Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication.

ATP2B1 is a known regulator of calcium (Ca2+) cellular export and homeostasis. Diminished levels of intracellular Ca2+ content have been suggested to impair SARS-CoV-2 replication. Here, we demonstrate that a nontoxic caloxin-derivative compound (PI-7) reduces intracellular Ca2+ levels and impairs SARS-CoV-2 infection. Furthermore, a rare homozygous intronic variant of ATP2B1 is shown to be associated with the severity of COVID-19. The mechanism of action during SARS-CoV-2 infection involves the PI3K/Akt signaling pathway activation, inactivation of FOXO3 transcription factor function, and subsequent transcriptional inhibition of the membrane and reticulum Ca2+ pumps ATP2B1 and ATP2A1, respectively. The pharmacological action of compound PI-7 on sustaining both ATP2B1 and ATP2A1 expression reduces the intracellular cytoplasmic Ca2+ pool and thus negatively influences SARS-CoV-2 replication and propagation. As compound PI-7 lacks toxicity in vitro, its prophylactic use as a therapeutic agent against COVID-19 is envisioned here.

Modulation of innate immunity related genes resulting in prophylactic antimicrobial and antiviral properties.

BACKGROUND: The innate immunity acts during the early phases of infection and its failure in response to a multilayer network of co-infections is cause of immune system dysregulation. Epidemiological SARS-CoV-2 infections data, show that Influenza Virus (FLU-A-B-C) and Respiratory Syncytial Virus (RSV) are co-habiting those respiratory traits. These viruses, especially in children (mostly affected by 'multi-system inflammatory syndrome in children' [MIS-C] and the winter pandemic FLU), in the aged population, and in 'fragile' patients are causing alteration in immune response. Then, bacterial and fungal pathogens are also co-habiting the upper respiratory traits (e.g., Staphylococcus aureus and Candida albicans), thus contributing to morbidity in those COVID-19 affected patients. METHODS: Liquid chromatography coupled with high-resolution mass spectrometry using the quadrupole orbital ion trap analyser (i.e., UHPLC-Q-Orbitrap HRMS) was adopted to measure the polyphenols content of a new nutraceutical formula (Solution-3). Viral infections with SARS-CoV-2 (EG.5), FLU-A and RSV-A viruses (as performed in BLS3 authorised laboratory) and real time RT-PCR (qPCR) assay were used to test the antiviral action of the nutraceutical formula. Dilution susceptibility tests have been used to estimate the minimum inhibitory and bactericidal concentration (MIC and MBC, respectively) of Solution-3 on a variety of microorganisms belonging to Gram positive/ negative bacteria and fungi. Transcriptomic data analyses and functional genomics (i.e., RNAseq and data mining), coupled to qPCR and ELISA assays have been used to investigate the mechanisms of action of the nutraceutical formula on those processes involved in innate immune response. RESULTS: Here, we have tested the combination of natural products containing higher amounts of polyphenols (i.e., propolis, Verbascum thapsus L., and Thymus vulgaris L.), together with the inorganic long chain polyphosphates 'polyPs' with antiviral, antibacterial, and antifungal behaviours, against SARS-CoV-2, FLU-A, RSV-A, Gram positive/ negative bacteria and fungi (i.e., Candida albicans). These components synergistically exert an immunomodulatory action by enhancing those processes involved in innate immune response (e.g., cytokines: IFNγ, TNFα, IL-10, IL-6/12; chemokines: CXCL1; antimicrobial peptides: HBD-2, LL-37; complement system: C3). CONCLUSION: The prophylactic antimicrobial success of this nutraceutical formula against SARS-CoV-2, FLU-A and RSV-A viruses, together with the common bacteria and fungi co-infections as present in human oral cavity, is expected to be valuable.

A new comprehensive MRI classification and grading system for lumbosacral central and lateral stenosis: clinical application and comparison with previous systems.

