Cytoplasmic localization of HTLV-1 HBZ oncoprotein: a biomarker of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of T cell neoplasia called Adult T cell Leukaemia (ATL) and of a neurologic disorder designated HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HBZ oncoprotein encoded by the minus strand of the HTLV-1 is thought to play an important role in both diseases. The recent isolation in our laboratory of the first described monoclonal antibody against HBZ protein has now permitted to investigate in detail the cellular and biochemical features of endogenous HBZ. In this direction our laboratory has recently established that HBZ is a nuclear protein in cells of ATL patients. My thesis was predominantly focused in expanding the analysis particularly in HAM/TSP patients, to assess similarities and/or diversities of HBZ subcellular distribution with respect to ATL patients and asymptomatic HTLV-1 carriers. Expression and localization of HBZ in peripheral blood mononuclear cells (PBMC) of ATL, HAM/TSP patients and in HTLV-1 asymptomatic carriers (AC) was analyzed by immunohistochemistry and confocal microscopy using the anti-HBZ 4D4-F3 mAb. Analysis of patients with HAM/TSP unequivocally showed that HBZ-positive cells presented an exclusive, never reported, cytoplasmic localization of the viral oncogenic protein. Interestingly, experiment with leptomycin B indicated that HBZ could not shuttle between cytoplasm and nucleus. This strict HBZ cytoplasmic localization was at variance with the distribution of the other HTLV-1 oncogenic protein, Tax-1, that could localize both in the cytoplasm and the nucleus, and could be sequestered totally in the nucleus after leptomycin B treatment of the cells. Additional extensive analysis of cells from ATL patients and asymptomatic recipients confirmed, instead, a nuclear localization of HBZ. I further supported this finding by studying HBZ and Tax-1 in the CIB cell line, a CD4+ IL-2-dependent T cell line derived from an HAM/TSP patient. The vast majority of CIB cells express significant amounts of HBZ exclusively in the cytoplasm, mostly in a speckle-like fashion. Tax-1 instead was expressed in 30% of the cells, either as a diffuse reticulum or distributed in a speckled-like fashion mainly in the cytoplasm. Interestingly, in cells co-expressing cytoplasmic HBZ and Tax-1, the two proteins did not co-localize, suggesting that they do not interact in vivo. Our results establish for the first time a distinctive and diverse pattern of sub-cellular localization of endogenous HBZ protein. Furthermore, and of potential importance in the pathogenesis of HTLV-1-associated diseases, our data suggest that the endogenous localization of HBZ protein in different cellular compartments may correlate with the different forms of the HTLV-1-mediated diseases

Cytoplasmic localization of HTLV-1 HBZ oncoprotein: a biomarker of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of T cell neoplasia called Adult T cell Leukaemia (ATL) and of a neurologic disorder designated HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HBZ oncoprotein encoded by the minus strand of the HTLV-1 is thought to play an important role in both diseases. The recent isolation in our laboratory of the first described monoclonal antibody against HBZ protein has now permitted to investigate in detail the cellular and biochemical features of endogenous HBZ. In this direction our laboratory has recently established that HBZ is a nuclear protein in cells of ATL patients. My thesis was predominantly focused in expanding the analysis particularly in HAM/TSP patients, to assess similarities and/or diversities of HBZ subcellular distribution with respect to ATL patients and asymptomatic HTLV-1 carriers. Expression and localization of HBZ in peripheral blood mononuclear cells (PBMC) of ATL, HAM/TSP patients and in HTLV-1 asymptomatic carriers (AC) was analyzed by immunohistochemistry and confocal microscopy using the anti-HBZ 4D4-F3 mAb. Analysis of patients with HAM/TSP unequivocally showed that HBZ-positive cells presented an exclusive, never reported, cytoplasmic localization of the viral oncogenic protein. Interestingly, experiment with leptomycin B indicated that HBZ could not shuttle between cytoplasm and nucleus. This strict HBZ cytoplasmic localization was at variance with the distribution of the other HTLV-1 oncogenic protein, Tax-1, that could localize both in the cytoplasm and the nucleus, and could be sequestered totally in the nucleus after leptomycin B treatment of the cells. Additional extensive analysis of cells from ATL patients and asymptomatic recipients confirmed, instead, a nuclear localization of HBZ. I further supported this finding by studying HBZ and Tax-1 in the CIB cell line, a CD4+ IL-2-dependent T cell line derived from an HAM/TSP patient. The vast majority of CIB cells express significant amounts of HBZ exclusively in the cytoplasm, mostly in a speckle-like fashion. Tax-1 instead was expressed in 30% of the cells, either as a diffuse reticulum or distributed in a speckled-like fashion mainly in the cytoplasm. Interestingly, in cells co-expressing cytoplasmic HBZ and Tax-1, the two proteins did not co-localize, suggesting that they do not interact in vivo. Our results establish for the first time a distinctive and diverse pattern of sub-cellular localization of endogenous HBZ protein. Furthermore, and of potential importance in the pathogenesis of HTLV-1-associated diseases, our data suggest that the endogenous localization of HBZ protein in different cellular compartments may correlate with the different forms of the HTLV-1-mediated diseases

