Multiple Sclerosis: From the Application of Oligoclonal Bands to Novel Potential Biomarkers.

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system with a high heterogeneity among patients. In the clinical setting, one of the main challenges is a proper and early diagnosis for the prediction of disease activity. Current diagnosis is based on the integration of clinical, imaging, and laboratory results, with the latter based on the presence of intrathecal IgG oligoclonal bands in the cerebrospinal fluid whose detection via isoelectric focusing followed by immunoblotting represents the gold standard. Intrathecal synthesis can also be evidenced by the measurement of kappa free light chains in the cerebrospinal fluid, which has reached similar diagnostic accuracy compared to that of oligoclonal bands in the identification of patients with multiple sclerosis; moreover, recent studies have also highlighted its value for early disease activity prediction. This strategy has significant advantages as compared to using oligoclonal band detection, even though some issues remain open. Here, we discuss the current methods applied for cerebrospinal fluid analysis to achieve the most accurate diagnosis and for follow-up and prognosis evaluation. In addition, we describe new promising biomarkers, currently under investigation, that could contribute both to a better diagnosis of multiple sclerosis and to its monitoring of the therapeutic treatment response.

Advances in "adiponcosis": Insights in the inner mechanisms at the base of adipose and tumour tissues interplay.

The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin-like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue-derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low-chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity-related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression.

Exploring the putative role of PRDM1 and PRDM2 transcripts as mediators of T lymphocyte activation.

BACKGROUND: T cell activation and programming from their naïve/resting state, characterized by widespread modifications in chromatin accessibility triggering extensive changes in transcriptional programs, is orchestrated by several cytokines and transcription regulators. PRDM1 and PRDM2 encode for proteins with PR/SET and zinc finger domains that control several biological processes, including cell differentiation, through epigenetic regulation of gene expression. Different transcripts leading to main protein isoforms with (PR +) or without (PR-) the PR/SET domain have been described. Although many studies have established the critical PRDM1 role in hematopoietic cell differentiation, maintenance and/or function, the single transcript contribution has not been investigated before. Otherwise, very few evidence is currently available on PRDM2. Here, we aimed to analyze the role of PRDM1 and PRDM2 different transcripts as mediators of T lymphocyte activation. METHODS: We analyzed the transcription signature of the main variants from PRDM1 (BLIMP1a and BLIMP1b) and PRDM2 (RIZ1 and RIZ2) genes, in human T lymphocytes and Jurkat cells overexpressing PRDM2 cDNAs following activation through different signals. RESULTS: T lymphocyte activation induced an early increase of RIZ2 and RIZ1 followed by BLIMP1b increase and finally by BLIMP1a increase. The "first" and the "second" signals shifted the balance towards the PR- forms for both genes. Interestingly, the PI3K signaling pathway modulated the RIZ1/RIZ2 ratio in favor of RIZ1 while the balance versus RIZ2 was promoted by MAPK pathway. Cytokines mediating different Jak/Stat signaling pathways (third signal) early modulated the expression of PRDM1 and PRDM2 and the relationship of their different transcripts confirming the early increase of the PR- transcripts. Different responses of T cell subpopulations were also observed. Jurkat cells showed that the acute transient RIZ2 increase promoted the balancing of PRDM1 forms towards BLIMP1b. The stable forced expression of RIZ1 or RIZ2 induced a significant variation in the expression of key transcription factors involved in T lymphocyte differentiation. The BLIMP1a/b balance shifted in favor of BLIMP1a in RIZ1-overexpressing cells and of BLIMP1b in RIZ2-overexpressing cells. CONCLUSIONS: This study provides the first characterization of PRDM2 in T-lymphocyte activation/differentiation and novel insights on PRDM1 and PRDM2 transcription regulation during initial activation phases.

RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. METHODS: We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. RESULTS: Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. CONCLUSIONS: Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism.

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors.

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum-Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.

PRDM12 in Health and Diseases.