PURPOSE: The purpose of our study was to provide a novel schematized and comprehensive classification of causes and severity grading system for lumbosacral stenosis. MATERIALS AND METHODS: The MRI system proposed consisted of a severity grading scale for central and lateral (recess and foramen) stenosis, together with a schematized indication of the main causes of the disease (disc, arthritis, epidural lipomatosis, and their combinations). The system was applied to a cohort of patients from a single Institution in the last 2-years. Two radiologists evaluated all the MRIs to determine intra- and inter-observer reliability according to Cohen Kappa (Kc, for non-ordered categorical variables) and weighted Kappa (Kw, for ordered variables). Two orthopaedic surgeons clinically evaluated all patients and provided a schematic grading system with a central and lateral stenosis clinical score (CS-CS and LS-CS). Associations between ordinals were tested with chi-square test and measured with the Goodman and Kruskal's gamma index (Gi, with 95% confidence interval [95% CI]). Lastly, the most used previous MRI systems were applied, and their performances were compared to the new system proposed. RESULTS: One hundred and twelve patients were included (55 females-mean age 63.3 ± 10.7 years). An almost perfect intra-observer agreement for the assessment of central stenosis, foramen stenosis, and lateral recess stenosis was found (Kw = 0.929, 0.928, and 0.924, respectively). The inter-observer agreement was almost perfect for central stenosis and foramen stenosis and substantial for lateral recess stenosis (Kw = 0.863, 0.834, and 0.633, respectively). Whatever the aetiologies involved in central and lateral stenosis, the intra-observer agreement was perfect (all Kc = 1), whereas the inter-observer agreements were almost perfect for arthritis (Kc = 0.838) and lipomatosis (Kc = 0.955) and substantial for disc (Kc = 0.691) regarding central stenosis. The inter-observer agreement for the causes of lateral stenosis was lower and variable, ranging from perfect (lipomatosis) to fair (disc, Kc = 0.224). The grading system revealed a strong association with CS-CS for both readers, with GI = 0.671 (95% CI 0.535-0.807) and 0.603 (95% CI = 0.457-0.749), respectively. The association with MRI grading and LS-CS was moderate for foraminal stenosis and for the concomitant presence of foraminal and lateral recess stenosis, with Gi = 0.337 (95% CI 0.121-0.554) and Gi = 0.299 (95% CI 0.098-0.500), respectively. A weak association was found between lateral recess grading alone and LS-CS with Gi = 0.102 (95% CI 0.193-0.397). The new grading systems showed higher Gi for associations with clinical symptoms, compared with previous ones, both for CS-CS and LS-CS. CONCLUSIONS: A standardized visual grading system for lumbar spinal stenosis that takes into account all of the major contributing factors-including disc, arthritis, and lipomatosis, for the central canal, lateral recess, and neural foramina could be a useful and practical tool for defining the stenosis, lowering inter-observer variability, and directing the various treatment options.

Preoperative Arterial Embolization for Heterotopic Ossification of the Hip.

PURPOSE: To investigate the efficacy and safety of preoperative arterial embolization for neurogenic heterotopic ossification (NHO) of the hip. MATERIALS AND METHODS: This single-center retrospective study reviewed outcomes in 16 consecutive patients who had surgical resection of NHO of the hip: 8 of whom underwent preoperative arterial embolization and 8 of whom did not. Both patient cohorts had similar baseline characteristics. A mean of 2.62 ± 1.9 arteries per patient, including the gluteal, lateral circumflex femoral, and deep circumflex iliac branches, were embolized using an n-butyl cyanoacrylate (NBCA)-ethiodized oil mixture. Data from both cohorts regarding intraoperative blood loss, volume of blood transfused, complications, and duration of hospitalization were compared. RESULTS: A mean of 2.6 ± 1.9 arteries were embolized with NBCA-ethiodized oil, mainly the gluteal arteries, lateral circumflex femoral artery, and deep circumflex iliac artery. In the embolization group, mean intraoperative blood loss was 875 mL ± 320, mean number of units of blood used was 0.5 ± 0.7, and mean number of days of hospitalization was 6.4 days ± 1.6. In the control group, mean intraoperative blood loss was 1,350 mL ± 120, mean number of units of blood used was 2 ± 1.1, and average number of days of hospitalization was 11.5 days ± 1.4. The embolization group had a mean reduction in blood loss of 40.7% (P = 0.035), reduction in units of blood administered of 75% (P = 0.021), and reduction in days of hospitalization of 44.7% (P = 0.014). No procedural complications were recorded. CONCLUSIONS: Preoperative arterial embolization is effective and safe in reducing intraoperative blood loss, number of hospitalization days, and need for blood transfusions in surgical resection of NHO of the hip.

