Erectile function and androgen and estrogen beta receptor gene polymorphisms in acromegalic men.

PURPOSE: Sexual dysfunctions are often experienced by male patients with acromegaly, due to a combination of hypogonadism and other comorbidities, but are a scarcely investigated complication. Erectile dysfunction is also closely related to cardiovascular diseases through endothelial dysfunction. Therefore, this project aimed to assess the prevalence of erectile dysfunction in a population of acromegalic men and evaluate its association with cardio-metabolic disorders, also exploring associations with androgen and estrogen receptor gene polymorphisms. METHODS: Sexually active men aged 18-65 with previous diagnosis of acromegaly were recruited. Clinical and laboratory data were retrospectively collected. Each patient also provided a blood sample for AR and ERß gene polymorphisms analyses and filled out the IIEF-15 questionnaire. RESULTS: Twenty men with previous diagnosis of acromegaly (mean age 48.4 ± 10.0 years) were recruited. 13/20 subjects (65%) had erectile dysfunction, but only four had a concurrent biochemical hypogonadism, with no significant correlation with IIEF-15 scores. Total testosterone negatively correlated with sexual intercourse satisfaction domain (ρ = - 0.595; p = 0.019) and general satisfaction domain (ρ = - 0.651; p = 0.009). IGF-1 levels negatively correlated with biochemical hypogonadism (ρ = - 0.585; p = 0.028). The number of CAG and CA repeats in AR and ERß receptors genes was not significantly associated with IIEF-15 scores or with GH/IGF-1 levels, but a negative correlation between CA repeats and the presence of cardiomyopathy (ρ = - 0.846; p = 0.002) was present. CONCLUSIONS: Men with acromegaly have a high prevalence of erectile dysfunction, but it does not appear to be correlated with treatments, testosterone levels and AR/ER-beta signaling. Nonetheless, a shorter CA polymorphic trait (ERbeta) is associated with the presence of cardiomyopathy. If confirmed, these data may suggest an association between an incorrect hormonal balance and increased cardiovascular risk in acromegaly subjects.

Mode of delivery and peripartum outcome in women with heart disease according to the ESC guidelines: an Italian multicenter study.

INTRODUCTION: The European Society of Cardiology (ESC) guidelines (GL) provide indications on the mode of delivery in women with heart disease. However available data suggests that the rate of Cesarean Delivery (CD) is high and widely variable among such patients. In this study, we aimed to investigate the degree of adherence to the ESC recommendations among women delivering in four tertiary maternity services in Italy and how this affects the maternal and neonatal outcomes. MATERIAL AND METHODS: Retrospective multicenter cohort study including pregnant women with heart disease who gave birth between January 2014 and July 2020. Composite adverse maternal outcome (CAM) was defined by the occurrence of one or more of the following: major postpartum hemorrhage, thrombo-embolic or ischemic event, de novo arrhythmia, heart failure, endocarditis, aortic dissection, need for re-surgery, sepsis, maternal death. Composite Adverse Neonatal outcome (CAN) was defined as cord arterial pH <7.00, APGAR <7 at 5 min, admission to the intensive care unit, and neonatal death. We compared the incidence of CAM and CAN between the cases with planned delivery in accordance (group "ESC consistent") or in disagreement (group "ESC not consistent") with the ESC GL. RESULTS: Overall, 175 women and 181 liveborn were included. A higher frequency of CAN was found when delivery was not planned accordingly to the ESC guidelines [("ESC consistent" 9/124 (7.2%) vs "ESC not consistent" 13/57 (22.8%) p = 0.002 OR 3.74 (CI 95% 1.49-9.74) , while the occurrence of CAM was comparable between the two groups. At logistic regression analysis, the gestational age at delivery was the only parameter independently associated with the occurrence of CAN (p = 0.006). CONCLUSION: Among pregnant women with heart disease, deviating from the ESC guidelines scheduling cesarean delivery does not seem to improve maternal outcomes and it is associated with worse perinatal outcomes, mainly due to lower gestational age at birth.