PRDM12 is a member of the PRDI-BF1 (positive regulatory domain I-binding factor 1) homologous domain (PRDM)-containing protein family, a subfamily of Kruppel-like zinc finger proteins, controlling key processes in the development of cancer. PRDM12 is expressed in a spatio-temporal manner in neuronal systems where it exerts multiple functions. PRDM12 is essential for the neurogenesis initiation and activation of a cascade of downstream pro-neuronal transcription factors in the nociceptive lineage. PRDM12 inactivation, indeed, results in a complete absence of the nociceptive lineage, which is essential for pain perception. Additionally, PRDM12 contributes to the early establishment of anorexigenic neuron identity and the maintenance of high expression levels of pro-opiomelanocortin, which impacts on the program bodyweight homeostasis. PRDMs are commonly involved in cancer, where they act as oncogenes/tumor suppressors in a "Yin and Yang" manner. PRDM12 is not usually expressed in adult normal tissues but its expression is re-activated in several cancer types. However, little information is currently available on PRDM12 expression in cancers and its mechanism of action has not been thoroughly described. In this review, we summarize the recent findings regarding PRDM12 by focusing on four main biological processes: neurogenesis, pain perception, oncogenesis and cell metabolism. Moreover, we wish to highlight the importance of future studies focusing on the PRDM12 signaling pathway(s) and its role in cancer onset and progression.

Multifaceted Role of PRDM Proteins in Human Cancer.

The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.

Adiponectin as Link Factor between Adipose Tissue and Cancer.

Adipose tissue is a key regulator of energy balance playing an active role in lipid storage as well as in synthesizing several hormones directly involved in the pathogenesis of obesity. Obesity represents a peculiar risk factor for a growing list of cancers and is frequently associated to poor clinical outcome. The mechanism linking obesity and cancer is not completely understood, but, amongst the major players, there are both chronic low-grade inflammation and deregulation of adipokines secretion. In obesity, the adipose tissue is pervaded by an abnormal number of immune cells that create an inflammatory environment supporting tumor cell proliferation and invasion. Adiponectin (APN), the most abundant adipokine, shows anti-inflammatory, anti-proliferative and pro-apoptotic properties. Circulating levels of APN are drastically decreased in obesity, suggesting that APN may represent the link factor between obesity and cancer risk. The present review describes the recent advances on the involvement of APN and its receptors in the etiology of different types of cancer.

Activation of Kv7 Potassium Channels Inhibits Intracellular Ca2+ Increases Triggered By TRPV1-Mediated Pain-Inducing Stimuli in F11 Immortalized Sensory Neurons.

Kv7.2-Kv7.5 channels mediate the M-current (IKM), a K+-selective current regulating neuronal excitability and representing an attractive target for pharmacological therapy against hyperexcitability diseases such as pain. Kv7 channels interact functionally with transient receptor potential vanilloid 1 (TRPV1) channels activated by endogenous and/or exogenous pain-inducing substances, such as bradykinin (BK) or capsaicin (CAP), respectively; however, whether Kv7 channels of specific molecular composition provide a dominant contribution in BK- or CAP-evoked responses is yet unknown. To this aim, Kv7 transcripts expression and function were assessed in F11 immortalized sensorial neurons, a cellular model widely used to assess nociceptive molecular mechanisms. In these cells, the effects of the pan-Kv7 activator retigabine were investigated, as well as the effects of ICA-27243 and (S)-1, two Kv7 activators acting preferentially on Kv7.2/Kv7.3 and Kv7.4/Kv7.5 channels, respectively, on BK- and CAP-induced changes in intracellular Ca2+ concentrations ([Ca2+]i). The results obtained revealed the expression of transcripts of all Kv7 genes, leading to an IKM-like current. Moreover, all tested Kv7 openers inhibited BK- and CAP-induced responses by a similar extent (~60%); at least for BK-induced Ca2+ responses, the potency of retigabine (IC50~1 µM) was higher than that of ICA-27243 (IC50~5 µM) and (S)-1 (IC50~7 µM). Altogether, these results suggest that IKM activation effectively counteracts the cellular processes triggered by TRPV1-mediated pain-inducing stimuli, and highlight a possible critical contribution of Kv7.4 subunits.

Adiponectin as novel regulator of cell proliferation in human glioblastoma.