Aneurysmal bone cyst: Is selective arterial embolization effective as curettage and bone grafting?

INTRODUCTION: Aneurysmal bone cyst (ABC) is a lytic benign bone lesion representing about 1% of all primary bone tumors. Method to treat ABC's have developed over time. The standard of care cure for ABC has been curettage with or without bone grafting of the defect but is burdened by recurrence rates of approximately 25%-31%. Based on the assumption that ABCs usually supplied by one or more pathological feeding arteries, selective arterial embolization has been described as an adjuvant preoperative procedure to reduce intra-operative hemorrhage, and as primary treatment for lesions in difficult surgical access. In the current study, we therefore asked whether (1) a single or a repeat selective arterial embolization (SAE) for treating ABCs would produce comparable healing rates compared with curettage and bone grafting; (2) evaluated the relationship of recurrence in relation to the site of the cyst, the age, and gender of the patients; and (3) the two techniques differ in term of long-term complication. MATERIAL AND METHODS: We retrospectively reviewed 265 patients who underwent curettage and bone grafting or SAE performed at our institute from 1994 to 2018. The diagnosis of ABC was always established with percutaneous CT-guided biopsy or open biopsy. Patients were followed clinically with plain radiographs or CT scan at 3, 6, 9, and 12 months then annually in the absence of symptoms. Treatment success was determined evaluating pre- and postprocedural imaging according to Chang classification. RESULTS: Two hundred and nineteen were treated with curettage and bone grafting (curettage group), and 46 with SAE Group. Of the 219 patients treated with Curettage and bone grafting (curettage group), 165 out of 219 (75.3%) experienced bone healing, while local recurrence was observed in 54 cases (24.7%) after 12 months on average (range: 3-120 months) from surgery. After the first SAE, bone ossification was seen in 27 (58.7%), without needing any further treatment. Eleven recurred patients were treated with SAE (four patients need two while seven need three SAE to heal), and eight patients with curettage and bone grafting. Thirty-eight out of 46 (82%) patients experienced bone ossification regardless the number of SAE. The overall rate of local recurrence for all patients was 26.7%. SAE group presented a lower complication rate (6%) where two patients experienced skin necrosis, and one limb-length discrepancies (2% of all cohort). DISCUSSION: The use of SAE is an attractive option to treat ABC as it combines on one hand a lower complication rate than curettage and bone grafting, on the other it can be carried out in case of nonresectable ABCs, significantly reducing the size of viable ABC lesions, fostering bone remodeling and mineralization, and most importantly, significantly improving the patient's quality of life.

Unraveling the enigma of Adamkiewicz: exploring the prevalence, anatomical variability, and clinical impact in spinal embolization procedures for bone metastases.

BACKGROUND: The artery of Adamkiewicz (AKA) is vital for spinal cord blood supply. Its role in embolization procedures for bone metastases can cause serious complications. We explored its prevalence, anatomical variation, and effect on spinal embolization using N-butyl cyanoacrylate (NBCA) in patients with bone metastases. PURPOSE: To understand the impact and variability of AKA in spinal embolizations in cases of bone metastases to reduce complications and improve patient outcomes. MATERIAL AND METHODS: We examined data from 454 patients who underwent spinal embolization with NBCA between 2009 and 2018. The presence, anastomoses, and tumor features of AKA were assessed via pre-procedure imaging and angiography. Complications were classified per the CIRSE Classification System. RESULTS: AKA was found in 22.8% of patients, predominantly left-sided and originating from T8 to L1. Direct and indirect anastomoses were present in 66.6% and 33.4% of patients, respectively. Extra-compartmental invasion was linked with direct anastomosis (P = 0.004). High-grade complications were rare but included one instance of bilateral lower limb paralysis. Partial embolization was necessary in 22.8% of cases due to AKA. CONCLUSION: The study underscores the need for rigorous preoperative evaluation of AKA origin and anastomoses in patients undergoing spinal embolization for bone metastases. Given the significant presence of AKA and related anastomoses, especially with renal extra-compartmental tumors, caution is advised to reduce complications and optimize patient outcomes. Further research is required for best practice guidelines involving bone metastases and AKA.

