Endothelial function in healthy centenarians living in the Madonie's district (Italy).

BACKGROUND: Endothelial function declines with age and plays a critical role in cardiovascular health. Therefore, investigating endothelial function in successful aging models, such as centenarians, is of interest. Flow-mediated dilation (FMD) of the brachial artery is the gold standard for measuring endothelial function in vivo in humans. Therefore, we investigated, for the first time, the FMD of the brachial artery in a group of healthy centenarians. METHODS: Selected as part of the ABCD project (nutrition, cardiovascular wellness, and diabetes) centenarians (aged ≥100 years) living in the municipalities of Madonie (Palermo, Italy) were compared with a younger (aged <65 years) sex-matched control group from the ABCD general cohort. FMD of the brachial artery was measured in all participants using a real-time computed video analysis system for B-mode ultrasound images. Body composition (bioimpedance), carotid intima-media thickness (IMT), and ankle-brachial index (ABI) were also measured. RESULTS: Eleven participants (males 36.4 %; age: 101 ± 1 years) out of 28 healthy centenarians successfully cooperated with the FMD test procedures, which require remaining with the upper limb immobile for approximately 10 min. This subgroup was compared with a control group of 76 healthy and younger individuals (males 36.8 %; aged: 41 ± 14 years; P < 0.001). Centenarians exhibited better endothelial function than the control group (FMD: 12.1 ± 4.3 vs 8.6 ± 5.3 %; P < 0.05). The carotid IMT was higher in the centenarian group than in the control group (0.89 ± 0.09 vs 0.56 ± 0.18 mm; P < 0.001), whereas the ABI was comparable between the two groups. CONCLUSIONS: This small group of centenarians demonstrated an unusually favorable endothelial function, which may contribute to their unique aging profile. Further research is needed to determine whether FMD is a valid prognostic marker for successful aging.

A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.

Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.

Factors associated with body weight gain and insulin-resistance: a longitudinal study.

BACKGROUND: Obesity is the result of energy intake (EI) chronically exceeding energy expenditure. However, the potential metabolic factors, including insulin resistance, remain unclear. This study longitudinally investigated factors associated with changes in body weight. SUBJECTS: A cohort of 707 adults without diabetes were investigated at the 4-year follow-up visit. The habitual intake of energy and macronutrients during the past 12 months was assessed using a validated Food Frequency Questionnaire for the local population. Homeostatic model assessment of ß-cell function and insulin resistance (HOMA-IR) was used as a surrogate measure of insulin resistance. Additionally, PNPLA3 was genotyped. RESULTS: Eighty-seven participants were weight gainers (G; cutoff value = 5 kg), and 620 were non-gainers (NG). Initial anthropometric (G vs. NG: age, 44 ± 13 vs 51 ± 13 years, P < 0.001; body mass index, 27.8 ± 6.5 vs 28.1 ± 5.1 kg/m2, P = ns; body weight, 76.7 ± 22.1 vs 74.2 ± 14.7 kg, P = ns; final body weight, 86.3 ± 23.7 vs 72.9 ± 14.2 kg, P < 0.001) and diet characteristics, as well as insulin concentrations and HOMA-IR values, were similar in both groups. Four years later, G showed significantly increased EI, insulin concentrations, and HOMA-IR values. G had a higher prevalence of the PNPLA3 CG and GG alleles than NG (P < 0.05). The presence of G was independently associated with age (OR = 1.031), EI change (OR = 2.257), and unfavorable alleles of PNPLA3 gene (OR = 1.700). Final body mass index, waist circumference, and EI were independently associated with final HOMA-IR (P < 0.001). CONCLUSIONS: EI is associated with body weight gain, and genetic factors may influence the energy balance. Insulin resistance is a consequence of weight gain, suggesting a possible intracellular protective mechanism against substrate overflow. CLINICAL TRIAL REGISTRATION: ISRCTN15840340.

Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

Fiber-deficient diet inhibits colitis through the regulation of the niche and metabolism of a gut pathobiont.