Male reproductive health after 3 months from SARS-CoV-2 infection: a multicentric study.

PURPOSE: While SARS-CoV-2 infection appears not to be clinically evident in the testes, indirect inflammatory effects and fever may impair testicular function. To date, few long-term data of semen parameters impairment after recovery and comprehensive andrological evaluation of recovered patients has been published. The purpose of this study was to investigate whether SARS-CoV-2 infection affect male reproductive health. METHODS: Eighty patients were recruited three months after COVID-19 recovery. They performed physical examination, testicular ultrasound, semen analysis, sperm DNA integrity evaluation (TUNEL), anti-sperm antibodies (ASA) testing, sex hormone profile evaluation (Total testosterone, LH, FSH). In addition, all patients were administered International Index of Erectile Function questionnaire (IIEF-15). Sperm parameters were compared with two age-matched healthy pre-COVID-19 control groups of normozoospermic (CTR1) and primary infertile (CTR2) subjects. RESULTS: Median values of semen parameters from recovered SARS-CoV-2 subjects were within WHO 2010 fifth percentile. Mean percentage of sperm DNA fragmentation (%SDF) was 14.1 ± 7.0%. Gelatin Agglutination Test (GAT) was positive in 3.9% of blood serum samples, but no positive semen plasma sample was found. Only five subjects (6.2%) had total testosterone levels below the laboratory reference range. Mean bilateral testicular volume was 31.5 ± 9.6 ml. Erectile dysfunction was detected in 30% of subjects. CONCLUSION: Our data remark that COVID-19 does not seem to cause direct damage to the testicular function, while indirect damage appears to be transient. It is possible to counsel infertile couples to postpone the research of parenthood or ART procedures around three months after recovery from the infection.

Detection of companion galaxies around hot dust-obscured hyper-luminous galaxy W0410-0913.

The phase transition between galaxies and quasars is often identified with the rare population of hyper-luminous, hot dust-obscured galaxies. Galaxy formation models predict these systems to grow via mergers, that can deliver large amounts of gas toward their centers, induce intense bursts of star formation and feed their supermassive black holes. Here we report the detection of 24 galaxies emitting Lyman-α emission on projected physical scales of about 400 kpc around the hyper-luminous hot dust-obscured galaxy W0410-0913, at redshift z = 3.631, using Very Large Telescope observations. While this indicates that W0410-0913 evolves in a very dense environment, we do not find clear signs of mergers that could sustain its growth. Data suggest that if mergers occurred, as models expect, these would involve less massive satellites, with only a moderate impact on the internal interstellar medium of W0410-0913, which is sustained by a rotationally-supported fast-rotating molecular disk, as Atacama Large Millimeter Array observations suggest.

A dusty compact object bridging galaxies and quasars at cosmic dawn.

Understanding how super-massive black holes form and grow in the early Universe has become a major challenge1,2 since it was discovered that luminous quasars existed only 700 million years after the Big Bang3,4. Simulations indicate an evolutionary sequence of dust-reddened quasars emerging from heavily dust-obscured starbursts that then transition to unobscured luminous quasars by expelling gas and dust5. Although the last phase has been identified out to a redshift of 7.6 (ref. 6), a transitioning quasar has not been found at similar redshifts owing to their faintness at optical and near-infrared wavelengths. Here we report observations of an ultraviolet compact object, GNz7q, associated with a dust-enshrouded starburst at a redshift of 7.1899 ± 0.0005. The host galaxy is more luminous in dust emission than any other known object at this epoch, forming 1,600 solar masses of stars per year within a central radius of 480 parsec. A red point source in the far-ultraviolet is identified in deep, high-resolution imaging and slitless spectroscopy. GNz7q is extremely faint in X-rays, which indicates the emergence of a uniquely ultraviolet compact star-forming region or a Compton-thick super-Eddington black-hole accretion disk at the dusty starburst core. In the latter case, the observed properties are consistent with predictions from cosmological simulations7 and suggest that GNz7q is an antecedent to unobscured luminous quasars at later epochs.