The human aortic endothelium undergoes dose-dependent DNA methylation in response to transient hyperglycemia.

BACKGROUND: Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming. METHODS: In the current study, we quantified genome-wide DNA methylation of cultured human endothelial aortic cells (HAECs) via reduced-representation bisulfite sequencing (RRBS) following exposure to diabetic (250 mg/dL), pre-diabetic (125 mg/dL), or euglycemic (100 mg/dL) glucose concentrations for 72 h (n = 2). RESULTS: We discovered glucose-dependent methylation of genomic regions (DMRs) encompassing 2199 genes, with a disproportionate number found among genes associated with angiogenesis and nitric oxide (NO) signaling-related pathways. Multi-omics analysis revealed differential methylation and gene expression of VEGF (↑5.6% DMR, ↑3.6-fold expression), and NOS3 (↓20.3% DMR, ↓1.6-fold expression), nodal regulators of angiogenesis and NO signaling, respectively. CONCLUSION: In the current exploratory study, we examine glucose-dependent and dose-responsive alterations in endothelial DNA methylation to examine a putative epigenetic mechanism underlying diabetic vasculopathy. Specifically, we uncover the disproportionate glucose-dependent methylation and gene expression of VEGF and NO signaling cascades, a physiologic imbalance known to cause endothelial dysfunction in diabetes. We therefore hypothesize that epigenetic mechanisms encode a glycemic memory within endothelial cells.

MRI in differential diagnosis between tuberculous and pyogenic spondylodiscitis.

PURPOSE: The aim of the study was to investigate whether MRI findings together with epidemiological data could help in differentiating between tuberculous and pyogenic spondylodiscitis. METHODS: Clinical records of 260 patients with a suspicion of spondylodiscitis were analysed. Patients were selected using the following inclusion criteria: confirmed diagnosis of spondylodiscitis either from pyogenic bacteria or from Mycobacterium tuberculosis and contrast-enhanced MRI performed before treatment. Clinical data concerning age, sex and country-of-origin were also collected. For each patient, several MRI-features were evaluated by two-expert musculoskeletal radiologists. A chi-squared test and a multiple logistic regression were used to find the best predictors of tuberculous or pyogenic spondylodiscitis. RESULTS: 114 patients were retrospectively enrolled, 30 with tuberculous and 84 with pyogenic spondylodiscitis. We found 18 MRI-features, significantly different between the two groups. Among these, the most strongly associated with tuberculous spondylodiscitis were: heterogeneous vertebral signal on T1w-sequences (Odds Ratio(OR) = 205.759-p < 0.001), presence of epidural abscess (OR = 86.221-p < 0.001), severe vertebral destruction (OR = 10.017-p < 0.001) and absence of epidural phlegmon (OR = 86.221-p < 0.001). Moreover, patients coming from countries with a middle-high prevalence of tuberculosis were more frequently affected by tuberculous spondylodiscitis than others were (OR = 229.136-p < 0.001). The best prediction model demonstrated a correct classification rate of 94.7%. CONCLUSION: To the best of our knowledge this is the largest study comparing MRI-features of tuberculous and pyogenic spondylodiscitis. The above-mentioned MRI-features and epidemiological data are crucial in the differential diagnosis between these two entities, guiding the choice of the appropriate therapy, especially when a pathogen cannot be clearly identified with other modalities.

Ultrasound-guided percutaneous irrigation of calcific tendinopathy outside the rotator cuff: short-term evaluation.