Exclusive enteral nutrition (EEN) with fiber-free diets is an effective steroid-sparing treatment to induce clinical remission in children with Crohn's disease (CD). However, the mechanism underlying the beneficial effects of EEN remains obscure. Using a model of microbiota-dependent colitis with the hallmarks of CD, we find that the administration of a fiber-free diet prevents the development of colitis and inhibits intestinal inflammation in colitic animals. Remarkably, fiber-free diet alters the intestinal localization of Mucispirillum schaedleri, a mucus-dwelling pathobiont, which is required for triggering disease. Mechanistically, the absence of dietary fiber reduces nutrient availability and impairs the dissimilatory nitrate reduction to ammonia (DNRA) metabolic pathway of Mucispirillum, leading to its exclusion from the mucus layer and disease remission. Thus, appropriate localization of the specific pathobiont in the mucus layer is critical for disease development, which is disrupted by fiber exclusion. These results suggest strategies to treat CD by targeting the intestinal niche and metabolism of disease-causing microbes.

Tuning of the magnetotransport properties of a spin-polarized 2D electron system using visible light.

We report on the effects of visible light on the low temperature electronic properties of the spin-polarized two dimensional electron system (2DES) formed at the interfaces between LaAlO[Formula: see text], EuTiO[Formula: see text] and (001) SrTiO[Formula: see text]. A strong, persistent modulation of both longitudinal and transverse conductivity was obtained using light emitting diodes (LEDs) with emissions at different wavelengths in the visible spectrum range. In particular, Hall effect data show that visible light induces a non-volatile electron filling of bands with mainly 3d[Formula: see text] character, and at the same time an enhancement of the anomalous Hall effect associated to the magnetic properties of the system. Accordingly, a suppression of the weak-anti localization corrections to the magneto-conductance is found, which correlates with an enhancement of the spin-polarization and of the ferromagnetic character of 2DES. The results establish the LED-induced photo-doping as a viable route for the control of the ground state properties of artificial spin-polarized oxide 2DES.

Pain prevalence and pain management in children and adolescents in an italian third level pediatric hospital: a cross-sectional study.

BACKGROUND: In 2016, we performed a one-day investigation to analyze the prevalence of pain, pain intensity, and pain therapy in the Departments of Surgery and Onco-Hematology of the Ospedale Pediatrico Bambino Gesù. To improve the knowledge gap highlighted in the previous study, refresher courses and even personalized audits have been carried out during these years. The purpose of this study is to evaluate if, after 5 years, there have been improvements in the management of pain. METHODS: The study was conducted on 25 January 2020. Pain assessment, pain therapies, pain prevalence and intensity in the preceding 24 h and during the recovery period were recorded. Pain outcomes were compared with previous audit results. RESULTS: Out of the 63 children with at least one documented pain assessment (starting from 100 eligible), 35 (55.4%) experienced pain: 32 children (50.7%) experienced moderate /severe pain while 3 patients (4%) felt mild pain. In the preceding 24 h, 20 patients (31.7%) reported moderate/severe pain while 10 (16%) reported moderate or severe pain during the interview. The average value of the Pain Management Index (PMI) was - 1.3 ± 0.9 with a minimum of -3 and a maximum of 0. 28 patients (87%) undergoing analgesic therapy for moderate/severe pain had a PMI of less than 0 (undertreated pain), while 3 patients (13%) scored value of 0 or higher (adequate pain therapy), 4 patients (12.5%) received multimodal analgesia with opioids and 2 patients (6%) opioids alone. Time-based therapy was prescribed to 20 patients (62.5%), intermittent therapy was prescribed to 7 patients (22%) and 5 patients (15.5%) did not receive any therapy. The prevalence of pain was higher during hospitalization and 24 h before the interview, while at the time of the interview, the proportion was the same. In this audit, the daily prescription modality of the therapy had some improvements (time-based: 62.5% vs. 44%; intermittent: 22%vs 25%; no therapy: 15.5% vs. 31%). CONCLUSION: Pain management in hospitalized children constantly requires special daily attention from health professionals aimed at mitigating the components of intractable pain and resolving those of treatable pain. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number (NCT04209764), registered 24 December 2019, https://clinicaltrials.gov/ct2/show/NCT04209764?term=NCT04209764&draw=2&rank=1 .

Personalized Oncology by In Vivo Chemical Imaging: Photoacoustic Mapping of Tumor Oxygen Predicts Radiotherapy Efficacy.

We hereby apply the approach of photoacoustic chemical imaging, performing an in vivo chemical analysis that is spatially resolved (200 µm) and in real time, to predict a given tumor's response to therapy. Using triple negative breast cancer as a model, we took photoacoustic images of tumors' oxygen distributions in patient-derived xenografts (PDXs) in mice using biocompatible, oxygen-sensitive tumor-targeted chemical contrast nanoelements (nanosonophores), which function as contrast agents for photoacoustic imaging. Following radiation therapy, we established a quantitatively significant correlation between the spatial distribution of the initial oxygen levels in the tumor and its spatial distribution of the therapy's efficacy: the lower the local oxygen, the lower the local radiation therapy efficacy. We thus provide a simple, noninvasive, and inexpensive method to both predict the efficacy of radiation therapy for a given tumor and identify treatment-resistant regions within the tumor's microenvironment.