PDE11A gene polymorphism in testicular cancer: sperm parameters and hormonal profile.

PURPOSE: Testicular germ cell tumours (TGCTs) is the most common malignancy among young adult males. The etiology is multifactorial and both environmental and genetic factors play an important role in the origin and development of TGCT. Genetic susceptibility may result from the interaction of multiple common and low-penetrance genetic variants and one of the main candidate genes is PDE11A. Many PDE11A polymorphisms were found responsible for a reduced PDE activity in TGCT patients, who often also display impaired hormone and sperm profile. The aim of this study was to investigate testicular function and PDE11A sequence in testicular cancer cases. METHODS: Semen analysis was performed in 116 patients with unilateral and bilateral sporadic TGCTs and in 120 cancer-free controls. We also investigated hormone profile and PDE11A polymorphisms using peripheral blood samples. RESULTS: Our data revealed that TGCT patients showed lower testosterone levels, higher gonadotropins levels and worse semen quality than controls, although the mean and the medians of sperm parameters are within the reference limits. PDE11A sequencing detected ten polymorphisms not yet associated with TGCTs before. Among these, G223A in homozygosity and A288G in heterozygosity were significantly associated with a lower risk of testicular tumour and they displayed a positive correlation with total sperm number. CONCLUSIONS: Our findings highlight the key role of PDE11A in testis and suggest the presence of an underlying complex and fine molecular mechanism which controls testis-specific gene expression and susceptibility to testicular cancer.

A dynamically cold disk galaxy in the early Universe.

The extreme astrophysical processes and conditions that characterize the early Universe are expected to result in young galaxies that are dynamically different from those observed today1-5. This is because the strong effects associated with galaxy mergers and supernova explosions would lead to most young star-forming galaxies being dynamically hot, chaotic and strongly unstable1,2. Here we report the presence of a dynamically cold, but highly star-forming, rotating disk in a galaxy at redshift6 z = 4.2, when the Universe was just 1.4 billion years old. Galaxy SPT-S J041839-4751.9 is strongly gravitationally lensed by a foreground galaxy at z = 0.263, and it is a typical dusty starburst, with global star-forming7 and dust properties8 that are in agreement with current numerical simulations9 and observations10. Interferometric imaging at a spatial resolution of about 60 parsecs reveals a ratio of rotational to random motions of 9.7 ± 0.4, which is at least four times larger than that expected from any galaxy evolution model at this epoch1-5 but similar to the ratios of spiral galaxies in the local Universe11. We derive a rotation curve with the typical shape of nearby massive spiral galaxies, which demonstrates that at least some young galaxies are dynamically akin to those observed in the local Universe, and only weakly affected by extreme physical processes.

Publisher Correction: A dynamically cold disk galaxy in the early Universe.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Autotransplatation of immature third molars as substitutes for congenitally missing second premolars: an alternative solution in a young patient with oligodontia.

Auto transplantation of immature donor teeth can be a strategic therapeutic solution in young patients. It is preferable to choose this approach instead of prosthetic restorations because it offers a unique and definitive solution. Orthodontic space closure is not always deemed desirable, especially in non-extraction cases (53,54). Successful auto transplantations allow alveolar growth through eruption of donor teeth together with the adjacent dentition when skeletal and dental development is not yet completed. Auto transplantation of third molars is less well-recognised and less documented. The available literature shows promising success rates. Immature donor teeth are reportedly associated with better outcomes than mature donor teeth. Aim of this case report was to analyse the short-term outcomes of auto transplantation of immature maxillary third molars to replace the missing mandibular second premolars in a 17-year-old healthy female with oligodontia. The surgical procedure was performed as a single step. Left and right lower second deciduous molars (7.5-8.5), close to exfoliation, were extracted. Donor upper third molars with developing root were extracted as a traumatically as possible and immediately placed into the surgically modified recipient sites. They were stabilized by a sectional wire. One year after surgery, the survival of both transplanted teeth was achieved. They showed periodontal health, normal mobility and continuation of root development during the follow-up period. The upper left third molar responded to all success criteria, no signs of ankylosis, root resorption (infection or inflammatory), and pulp necrosis. The upper right third molar had long-standing evidence of not progressive cervical external inflammatory root resorption without any clinical signs. Further research is needed to determine their long-term survival and success rates.