RATIONALE AND OBJECTIVES: While ultrasound-guided percutaneous irrigation for painful calcific tendinopathy (US-PICT) is the treatment of choice for the rotator cuff, there is a lack of knowledge regarding the treatment of this condition with atypical location. The purpose of our study is to assess if US-PICT can be applied safely and successfully in atypical sites, outside of the rotator cuff. MATERIALS AND METHODS: We retrospectively reviewed the US-PICT performed outside the rotator cuff, in the last 5 years in a single institution. A total of 16 patients have been included in this study. We collected the values of the numerical rating scale (NRS) for pain pre- and post-procedure (7 days and 3-month follow-up). Moreover, we assessed the imaging studies available pre- and post-procedure (ultrasound and plain radiography) to assess complications. RESULTS: In all the 16 patients (10F, 6 M; mean age 50.2; range 24-65-year-old), no complications have been observed during and after the procedures. The mean pain NRS before treatment was 8.7 (range 10-6) and dropped to 1.1 (6-0) after 1 week as well after 3 months 1.1 (6-0). The NRS pain reduction from baseline resulted to be statistically significant after 7 days and 3 months (p < 0.001). CONCLUSION: Our results suggest the safety and efficacy of this procedure, underlining the great potential of US-PICT applied even in different atypical locations.

Current concepts in the diagnosis and treatment of adhesive capsulitis: role of diagnostic imaging and ultrasound-guided interventional procedures.

Adhesive capsulitis is a common cause of painful shoulder, characterized by pain and restricted range of motion of the glenohumeral joint. With a well-known clinical presentation, and an increasing understanding of its clinical and radiologic features, early diagnosis of adhesive capsulitis is becoming a reality. Although often treated conservatively, for refractory cases arthroscopic release and open capsulotomy have been the only therapeutic option for a long time. Therefore, in the last years, a particular effort was put into the development of novel minimal-invasive techniques capable of pain relief and functional range improvement of the glenohumeral joint. The purpose of this literature review is to report the main updates on diagnosis and treatment for adhesive capsulitis with a focus on imaging diagnosis techniques and novel minimally invasive ultrasound-guided treatments. Results showed that ultrasound-guided procedures come with a high success rate in terms of pain reduction and improved range of motion, thus making the ultrasound a unique tool capable of giving the operator real-time diagnostic information confirming the clinical suspicion, and subsequently performing an interventional procedure.

Prevalence and characteristics of diffuse idiopathic skeletal hyperostosis (DISH) in Italy.

PURPOSE: Diffuse idiopathic skeletal hyperostosis (DISH) is a benign condition characterized by ossification of the spine and prominent enthesopathies. Highly heterogeneous epidemiological figures have been reported in the literature, while in Italy the largest study has been conducted in 1992. The aim of our research is to contribute updated information about prevalence of DISH in Italy and to describe the clinical and radiographic characteristics associated with the disorder. MATERIAL AND METHODS: A retrospective review of lumbosacral spine, thoracic spine and pelvis radiographs was performed. Consecutive patients visiting the emergency department of our Institution over 3 years were enrolled. Presence of DISH was evaluated applying the Resnick and Niwayama criteria. Clinical and radiological features were also assessed. RESULTS: We included 1012 individuals (60.6% women), and DISH was present in 130 cases. The overall prevalence of DISH was 12.8% (95% CI 10.8-15.1), with higher figures in the male sample (16.8%) than in females (10.3%). In binary logistic regression adjusted for age, BMI (OR 1.50, p < 0.001) diabetes (OR 1.85, p = 0.003), hypertension (OR 2.04, p = 0.007) ischiopubic enthesopathy (OR 7.08, p < 0.001), iliac crest enthesopathy (OR 4.63, p < 0.001) and greater trochanter enthesopathy (OR 3.51, p < 0.001), were significantly associated with the condition. CONCLUSION: The prevalence of DISH observed in our study is consistent with previous literature, and we confirm that the disorder is more frequently retrieved in men and that it is associated with the presence of metabolic disorders and pelvic enthesopathy. Knowledge about the epidemiology and characteristics of DISH is needed to properly identify the condition.

Preliminary Characterization of the Epigenetic Modulation in the Human Mesenchymal Stem Cells during Chondrogenic Process.

