Adenoidal Disease and Chronic Rhinosinusitis in Children-Is there a Link?

Adenoid hypertrophy (AH) is an extremely common condition in the pediatric and adolescent populations that can lead to various medical conditions, including acute rhinosusitis, with a percentage of these progressing to chronic rhinosinusitis (CRS). The relationship between AH and pediatric CRS has been extensively studied over the past few years and clinical consensus on the treatment has now been reached, allowing this treatment to become the preferred clinical practice. The purpose of this study is to review existing literature and data on the relationship between AH and CRS and the options for treatment. A systematic literature review was performed using a search line for "(Adenoiditis or Adenoid Hypertrophy) and Sinusitis and (Pediatric or Children)". At the end of the evaluation, 36 complete texts were analyzed, 17 of which were considered eligible for the final study, dating from 1997 to 2018. The total population of children assessed in the various studies was of 2371. The studies were categorized as surgical-observational, microbiological, genetic-immunological, and radiological. The analysis of the studies confirms the relationship between AH and CRS and supports the existing consensus on medical and surgical therapy. Furthermore, these studies underline the necessity to adapt medical and surgical treatment considering age, comorbidities including asthma and, if present, the Computed Tomography (CT) score

DMBT1 expression is down-regulated in breast cancer.

BACKGROUND: We studied the expression of DMBT1 (deleted in malignant brain tumor 1), a putative tumor suppressor gene, in normal, proliferative, and malignant breast epithelium and its possible relation to cell cycle. METHODS: Sections from 17 benign lesions and 55 carcinomas were immunostained with anti DMBT1 antibody (DMBTh12) and sections from 36 samples, were double-stained also with anti MCM5, one of the 6 pre-replicative complex proteins with cell proliferation-licensing functions. DMBT1 gene expression at mRNA level was assessed by RT-PCR in frozen tissues samples from 39 patients. RESULTS: Normal glands and hyperplastic epithelium in benign lesions displayed a luminal polarized DMBTh12 immunoreactivity. Normal and hyperplastic epithelium adjacent to carcinomas showed a loss of polarization, with immunostaining present in basal and perinuclear cytoplasmic compartments. DMBT1 protein expression was down-regulated in the cancerous lesions compared to the normal and/or hyperplastic epithelium adjacent to carcinomas (3/55 positive carcinomas versus 33/42 positive normal/hyperplastic epithelia; p = 0.0001). In 72% of cases RT-PCR confirmed immunohistochemical results. Most of normal and hyperplastic mammary cells positive with DMBTh12 were also MCM5-positive. CONCLUSIONS: The redistribution and up-regulation of DMBT1 in normal and hyperplastic tissues flanking malignant tumours and its down-regulation in carcinomas suggests a potential role in breast cancer. Moreover, the concomitant expression of DMTB1 and MCM5 suggests its possible association with the cell-cycle regulation

Antenatal Microbial Colonization of Mammalian Gut

The widely accepted dogma of intrauterine sterility and initial colonization of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta, and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations and to assess fetal colonization before parturition. To this end, we analyzed sterilely collected intestinal tissues, placenta, and amniotic fluid from rodent fetuses and tissues from autoptic human fetuses. Total bacterial DNA was extracted from collected samples and analyzed by Next Generation Sequencing (NGS) techniques using hypervariable 16S ribosomal RNA (rRNA) regions (V3-V4). Colonizing microbes were visualized in situ, using labeled probes targeting 16S ribosomal DNA by fluorescent in situ hybridization. The NGS analysis showed the presence of pioneer microbes in both rat and human intestines as well as in rodent placentas and amniotic fluids. Microbial communities showed fetus- and dam-dependent clustering, confirming the high interindividual variability of commensal microbiota even in the antenatal period. Fluorescent in situ hybridization analysis confirmed the microbes' presence in the lumen of the developing gut. These findings suggest a possible antenatal colonization of the developing mammalian gut

Therapeutic Effect of Iron Citrate in Blocking Calcium Deposition in High Pi-Calcified VSMC: Role of Autophagy and Apoptosis