PPPC 4 DMν\nu: A Poor Particle Physicist Cookbook for Neutrinos from DM annihilations in the Sun

We provide ingredients and recipes for computing neutrino signals of TeV-scale Dark Matter annihilations in the Sun. For each annihilation channel and DM mass we present the energy spectra of neutrinos at production, including: state-of-the-art energy losses of primary particles in solar matter, secondary neutrinos, electroweak radiation. We then present the spectra after propagation to the Earth, including (vacuum and matter) flavor oscillations and interactions in solar matter. We also provide a numerical computation of the capture rate of DM particles in the Sun. These results are available in numerical form.Comment: 27 pages, many figures. v2: a typo corrected in eq.(18). All results are available at http://www.marcocirelli.net/PPPC4DMID.htm

Editorial: Pulmonary fibrosis: One manifestation, various diseases

This research topic collection entitled “Pulmonary Fibrosis: one manifestation, various diseases”, involving authors from different countries, confirms that this disease is a hot topic (Confalonieri P et al.,2022, Orlandi M et al., 2022). There are over 200 different types of pulmonary fibrosis (PF), the most common is the idiopathic pulmonary fbrosis (IPF), called idiopathic because it has no known cause. Another rare form is familial PF, for which several studies reported correlation with few genes. An important group of PF are due to other diseases, for example, autoimmune diseases such as rheumatoid arthritis, systemic sclerosis or Sjogren’s syndrome (Ruaro et al., 2022, Trombetta AC et al., 2017, Bernero Eet al., 2013). PF could correlate to viral infections (e.g. COVID-19), gastroesophageal reflux disease (GERD) (Baratella E et al, 2021, Ruaro et al., 2018), and the exposure to various materials (including naturally occurring such as bird or animal droppings, and occupational such as asbestos or silica). Furthermore, smoking, radiation treatments, and certain drugs can increase risk of developing PF

Pulmonary fibrosis: one manifestation, various diseases

This research topic collection entitled “Pulmonary Fibrosis: one manifestation, various diseases”, involving authors from different countries, confirms that this disease is a hot topic (Confalonieri P et al.,2022, Orlandi M et al., 2022). There are over 200 different types of pulmonary fibrosis (PF), the most common is the idiopathic pulmonary fbrosis (IPF), called idiopathic because it has no known cause. Another rare form is familial PF, for which several studies reported correlation with few genes. An important group of PF are due to other diseases, for example, autoimmune diseases such as rheumatoid arthritis, systemic sclerosis or Sjogren’s syndrome (Ruaro et al., 2022, Trombetta AC et al., 2017, Bernero Eet al., 2013). PF could correlate to viral infections (e.g. COVID-19), gastroesophageal reflux disease (GERD) (Baratella E et al, 2021, Ruaro et al., 2018), and the exposure to various materials (including naturally occurring such as bird or animal droppings, and occupational such as asbestos or silica). Furthermore, smoking, radiation treatments, and certain drugs can increase risk of developing PF. In the first article (Saketkoo et al.) of the collection, the authors evaluate the use of International Classification of Functioning, Disability, and Health (ICF) approved by World Health Organization (WHO) in patients affected by interstitial lung diseases (ILD)

The Complex Behaviour of s-Process Element Abundances at Young Ages

Open clusters appear as simple objects in many respects, with a high degree of homogeneity in their (initial) chemical composition, and the typical solar-scaled abundance pattern that they exhibit for the majority of the chemical species. The striking singularity is represented by heavy elements produced from the slow process of the neutron-capture reactions. In particular, young open clusters (ages less than a few hundred Myr) give rise to the so-called barium puzzle: that is an extreme enhancement in their [Be/Fe] ratios, up to a factor of four of the solar value, which is not followed by other nearby s-process elements (e.g., lanthanum and cerium). The definite explanation for such a peculiar trend is still wanting, as many different solutions have been envisaged. We review the status of this field and present our new results on young open clusters and the pre-main sequence star RZ Piscium

Editorial: Obstructive sleep apnea syndrome (OSAS). What's new?