Synaptotagmin 13 is neuroprotective across motor neuron diseases.

In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.

Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons.

AIMS: The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients. METHODS: A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MS patients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. RESULTS: Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. CONCLUSION: These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.

Fetal cardiac growth is associated with in utero gut colonization.

BACKGROUND AND AIMS: Intra-uterine metabolic environment predicts newborns' cardiac morphology, metabolism and future health. In adults, gut microbiota composition relates to altered cardiac structure and metabolism. We investigated the relationship between gut microbiota colonization and fetal cardiac growth. METHODS AND RESULTS: Bacterial composition in meconium samples of 26 healthy, full-term newborns was assessed by 16S rDNA gene sequencing. Its relationship with birth echocardiographic parameters, and the interaction with cord blood levels of inflammatory markers were investigated. Correlative and cluster analysis, linear discriminant analysis effect size and predictive functional analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied. Fetal left ventricle growth was related to gut microbiota composition at birth. Specifically, left ventricle posterior wall thickness (LVPW) greater than 4 mm was associated with lower microbiota beta and alpha diversity, depletion (LDA score > 3) of several bacteria at each taxonomic level, including Lactobacillales, and enrichment (LDA score > 5) in Enterobacteriales and Enterobacteriaceae. The latter was significantly related to cord blood gamma-glutamyltransferase levels (r = 0.58, p = 0.0057). Functionally, a thicker LVPW was related to up-regulation of pathways involved in lipopolysaccharide biosynthesis (+50%, p = 0.045 in correlative analysis) and energy metabolism (+12%, p = 0.028), and down-regulation of pathways involved in xenobiotic biodegradation (-21 to -53%, p = 0.0063-0.039), PPAR signaling (-24%, p = 0.021) and cardiac muscle contraction (-100%, p = 0.049). CONCLUSION: Fetal cardiac growth and gut colonization are associated. Greater neonatal LVPW thickness is related to lower diversity of the gut microbiota community, depletion of bacteria having anti-remodeling effects, and enrichment in bacteria functionally linked to inflammation.

The Two by Four appliance: a nationwide cross-sectional survey.

AIM: The aim of the study was to investigate how widespread is the use of the 2 x 4 appliance among Italian general dentists and specialists in orthodontics, as well as the type of treatment employed and length of use. MATERIALS AND METHODS: We conducted a nationwide cross-sectional survey from July 14, 2016 to January 12, 2017 using an online questionnaire of 8 multiple choice questions, created by the SurveyMonkey® Company, on a population of Italian dentists and specialists in orthodontics affiliated with the Italian Society of Paediatric Dentistry (SIOI). This was made to assess how many clinicians knew and used this device in their clinical practice. We included 200 Italian dentists, 99 specialists in orthodontics and 101 general dentists of a mean age of 45 ± 15 years. RESULTS: Results show that 93.94% of orthodontists have knowledge of and use this device in their clinical practice, while only 51.49% of the general dentists have knowledge of and use it (p<0.001). The 51.92% of dentists and the 52.13% of orthodontists used the 2x4 appliance to treat both space management and incorrect overjet. Most of general dentists and orthodontists combined the 2x4 appliance with pre-adjusted brackets and accessory components such as coil springs and power chains. While most of dentists (45.90%) used the 2x4 in association with appliances for space management, most of specialists (46.15%) applied the 2×4 in combination with both appliances for space management and high-pull headgear. Statistically significant differences were found also for the answers to the question "what is the average time of treatment?" among general dentists: the 32.79% used the 2 x 4 for less than 6 months of treatment, and the 67.21% used the 2 x 4 for more than 6 months of treatment. On the other hand 49.46% of orthodontists used the 2 x 4 for less than 6 months of treatment, and 50.54% of them for more than 6 months of treatment (p=0.041). CONCLUSIONS: We conclude that the 2 x 4 appliance is widespread among orthodontists and about half of the general dentists, 93.94% and 51.49% (p<0.001) respectively. We found that 67.21% of general dentists used the 2 x 4 for a more than 6 months of treatment. As far as the orthodontists, 49.46% used the device for less than 6 months of treatment and 50.54% of them for more than 6 months of treatment. These differences were statistically significant (p=0.041).