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression of calcification in high-phosphate (Pi) calcified VSMC. Iron arrested further calcification when added on days 7\u201315 in the presence of high Pi (1.30 \ub1 0.03 vs 0.61 \ub1 0.02; OD/mg protein; day 15; Pi vs Pi + Fe, p < 0.01). We next investigated apoptosis and autophagy. Adding iron to high-Pi-treated VSMC, on days 7\u201311, decreased apoptotic cell number (17.3 \ub1 2.6 vs 11.6 \ub1 1.6; Annexin V; % positive cells; day 11; Pi vs Pi + Fe; p < 0.05). The result was confirmed thorough analysis of apoptotic nuclei both in VSMCs and aortic rings treated on days 7\u201315 (3.8 \ub1 0.2 vs 2.3 \ub1 0.3 and 4.0 \ub1 0.3 vs 2.2 \ub1 0.2; apoptotic nuclei; arbitrary score; day 15; Pi vs Pi + Fe; VSMCs and aortic rings; p < 0.05). Studying the prosurvival axis GAS6/AXL, we found that iron treatment on days 9\u201314 counteracted protein high-Pi-stimulated down-regulation and induced its de novo synthesis. Moreover, iron added on days 9\u201315 potentiated autophagy, as detected by an increased number of autophagosomes with damaged mitochondria and an increase in autophagic flux. Highlighting the effect of iron on apoptosis, we demonstrated its action in blocking the H2O2-induced increase in calcification added both before high Pi treatment and when the calcification was already exacerbated. In conclusion, we demonstrate that iron arrests further high Pi-induced calcium deposition through an anti-apoptotic action and the induction of autophagy on established calcified VSMC

Mini-invasive approach to preneoplastic and neoplastic endometrial lesions. Comparative study among histological, cytological and immunohistochemical diagnosis

Objective: To compare the accuracy of cytology plus immunoistochemistry vs histology in the preoperative diagnosis of endometrial malignancy. Methods: We prospectively analyzed 142 women with a proliferative endometrial lesion undergoing operative hysteroscopy (ISC): at the time of ISC, the fluid used for saline contrast sonohysterography (SCSH) was collected for cytological analysis and compared to histology. In 9 women a markers board (Notch-1+ER-\u3b1+PR-\u3b2) expression was analyzed semiquantitatively in term of presence and intensity, on both glandular and stromal samples. Results: Table 1 shows the comparison between cytological and histological diagnosis. ISC histological results Benign Lesions n=134 Malignant Lesions n=8 Endometrial Polyps n=124 Hypertrophy n=3 Typical hyperplasia n=7 Atypical hyperplasia n=4 Cancer n=4 CTM - 0 0 0 0 0 CTM + 0 0 0 0 3 SCSH cytological results Atypia - 116 3 6 1 0 Atypia + 2 0 0 3 3 Inadequate (5%) 5 (4 cervical cells) (1 scant sample) 0 1 (1 cervical cells) 0 1 (hypocellulated) Cytological sampling was inadequate in 7 cases (5%). The K value between cytology and histology was 98.4% for benign and 85.7% for malignant lesions. Notch-1 revealed a changing expression pattern: absent in benign lesions, focal and marked in atypical hyperplasia and widespread and marked in cancers. Moreover Notch-1 expression was mild and focal in originally cyto-hystologycal benign lesions which turned into atypical hyperplasia during follow up. In cancer cases, ER-\u3b1 and PR-\u3b2 were widespread and markedly expressed either in the glandular or stromal layer. Conclusions: Cytological analysis could be used as a screening test, at least for women at high surgical risk. Notch-1+ER-\u3b1+PR-\u3b2 expression could be predictive for the risk of endometrial malignancy even at an earlier stadium than hyperplasia and could be used to identify the glandular or stromal origin of cancer thus helping in identifying women at increased risk of malignancy

Dynamic acetylation profile during mammalian neurulation

Neural tube defects (NTDs) result from failure of neural tube closure during embryogenesis. These severe birth defects of the central nervous system include anencephaly and spina bifida, and affect 0.5-2 per 1,000 pregnancies worldwide in humans. It has been demonstrated that acetylation plays a pivotal role during neural tube closure, as animal models for defective histone acetyltransferase proteins display NTDs. Acetylation represents an important component of the complex network of posttranslational regulatory interactions, suggesting a possible fundamental role during primary neurulation events. This study aimed to assess protein acetylation contribution to early patterning of the central nervous system both in human and murine specimens

Dynamic and cell-specific DACH1 expression in human neocortical and striatal development

DACH1 is the human homolog of the Drosophila dachshund gene, which is involved in the development of the eye, nervous system, and limbs in the fly. Here, we systematically investigate DACH1 expression patterns during human neurodevelopment, from 5 to 21 postconceptional weeks. By immunodetection analysis, we found that DACH1 is highly expressed in the proliferating neuroprogenitors of the developing cortical ventricular and subventricular regions, while it is absent in the more differentiated cortical plate. Single-cell global transcriptional analysis revealed that DACH1 is specifically enriched in neuroepithelial and ventricular radial glia cells of the developing human neocortex. Moreover, we describe a previously unreported DACH1 expression in the human striatum, in particular in the striatal medium spiny neurons. This finding qualifies DACH1 as a new striatal projection neuron marker, together with PPP1R1B, BCL11B, and EBF1. We finally compared DACH1 expression profile in human and mouse forebrain, where we observed spatio-temporal similarities in its expression pattern thus providing a precise developmental description of DACH1 in the 2 mammalian species