Regenerative medicine represents a growing hot topic in biomedical sciences, aiming at setting out novel therapeutic strategies to repair or regenerate damaged tissues and organs. For this perspective, human mesenchymal stem cells (hMSCs) play a key role in tissue regeneration, having the potential to differentiate into many cell types, including chondrocytes. Accordingly, in the last few years, researchers have focused on several in vitro strategies to optimize hMSC differentiation protocols, including those relying on epigenetic manipulations that, in turn, lead to the modulation of gene expression patterns. Therefore, in the present study, we investigated the role of the class II histone deacetylase (HDAC) inhibitor, MC1568, in the hMSCs-derived chondrogenesis. The hMSCs we used for this work were the hMSCs obtained from the amniotic fluid, given their greater differentiation capacity. Our preliminary data documented that MC1568 drove both the improvement and acceleration of hMSCs chondrogenic differentiation in vitro, since the differentiation process in MC1568-treated cells took place in about seven days, much less than that normally observed, namely 21 days. Collectively, these preliminary data might shed light on the validity of such a new differentiative protocol, in order to better assess the potential role of the epigenetic modulation in the process of the hypertrophic cartilage formation, which represents the starting point for endochondral ossification.

The role of percutaneous transarterial embolization in the management of spinal bone tumors: a literature review.

PURPOSE: Spinal bone tumors include a heterogeneous broad of primary or metastatic lesions that may present as incidental findings or manifest with painful symptoms and pathological fractures. Optimal management of spine bone lesions is often difficult and treatment algorithms are usually solidly based on surgery. We aimed to evaluate the contribution of trans-arterial embolization in this field, with particular attention to the procedure efficacy, technical difficulties and complications. METHODS: We present a literature review on the role of trans-arterial embolization in the management of spinal bone tumors, both primary and metastatic, evaluating its contribution as preoperative treatment, palliative procedure and standalone curative strategy. RESULTS: Trans-arterial embolization provides an important contribution to reducing surgery hemorrhagic risks, offering a better visualization of the operating field, and possibly increasing tumor susceptibility to chemotherapy or radiation therapy. Nonetheless, it plays an important part in pain palliation, with the unquestionable advantage of being easily repeatable in case of necessity. Its curative role as a standalone therapy is still subject of debate, and at the present time, satisfactory results have been recorded only in the treatment of aneurysmal bone cysts. CONCLUSION: Percutaneous trans-arterial embolization has established as a highly useful minimally invasive procedure in the management of spinal bone lesions, particularly as adjuvant preoperative therapy and palliative treatment.

Pediatric Obstructive Sleep Apnea Syndrome: Emerging Evidence and Treatment Approach.

OSA pediatric subjects suffer from episodes of upper airway obstruction that can be partial or complete, with atypical sleep patterns and blood-gas level alteration. If poor treated and/or diagnosed, it can cause cardiovascular disease, learning difficulties, behavioural issues, and retardation of growth. In the literature, there are conflicting evidence about OSA assessment and treatment in pediatric age, so the aim of this paper is to highlight the multidisciplinary approach in the management of sleep disorders, stressing the role of the pediatric dentist in both diagnosing and treating the OSAS in children, according to the current evidence of the treatment options effectiveness of the syndrome itself. Conclusions. Scientific evidence shows that OSAS management requires a multidisciplinary approach in order to make an early diagnosis and a correct treatment plan. The orthodontic treatment approach includes orthopedic maxillary expansion and mandibular advancement using intraoral appliances. Hence, the orthodontist and the pediatric dentist play an important role not only in early diagnosis but also in the treatment of pediatric OSAS.

Osteoid osteoma: which is the best mininvasive treatment option?

Osteoid osteoma is the third most common benign bone tumor, with well-known clinical presentation and radiological features. Although surgical excision has been the only therapeutic option for a long time, to date it has been replaced by minimally invasive techniques, which proved satisfactory success rates and low complication occurrence. Therefore, the purpose of this literature review was to describe the main updates of these recent procedures in the field of interventional radiology, with particular attention paid to the results of the leading studies relating to the efficacy, complications, and recurrence rate. Nevertheless, this study aimed to analyze the peculiarities of each reported technique, with specific focus on the possible improvements and pitfalls. Results proved that all mininvasive procedures boast a high success rate with slight number of complications and a low recurrence rate. Radiofrequency ablation is still considered the gold standard procedure for percutaneous treatment of osteoid osteoma, and it has the possibility to combine treatment with a biopsy. Interstitial laser ablation's advantages are the simplicity of use and a lower cost of the electrodes, while cryoablation allows real-time visualization of the ablated zone, increasing the treatment safety. Magnetic resonance-guided focused ultrasound surgery is the most innovative non-invasive procedure, with the unquestionable advantage to be radiation free.