Adiponectin (Acrp30) is an adipocyte-secreted hormone with pleiotropic metabolic effects, whose reduced levels were related to development and progression of several malignancies. We looked at the presence of Acrp30 receptors in human glioblastomas (GBM), hypothesizing a role for Acrp30 also in this untreatable cancer. Here we demonstrate that human GBM express Acrp30 receptors (AdipoR1 and AdipoR2), which are often co-expressed in GBM samples (70% of the analyzed tumors). To investigate the effects of Acrp30 on GBM growth, we used human GBM cell lines U87-MG and U251, expressing both AdipoR1 and AdipoR2 receptors. In these cells, Acrp30 treatment inhibits DNA synthesis and cell proliferation rate, inducing arrest in G1 phase of the cell cycle. These effects were correlated to a sustained activation of ERK1/2 and Akt kinases, upon Acrp30 treatment. Our results suggest that Acrp30 may represent a novel endogenous negative regulator of GBM cell proliferation, to be evaluated for the possible development of novel pharmacological approaches.

Liquid Biopsy and Cancer: An Ongoing Story.

The concept that body fluids may reveal the presence of disease dates back to ancient Greek history, when Hippocrates (ca [...].

History of how viruses can fight cancer: From the miraculous healings to the approval of oncolytic viruses.

Since the nineteenth century, several reports in the historical medical literature emphasized that, occasionally, cancer patients showed a clinical remission, called "Saint Peregrine tumor" as a result of natural infections. Moreover, additional evidence indicated that viruses show a tropism toward cancer cells, leading to the discovery of oncolytic activity of several viruses, called oncolytic viruses (OVs). With the technological and scientific advancements, the advent of rodent models, the establishment of in vitro cell lines, the introduction of methods for virus propagation, several attempts through the 1950s and 1970s have been made to increase OVs specificity, efficacy and safety; however, inconclusive/negative results have been reached and many researchers abandoned the field. Only in the later 1990s, the genetic engineering and the recombinant DNA techniques that allowed the generation of potent, specific and safe OVs and a better understanding of cancer cells renewed the interest in virotherapy. Currently, virotherapy represents a cancer therapeutic strategy based on the use of OVs that selectively infect and lyse cancer cells, without harming normal cells. Over the past years, several "natural" and "genetic engineered" viruses, have been investigated in clinical studies and some of them revealed encouraging results. Recently, the clinical use of OVs has also been supported by the immune stimulatory property of OVs against tumor cells. Here, we analyze the early oncolytic virotherapy before genetic engineering to highlight the relevant progresses reached, and the mechanism to stimulate host immune response, a significant challenge in current virotherapy field.

Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis.

Studies on the COVID-19 pandemic effects on gestational diabetes mellitus (GDM) remain limited and controversial. This study aimed to investigate the impact of the COVID-19 lockdown on the glycemic balance of pregnant women and GDM risk. To this aim, a single-center retrospective cohort analysis assessing glucose homeostasis using the oral glucose tolerance test in 862 pregnant women before (from March 9, 2019 to March 8, 2020 - Group 1), during (from March 9, 2020 to March 8, 2021 - Group 2), and after (from March 9, 2021 to March 8, 2022 - Group 3) the COVID-19 lockdown in Molise, a region of central Italy, was conducted. We observed that the blood glucose concentration of pregnant women was significantly lower during the COVID-19 lockdown than during the previous and following years at all time points evaluated (time 0, 60', and 120'). Specifically, at time 0, it was 82.14 mg/dl for group 2 vs 85.94 for group 1 (p = 0.0001) and 85.87 for group 3 (p = 0.001). Similarly, at 60', it was 121.38 mg/dl for group 2 vs 129.30 mg/dl for group 1 (p = 0.0029) and 131.68 mg/dl for group 3 (p = 0.0006). Moreover, at 120', it was 104.20 mg/dl for group 2 vs 111.51 mg/dl (p = 0.0004) for group 1, and 116.06 mg/dl for group 3 (p = 0.0001). In contrast with previous findings, the COVID-19 lockdown was associated with an improved glycemic balance. Further studies are needed to better clarify the influence of lockdown restrictions on glucose metabolism and, consequently, on GDM risk.

Vitamin D, a Regulator of Androgen Levels, Is Not Correlated to PSA Serum Levels in a Cohort of the Middle Italy Region Participating to a Prostate Cancer Screening Campaign.

