specimens at a constant speed of 1 mm/min. A SEM analysis before the fracture test was performed to visually analyze the tooth-restoration margins. A statistical analysis was performed with a two-way ANOVA and a post-hoc pairwise comparison was performed using the Tukey test. The two-way ANOVA test showed that both the preparation design factor (p = 0.0429) and the CAD/CAM material factor (p = 0.0002) had a significant influence on the fracture resistance of the adhesive indirect restorations. The interaction between the two variables did not show any significance (p = 0.8218). The occlusal veneer had a lower fracture resistance than the adhesive crown (p = 0.042) but not lower than the overlay preparation (p = 0.095). LS was more resistant than PICN (p = 0.002). In conclusion, in the case of endodontically treated teeth, overlay preparation seems to be a valid alternative to the traditional full crown preparation, while occlusal veneers should be avoided in restoring non-vital molars with a high loss of residual tooth structure. LS material is more resistant compared to PICN