Monoacylglycerides from the Diatom Skeletonema marinoi Induce Selective Cell Death in Cancer Cells.

Microalgae are an excellent source of valuable compounds for nutraceutical and cosmeceutical applications. These photosynthesizing microorganisms are amenable for large-scale production, thus overcoming the bottleneck of biomass supply for chemical and activity characterization of bioactive compounds. This characteristic has recently also prompted the screening of microalgae for potential pharmaceutical applications. Here, we show that monoacylglycerides (MAGs) purified from the marine diatom Skeletonema marinoi have selective cytotoxic activity against the haematological cancer cell line U-937 and colon cancer cell line HCT-116 compared to normal MePR-2B cells. LC-MS analysis of the raw extract revealed that in their natural form, MAGs occur as 2-monoacyl derivatives and include mainly C16 and C20 analogues, but they are converted into the corresponding 1-isomers during purification processes. Pure compounds along with the synthetic 1-monoarachidonoylglycerol tested on HCT-116 and U-937 tumor cell lines induced cell death via apoptosis. The mechanism of action was investigated, and we show that it involves the induction of apoptosis through caspase 3/7 activation. These findings pave the way for the possible use of these molecules as potential anticancer agents or as precursors for the generation of new and more potent and selective compounds against tumor cells.

Secretome profiling of cytokines and growth factors reveals that neuro-glial differentiation is associated with the down-regulation of Chemokine Ligand 2 (MCP-1/CCL2) in amniotic fluid derived-mesenchymal progenitor cells.

Secreted cytokines and growth factors play a key role in the modulation of stem cell proliferation, differentiation and survival. To investigate the interplay between the changes in their expression levels, we used the newly characterized human amniotic fluid derived-mesenchymal progenitor MePR-2B cell line differentiated to a neuro-glial phenotype and exploited the very high sensitivity and versatility of magnetic beads-based immunoassays. We found that a sub-set of proteins, including the cytokines IL-6, TNFα, IL-15, IFNγ, IL-8, IL-1ra, MCP-1/CCL2, RANTES and the growth factor PDGFbb, underwent a significant down-regulation following neuro-glial differentiation, whereas the expression levels of IL-12 p70, IL-5, IL-7, bFGF, VEGF and G-CSF were increased. The role of MCP-1/CCL2, previously identified as a regulator of neural progenitor stem cell differentiation, has been further investigated at transcriptional level, revealing that both the chemokine and its receptor are co-expressed in MePR-2B cells and that are regulated upon differentiation, suggesting the presence of an autocrine and paracrine loop in differentiating cells. Moreover, we demonstrated that exogenous CCL2 is capable to affect neuro-glial differentiation in MePR-2B cells, thus providing novel evidences for the potential involvement of chemokine-mediated signaling in progenitor/stem cells differentiation processes and fate specification.

Fat Embolism Syndrome: Lung Computed Tomography Findings in 18 Patients.

OBJECTIVE: The purpose of this study was to evaluate the lung computed tomography (CT) findings in fat embolism (FE) syndrome. METHODS: We retrospectively evaluated 19 CT examinations of 18 patients with FE syndrome, diagnosed clinically using the Gurd and Wilson criteria. RESULT: Fat embolism syndrome showed 3 patterns: negative examination, bilateral interstitial-alveolar involvement, and adult respiratory distress syndrome like. Frequent findings included consolidations (17 patients), mostly with gravity dependent distribution, and ground-glass opacities (17 patients), mostly with patchy distribution. Fifteen patients showed an overlapping random nodular pattern. Less common findings included lobular ground-glass opacities and lobular consolidations, smooth septal thickening, thickening of the bronchial wall, and areas of crazy paving. The extension of the consolidations correlates with the duration of assisted ventilation. CONCLUSIONS: In FE syndrome, pulmonary CT findings are ground-glass opacities and dependent consolidations, associated with other variably overlapping signs, such as lobular opacities, random nodules, septal thickening, and bronchial wall thickening.