Advanced Differentiated Thyroid Cancer. A Complex Condition Needing a Tailored Approach

Differentiated thyroid cancers (DTCs) are slow-growing malignant tumours, including papillary and follicular carcinomas. Overall, prognosis is good, although it tends to worsen when local invasion occurs with bulky cervical nodes, or in the case of distant metastases. Surgery represents the main treatment for DTCs. However, radical excision is challenging and significant morbidity and functional loss can follow the treatment of the more advanced forms. Literature on advanced thyroid tumours, both differentiated and undifferentiated, does not provide clear and specific guidelines. This emerges the need for a tailored and multidisciplinary approach. In the present study, we report our single-centre experience of 111 advanced (local, regional, and distant) DTCs, investigating the rate of radical excision, peri-procedural and post-procedural complications, quality of life, persistence, recurrence rates, and survival rates. Results are critically appraised and compared to the existing published evidence review

Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications

BACKGROUND & AIMS: Human hepatocarcinogenesis in cirrhosis is thought to be multistep and characterized by a spectrum of nodular lesions, ranging from low to high grade dysplastic nodules (LGDN and HGDN) to early and progressed hepatocellular carcinoma (eHCC and pHCC). Aim of this study was to investigate the morpho-phenotypical changes of this sequence and their potential translational significance. METHODS: We scored the vascular profile, ductular reaction/stromal invasion and overexpression of 5 biomarkers (GPC3, HSP70, GS, CHC, and EZH2), in a series of 100 resected nodules (13 LGDN, 16 HGDN, 42 eHCC and 29 small pHCC). RESULTS: The score separated the 4 groups of nodules as individual entities (p<0.01). In the sequence, biomarkers overexpression progressively increased with parallel decrease of ductular reaction; the vascular remodeling started very early (LGDN) but did not further develop in a proportion of HCC. eHCC was the most heterogeneous entity, with marginal overlap with HGDN and pHCC. Liver environment (fibrosis, etiology) did not impact on the phenotype of the different nodules. A subclass of eHCC (16/42) without evidence of stromal invasion was identified, suggesting a "preinvasive stage" (p<0.05). For diagnosis, the application of 4 and 5 biomarkers (rather than the usual 3) improved the sensitivity of the assay for the detection of eHCC (76% and 93% vs. 52%); biomarkers in alternative combinations also increased the sensitivity of the assay (GS+CHC+EZH2: 76%; GS+CHC+EZH2+HSP70: 90%). CONCLUSIONS: This study supports the multistep nature of human hepatocarcinogenesis, suggests that eHCC is more heterogeneous than previously thought and provides information of potential translational significance into the clinical practice

PKA regulatory subunit R2B is required for murine and human adipocyte differentiation

ADIPOGENESIS IS A COMPLEX PROCESS MODULATED BY SEVERAL FACTORS, INCLUDING CAMP SIGNALING. THE MAIN CAMP TARGET IS PROTEIN KINASE A (PKA), A TETRAMERIC ENZYME WITH FOUR REGULATORY SUBUNITS SHOWING TISSUE-SPECIFIC EXPRESSION AND FUNCTION: PRKAR2B is the main regulatory subunit in adipose tissue in mice and in adult humans. This study aimed to evaluate the expression of PKA regulatory subunits in human adipose tissue during fetal development and to investigate their role in the differentiation of 3T3-L1 and primary human preadipocytes. The expression of PKA regulatory subunits was evaluated in fetal adipose tissue (immunohistochemistry) and in cultured 3T3-L1 and primary human preadipocytes (western blot analysis). Cultured cells were transiently transfected with siRNA against PRKAR2B and induced to differentiate. Differentiation was evaluated by intracellular triglyceride staining (Oil Red O) and expression of molecular markers of adipocyte differentiation. In this study, we found that PRKAR2B is the main regulatory subunit in human adipose tissue during fetal development, from 12 weeks of gestation to the end of gestation, as well as in 3T3-L1 and primary human preadipocytes. The expression of PRKAR2B increases progressively during in vitro differentiation. The silencing of PRKAR2B abolishes the increase in the expression of peroxisome proliferator-activated receptor gamma (PPAR\u3b3 (PPARG)), fatty acid synthase, aP2 (FABP4), and lipoprotein lipase, as well as intracellular triglyceride accumulation, resulting in impaired adipocyte differentiation in both mouse and human cell systems. In conclusion, PRKAR2B is the key PKA regulatory subunit involved in mouse and human adipose tissue development. The physiological increase in the expression of PRKAR2B is an essential event in adipogenesis in both mice and humans, and it might represent a possible target for future strategies for obesity treatment