Prominent Follicular Keratosis in Multiple Intestinal Atresia with Combined Immune Deficiency Caused by a TTC7A Homozygous Mutation.

Multiple intestinal atresia with combined immune deficiency (MIA-CID) is an autosomal recessive syndrome due to mutations in the TTC7A gene implicated in the polarization of intestinal and thymic epithelial cells. MIA-CID is lethal in the first year of life in the majority of patients. Dermatological manifestations have been reported in a few cases. We describe a child affected with MIA-CID due to a previously unreported TTC7A homozygous missense mutation. Surgery for bowel occlusion was performed in the first days of life. The patient was totally dependent on parenteral nutrition since birth and presented severe diarrhea and recurrent infections. He underwent hematopoietic stem cell transplantation at 17 months with complete donor engraftment and partial immunity improvement. In the second year of life, he progressively developed diffuse papular follicular keratoses on ichthyosiform skin, nail clubbing, and subungual hyperkeratosis. Histopathology showed hyperkeratosis with follicular plugging and scattered apoptotic keratinocytes, visualized at an ultrastructural examination. Our findings expand the spectrum of dermatological manifestations which can develop in MIA-CID patients. Examination of further patients will allow defining whether keratinocyte apoptosis is also a disease feature.

High fat stems tumor immune surveillance.

In a recent issue of Cell Stem Cell, Beyaz et al. show that high-fat diets promote tumorigenesis by reducing major histocompatibility complex (MHC) class II expression in intestinal stem cells. Dietary modulation of epithelial MHC II expression is regulated by the gut microbiota.

Gut microbiota and systemic immunity in health and disease.

The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. Although the influence of the gut microbiota on intestinal physiology and immunity is well known, mounting evidence suggests a key role for intestinal symbionts in controlling immune cell responses and development outside the gut. Although the underlying mechanisms by which the gut symbionts influence systemic immune responses remain poorly understood, there is evidence for both direct and indirect effects. In addition, the gut microbiota can contribute to immune responses associated with diseases outside the intestine. Understanding the complex interactions between the gut microbiota and the host is thus of fundamental importance to understand both immunity and human health.

Neuroblastoma-secreted exosomes carrying miR-375 promote osteogenic differentiation of bone-marrow mesenchymal stromal cells.

Bone marrow (BM) is the major target organ for neuroblastoma (NB) metastasis and its involvement is associated with poor outcome. Yet, the mechanism by which NB cells invade BM is largely unknown. Tumour microenvironment represents a key element in tumour progression and mesenchymal stromal cells (MSCs) have been recognized as a fundamental part of the associated tumour stroma. Here, we show that BM-MSCs isolated from NB patients with BM involvement exhibit a greater osteogenic potential than MSCs from non-infiltrated BM. We show that BM metastasis-derived NB-cell lines secrete higher levels of exosomal miR-375, which promotes osteogenic differentiation in MSCs. Of note, clinical data demonstrate that high level of miR-375 correlates with BM metastasis in NB patients. Our findings suggest, indeed, a potential role for exosomal miR-375 in determining a favourable microenvironment in BM to promote metastatic progression. MiR-375 may, thus, represent a novel biomarker and a potential target for NB patients with BM involvement.

Host-microbiota interactions in inflammatory bowel disease.

The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.

Dynamic and Asymmetric Changes of the Microbial Communities after Cohousing in Laboratory Mice.

Horizontal transmission of the microbiota between different individuals is widely used to normalize the microbiota in laboratory mice. However, little is known about the dynamics of microbial communities and the level of microbiota transmission after cohousing. We extensively analyzed the fecal microbiota in Jackson and Taconic C57BL/6 mice to study horizontal transmission after weaning. Changes in the microbiota were clearly detected on day 3, almost plateaued on day 7, and resulted in near-comparable composition by day 28 after cohousing. Notably, the transmission of bacterial species was asymmetric in kinetics and abundance, resulting in a microbiota that is more similar to that of Jackson mice than Taconic. Several operational taxonomic units (OTUs) increased their abundance rapidly after cohousing in Taconic mice whereas several OTUs including two mucus-associated bacteria increased their abundance with delayed kinetics in Jackson mice. These studies provide insight into the dynamics and normalization of the microbiota during horizontal transmission.