Pushing the limits of applicability of REBCO coated conductor films through fine chemical tuning and nanoengineering of inclusions.

An outstanding current carrying performance (namely critical current density, Jc) over a broad temperature range of 10-77 K for magnetic fields up to 12 T is reported for films of YBa2Cu3O7-x with Ba2Y(Nb,Ta)O6 inclusion pinning centres (YBCO-BYNTO) and thicknesses in the range of 220-500 nm. Jc values of 10 MA cm-2 were measured at 30 K - 5 T and 10 K - 9 T with a corresponding maximum of the pinning force density at 10 K close to 1 TN m-3. The system is very flexible regarding properties and microstructure tuning, and the growth window for achieving a particular microstructure is wide, which is very important for industrial processing. Hence, the dependence of Jc on the magnetic field angle was readily controlled by fine tuning the pinning microstructure. Transmission electron microscopy (TEM) analysis highlighted that higher growth rates induce more splayed and denser BYNTO nanocolumns with a matching field as high as 5.2 T. Correspondingly, a strong peak at the B||c-axis is noticed when the density of vortices is lower than the nanocolumn density. YBCO-BYNTO is a very robust and reproducible composite system for high-current coated conductors over an extended range of magnetic fields and temperatures.

Association between false-positive TORCH and antiphospholipid antibodies in healthy pregnant women.

The present study investigated: (a) the presence of antiphospholipid antibodies and (b) the obstetric outcome in healthy pregnant women showing false-positive TORCH-Toxoplasmosis, Other: syphilis, varicella-zoster, Rubella, Cytomegalovirus (CMV), and Herpes infections-results. Data from 23 singleton healthy pregnancies with false-positive TORCH results were collected. Each woman was systematically screened for TORCH IgG and IgM during the pre-conception assessment and/or at the beginning of pregnancy. In the presence of IgM positivity, when indicated (CMV, toxoplasmosis, rubella, herpes simplex virus), IgG avidity was evaluated and, if possible, polymerase chain reaction was performed on an amniotic fluid sample in order to distinguish between primary infection or false positivity. The antiphospholipid antibodies tests were: lupus anticoagulant, anticardiolipin antibodies IgG, IgM, and anti-ß2glicoprotein I IgG, IgM. The antiphospholipid antibodies tests, if positive, were repeated after 12 weeks to confirm the results. In pregnant women with false-positive TORCH, the overall prevalence of positive antiphospholipid antibodies for one or more tests was 52.2%. To clarify the correlation of false-positive TORCH results with clinical practice, obstetric outcome was analyzed in terms of live births, week of delivery, neonatal birth weight, and neonatal birth weight percentile. A statistically significant lower neonatal birth weight and neonatal birth weight percentile were observed in women with false-positive TORCH associated with antiphospholipid antibodies positivity (Group A) in comparison with those in women with false-positive TORCH without antiphospholipid antibodies positivity (Group B). No statistically significant difference was found for the week of delivery between the two groups. It is hoped that future studies will verify the life-long persistence of antiphospholipid antibodies positivity by follow-up of these women and identify who will develop a classical antiphospholipid syndrome or other autoimmune disorders.