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men worldwide, and it represents the fifth leading cause of death. It has long been recognized that dietary habits can impact prostate health and improve the benefits of traditional medical care. The activity of novel agents on prostate health is routinely assessed by measuring changes in serum prostate-specific antigen (PSA) levels. Recent studies hypothesized that vitamin D supplementation reduces circulating androgen levels and PSA secretion, inhibits cell growth of the hormone-sensitive PCa cell lines, counteracts neoangiogenesis and improves apoptosis. However, the results are conflicting and inconsistent. Furthermore, the use of vitamin D in PCa treatments has not achieved consistently positive results to date. In order to assess the existence of a correlation between the PSA and 25(OH)vitamin D levels as widely hypothesized in the literature, we analyzed the serum PSA and 25(OH)vitamin D concentration on a cohort of one hundred patients joining a PCa screening campaign. Additionally, we performed medical and pharmacological anamnesis and analyzed lifestyle, as sport practice and eating habits, by administering a questionnaire on family history. Although several studies suggested a protective role of vitamin D in PCa onset prevention and progression, our preliminary results revealed a clear absence of correlation between the serum vitamin D and PSA concentration levels, suggesting that vitamin D has no impact on PCa risk. Further investigations enrolling a huge number of patients are needed with particular attention to vitamin D supplementation, calcium intake, solar radiation that influences vitamin D metabolism and other potential indicators of health to confirm the absence of correlation observed in our study.

Acute Effects of Combining Whole-Body Electromyostimulation with Resistance Training in Active Women.

Strength training elicits benefits both in performance and on a psychological level in women, such as increased muscle strength and improved self-esteem. Whole-body electromyostimulation (WB-EMS) could be a training strategy for enhancing muscular strength. The aim of this study was to assess the acute effects of a single session of WB-EMS superimposed over classic resistance training on isometric strength, endurance strength and flexibility. Furthermore, the safety of the protocol was assessed by monitoring the levels of creatine kinase (CK) 48 h after the training protocol was completed. Sixteen active women (aged 22.06 ± 1.88) were randomly assigned to an experimental group (EG) (n = 8) and a control group (CG) (n = 8). The EG performed four sets of 12 repetitions of three strength exercises with superimposed WB-EMS, while the CG performed the same protocol without WB-EMS. RM-ANOVA showed a significant time*group interaction on posterior kinetic chain extensors' mean and peak strength in the EG (F(1,14) = 10.036; p = 0.007; and F(1,14) = 20.719; p < 0.001; respectively). A significant time*group interaction was found in the sit and reach test for the EG (F(1,14) = 10.362; p = 0.006). Finally, ANOVA performed on the CK levels showed no significant difference between the groups (F(1,14) = 0.715; p = 0.412). WB-EMS training led to an immediate improvement in strength performance and flexibility, and this protocol was shown to be safe in terms of CK levels, 48 h after completing the training protocol.

A Novel Low-Cost Uroflowmetry for Patient Telemonitoring.

Uroflowmetry (UF) is a crucial guideline-recommended tool for men with benign prostatic obstruction (BPO). Moreover, UF is a helpful decision-making tool for the management of patients with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). In the last few years, telemedicine and telehealth have increased exponentially as cost-effective treatment options for both patients and physicians. Telemedicine and telehealth have been well positioned during the COVID-19 pandemic to prevent healthcare system overload and to ensure adequate management of patients through screening, diagnosis, and follow-up at home. In the present manuscript, the main characteristics and performance of a novel and low-cost device for home-based UF have been analyzed. The simple weight-transducer method has been applied to perform UF. An inexpensive load cell connected to a 24 bit analogic digital converter (ADC) sends data to a cloud server via SIM card or home Wi-Fi. Data are processed and shown in graphics with both volume and flow rate as a function of time, allowing for measurement of average flow rate, maximum flow rate, voided volume, and voiding time. A numerical algorithm allows for filtering of the dynamic effect due to the urine gravity acceleration and for removing the funnel to simplify the home measurement procedure. Through an online platform, the physician can see and compare each UF data. The device's reliability has been validated in a first laboratory setting and showed excellent performance. This approach based on domiciliary tests and an online platform can revolutionize the urologic clinic landscape by offering a constant patient cost-effective follow-up, eliminating the time wasted waiting in the office setting.

Identification of a functional estrogen-responsive enhancer element in the promoter 2 of PRDM2 gene in breast cancer cell lines.