Burkitt lymphoma in a patient with Kabuki syndrome carrying a novel KMT2D mutation.

Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients. Here, we report the case of a 5-year-old boy affected by KS who developed Burkitt lymphoma (BL). Genetic analysis revealed the presence of a novel heterozygous mutation in the splice site of the intron 4 of KMT2D gene in both peripheral blood-extracted DNA and tumour cells. In addition, the tumour sample of the patient was positive for the classical somatic chromosomal translocation t(8;14) involving the c-MYC gene frequently identified in BL. We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients.

Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn's disease.

It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome. We hypothesized that CD susceptibility genes interact with cigarette smoking, a major CD environmental risk factor, to trigger Paneth cell defects. We found that both CD subjects and mice with ATG16L1T300A (T300A; a prevalent CD susceptibility allele) developed Paneth cell defects triggered by tobacco smoke. Transcriptional analysis of full-thickness ileum and Paneth cell-enriched crypt base cells showed the T300A-smoking combination altered distinct pathways, including proapoptosis, metabolic dysregulation, and selective downregulation of the PPARγ pathway. Pharmacologic intervention by either apoptosis inhibitor or PPARγ agonist rosiglitazone prevented smoking-induced crypt apoptosis and Paneth cell defects in T300A mice and mice with conditional Paneth cell-specific knockout of Atg16l1. This study demonstrates how explicit G+E can drive disease-relevant phenotype and provides rational strategies for identifying actionable targets.

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease.

The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are referred to collectively as the gut microbiota. These indigenous microorganisms have co-evolved with the host in a symbiotic relationship. In addition to metabolic benefits, symbiotic bacteria provide the host with several functions that promote immune homeostasis, immune responses, and protection against pathogen colonization. The ability of symbiotic bacteria to inhibit pathogen colonization is mediated via several mechanisms including direct killing, competition for limited nutrients, and enhancement of immune responses. Pathogens have evolved strategies to promote their replication in the presence of the gut microbiota. Perturbation of the gut microbiota structure by environmental and genetic factors increases the risk of pathogen infection, promotes the overgrowth of harmful pathobionts, and the development of inflammatory disease. Understanding the interaction of the microbiota with pathogens and the immune system will provide critical insight into the pathogenesis of disease and the development of strategies to prevent and treat inflammatory disease.

Statistics of localized phase slips in tunable width planar point contacts.

The main dissipation mechanism in superconducting nanowires arises from phase slips. Thus far, most of the studies focus on long nanowires where coexisting events appear randomly along the nanowire. In the present work we investigate highly confined phase slips at the contact point of two superconducting leads. Profiting from the high current crowding at this spot, we are able to shrink in-situ the nanoconstriction. This procedure allows us to investigate, in the very same sample, thermally activated phase slips and the probability density function of the switching current Isw needed to trigger an avalanche of events. Furthermore, for an applied current larger than Isw, we unveil the existence of two distinct thermal regimes. One corresponding to efficient heat removal where the constriction and bath temperatures remain close to each other, and another one in which the constriction temperature can be substantially larger than the bath temperature leading to the formation of a hot spot. Considering that the switching current distribution depends on the exact thermal properties of the sample, the identification of different thermal regimes is of utmost importance for properly interpreting the dissipation mechanisms in narrow point contacts.

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood.

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m2 /dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL.

Magnetic resonance imaging patterns of treatment-related toxicity in the pediatric brain: an update and review of the literature.

Treatment-related neurotoxicity is a potentially life-threatening clinical condition that can represent a diagnostic challenge. Differentiating diagnoses between therapy-associated brain injury and recurrent disease can be difficult, and the immediate recognition of neurotoxicity is crucial to providing correct therapeutic management, ensuring damage reversibility. For these purposes, the knowledge of clinical timing and specific treatment protocols is extremely important for interpreting MRI patterns. Neuroradiologic findings are heterogeneous and sometimes overlapping, representing the compounding effect of the different treatments. Moreover, MRI patterns can be acute, subacute or delayed and involve different brain regions, depending on (1) the mechanism of action of the specific medication and (2) which brain regions are selectively vulnerable to specific toxic effects. This review illustrates the most common radiologic appearance of radiotherapy, chemotherapy and medication-associated brain injury in children, with special focus on the application of advanced MRI techniques (diffusion, perfusion and proton spectroscopy) in the diagnosis of the underlying processes leading to brain toxicity.