Composição química da forragem e do ensilado de azevém anual em função de diferentes tempos de secagem e estádios fenológicos / Chemical composition of annual ryegrass forage and silage for different drying times and phenological phases

O objetivo do presente estudo foi determinar como o tempo de secagem e o estádio fenológico da planta influenciam na composição química e qualidade da silagem de azevém (Lolium multiflorum, Lam.). O delineamento experimental foi de blocos ao acaso, com seis tratamentos (vegetativo: cortar e ensilar; cortar + pré-secagem de 4 horas e ensilar; cortar + pré-secagem de 7 horas e ensilar; pré-florescimento: ensilagem, cortar e ensilar e pré-secagem de 4 horas; florescimento: cortar e ensilar) e quatro repetições, com quatro meses de conservação da silagem. Foram determinados: desaparecimento de massa após o corte, rendimento de massa seca, proteína bruta e frações fibrosas. Além disso, foram determinados na silagem: pH, lipídios totais, nitrogênio insolúvel em detergente neutro e ácido. O manejo empregado auxilia na desidratação da forragem, com perda na quantidade de nitrogênio no vegetativo. No pré-florescimento, essa perda não ocorre. O avanço do ciclo da forrageira ocasiona diminuição na quantidade de nutrientes na biomassa, entretanto a produção de forragem é aumentada. A silagem apresentou composição bromatológica semelhante à observada na massa verde de azevém, o que demonstra a eficiência do método de conservação. A ensilagem em estádios mais avançados é aconselhada quando se busca maior quantidade de biomassa ensilada, porém com qualidade inferior.(AU)

The aim was how to define the effect of pre-drying time and the plant phase's influence on chemical composition and quality of ryegrass silage. The experimental design was randomized blocks with six treatments (Vegetative: Cut and ensiled; cut + pre-drying 4 hours and ensiled and; cut + pre-drying of 7 hours and ensiled; Pre-flowering: Silage cutting and ensiled and pre-drying 4 hours Flowering:. cut and ensiled) and four repetitions. The silage was stowed for four months. It were determined the mass disappearance after cutting, dry matter yield, crude protein and fiber fractions. Moreover, it was determined on silage pH, total lipids and insoluble protein content. The management used aids in dehydration of fodder, resulting in losses on the amount of nitrogen on vegetative phase. For pre-flowering, this loss has not occur. The advance of fodder cycle causes a decrease in the amount of nutrients in biomass, but fodder yield increased. Ryegrass silage presented chemical composition similar to that observed on green mass of ryegrass, evinced the efficiency of fodder conservation method. The silage in more advanced phases is advised when seeking greater amount of ensiled biomass, but lower quality.(AU)

Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy.

Although promising, the clinical benefit provided by dendritic cell (DC)-based vaccines is still limited and the choice of the optimal antigen formulation is still an unresolved issue. We have developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC) with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing immunogenic cell death. We show that treatment of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 9-cis-retinoic acid and IFNα (RA/IFNα) induces early membrane exposure of Calreticulin, HSP70 and 90 together with CD47 down-regulation and enhanced HMGB1 secretion. Consistently, RA/IFNα-treated apoptotic cells and -TCLs were more efficiently phagocytosed by DCs compared to controls. Notably, cytotoxic T cells (CTLs) generated with autologous DCs pulsed with RA/IFNα-TCLs more efficiently recognized and specifically lysed MCL or DLBCL cells or targets loaded with several HLA-A*0201 cyclin D1 or HLA-B*0801 survivin epitopes. These cultures also showed an expansion of Th1 and Th17 cells and an increased Th17/Treg ratio. Moreover, DCs loaded with RA/IFNα-TCLs showed enhanced functional maturation and activation. NOD/SCID mice reconstituted with human peripheral blood lymphocytes and vaccinated with autologous RA/IFNα-TCL loaded-IFN-DCs showed lymphoma-specific T-cell responses and a significant decrease in tumor growth with respect to mice treated with IFN-DC unpulsed or loaded with untreated TCLs. This study demonstrates the feasibility and efficacy of the use of RA/IFNα to generate a highly immunogenic TCL as a suitable tumor antigen formulation for the development of effective anticancer DC-based vaccines.

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.