The retinoblastoma protein-interacting zinc-finger (RIZ) gene, also known as PRDM2, encodes two protein products, RIZ1 and RIZ2, differing for the presence of a 202 aa domain, called PR domain, at the N-terminus of the RIZ1 molecule. While the histone H3 K9 methyltransferase activity of RIZ1 is associated with the negative control of cell proliferation, no information is currently available on either expression regulation of the RIZ2 form or on its biological activity. RIZ proteins act as ER co-activators and promote optimal estrogen response in female reproductive tissues. In estrogen-responsive cells, 17-ß estradiol modulates RIZ gene expression producing a shift in the balanced expression of the two forms. Here, we demonstrate that an estrogen-responsive element (ERE) within the RIZ promoter 2 is regulated in a ligand-specific manner by ERα, through both the AF1 and AF2 domains. The pattern of ERα binding, histone H4 acetylation, and histone H3 cyclical methylation of lysine 9 was comparable to other estrogen-regulated promoters. Association of topoisomerase IIß with the RIZ promoter 2 confirmed the transcriptional activation induced by estrogen. We hypothesize that RIZ2, acting as a negative regulator of RIZ1 function, mediates the proliferative effect of estrogen through regulation of survival and differentiation gene expression.

The nineteenth-century experience of the kingdom of the two Sicilies on mandatory vaccination: An Italian phenomenon?

The current health emergency caused by COVID-19 disease shows several similarities with well-known epidemics of the past. The knowledge of their management and overcoming could give us useful tools to face the present COVID-19 pandemic. The Bourbon king Ferdinand I planned the first free large-scale mass vaccination programme conducted in Italy and one of the first in Europe to counteract smallpox. The vaccination campaign was characterized by many difficulties and the efforts made by the Southern Kingdoms governors were enormous. For example, the "ante litteram communication campaign", aimed at convincing the so-called "hesitant" people and at confuting the arguments of vaccination opponents, was impressive. In 1821, the compulsory vaccination significantly reduced smallpox infections and death rates. Subsequently, several experiences followed this initiative, not without doubts and debates. Smallpox was finally eradicated worldwide only on the 9th December 1979. Despite to other countries, the "mandatory vaccination" is a topic often debated by Italian scientific and social communities.

Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine.

Reproduction is a complex process, which is based on the cooperation between the endocrine-immune system and the microbiota. Testicular immunity is characterized by the so-called immune privilege, a mechanism that avoids autoimmune attacks against proteins expressed by spermatozoa. Testicular microbiota is connected with the gut microbiota, the most prevalent site of commensals inthe body. Both microbiotas take part inthe development of the immune system and protection againstpathogen invasion. Dysbiosis is caused by concurrent pathologies, such as obesity, diabetes, infections and trauma. The substitution of beneficial bacteria with pathogens may lead to destruction of spermatozoa directly or indirectly and, ultimately, to male infertility. Novel therapeutic interventions, i.e., nutritional interventions and supplementation of natural products, such as, probiotics, prebiotics, antioxidants and polyphenols, may lead to the restoration of the otherwise-impaired male reproductive potential, even if experimental and clinical results are not always concordant. In this review, the structure and immune function of the testis will be described with special reference to the blood-testisbarrier. The regulatory role of both the gut and testicular microbiota will be illustrated in health and disease, also emphasizing therapeutic attempts with natural products for the correction of male infertility, in the era of personalized medicine.

Immune Checkpoint Inhibitors as a Neoadjuvant/Adjuvant Treatment of Muscle-Invasive Bladder Cancer: A Systematic Review.

Bladder cancer is the ninth most common cancer worldwide. Over 75% of non-muscle invasive cancer patients require conservative local treatment, while the remaining 25% of patients undergo radical cystectomy or radiotherapy. Immune checkpoint inhibitors represent a novel class of immunotherapy drugs that restore natural antitumoral immune activity via the blockage of inhibitory receptors and ligands expressed on antigen-presenting cells, T lymphocytes and tumour cells. The use of immune checkpoint inhibitors in bladder cancer has been expanded from the neoadjuvant setting, i.e., after radical cystectomy, to the adjuvant setting, i.e., before the operative time or chemotherapy, in order to improve the overall survival and to reduce the morbidity and mortality of both the disease and its treatment. However, some patients do not respond to checkpoint inhibitors. As result, the capability for identifying patients that are eligible for this immunotherapy represent one of the efforts of ongoing studies. The aim of this systematic review is to summarize the most recent evidence regarding the use of immune checkpoint inhibitors, in a neoadjuvant and adjuvant setting, in the treatment of muscle-invasive bladder cancer.