This Research Topic entitled “Obstructive sleep apnea syndrome (OSAS). What's new?”, involving authors from different specializations and numerous countries, confirms that OSAS is a hot topic. OSA syndrome is an airway obstruction (i.e. complete or partial) with numerous etiologies (1–4). Different papers have demonstrated that the prevalence of OSAS is 2–4% in men and 1–2% in women of average age. The reference tools for OSAS diagnosis are clinical polysomnography or nocturnal portable multi-channel monitoring. Frequently, continuous positive airway pressure (CPAP) therapy is the first treatment for a patient (5, 6). Long-term CPAP treatment may present limited compliance, and there is no unanimous opinion on other alternative treatments for OSAS in literature on the subject. This special issue discusses several of these “unmet needs”

Emergency Laser Treatment of a Tracheobronchial Carcinoid during ECMO

Early diagnosis of endobronchial carcinoids is challenging, as they often mimic other common acute respiratory conditions at first presentation. Increasing consensus favours surgical resection over endoscopic management of bronchial carcinoids whenever possible. ECMO has been reported to be an effective supportive strategy in many cases of elective and urgent surgical or endoscopic airway procedures. However, it has never been described as a supportive technique for the emergency endoscopic management of an endobronchial carcinoid. Herein we report the case of a 17 year-old girl presenting with spontaneous pneumomediastinum and an almost complete endotracheal obstruction at the level of the main carina, due to a typical carcinoid that was treated successfully by endoscopic laser disruption under veno-venous extracorporeal circulation in an emergency scenario

The Complex Behaviour of s-Process Element Abundances at Young Ages

Open clusters appear as simple objects in many respects, with a high degree of homogeneity in their (initial) chemical composition, and the typical solar-scaled abundance pattern that they exhibit for the majority of the chemical species. The striking singularity is represented by heavy elements produced from the slow process of the neutron-capture reactions. In particular, young open clusters (ages less than a few hundred Myr) give rise to the so-called barium puzzle: that is an extreme enhancement in their [Be/Fe] ratios, up to a factor of four of the solar value, which is not followed by other nearby s-process elements (e.g., lanthanum and cerium). The definite explanation for such a peculiar trend is still wanting, as many different solutions have been envisaged. We review the status of this field and present our new results on young open clusters and the pre-main sequence star RZ Piscium

Chronic Thromboembolic Pulmonary Hypertension: An Observational Study

Background and Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) has a high mortality. The treatment of CTEPH could be balloon pulmonary angioplasty (BPA), medical (MT) or pulmonary endarterectomy (PEA). This study aims to assess the clinical characteristics of CTEPH patients, surgically or medically treated, in a pulmonology referral center. Materials and Methods: A total of 124 patients with PH with suspected CTEPH (53 male subjects and 71 female subjects; mean age at diagnosis 67 ± 6) were asked to give informed consent and then were evaluated. The presence of CTEPH was ascertained by medical evaluations, radiology and laboratory tests. Results: After the evaluation of all clinical data, 65 patients met the inclusion criteria for CTEPH and they were therefore enrolled (22 males and 43 females; mean age at diagnosis was 69 ± 8). 26 CTEPH patients were treated with PEA, 32 with MT and 7 with BPA. There was a statistically significant age difference between the PEA and MT groups, at the time of diagnosis, the PEA patients were younger than the MT patients, whereas there was no statistically significant difference in other clinical characteristics (e.g., smoking habit, thrombophilia predisposition), as well as functional and hemodynamic parameters (e.g., 6-min walk test, right heart catheterization). During three years of follow-up, no patients in the PEA groups died; conversely, eleven patients in the MT group died during the same period (p < 0.05). Furthermore, a significant decrease in plasma BNP values and an increase in a meter at the six-minute walk test, 1 and 3 years after surgery, were observed in the PEA group (p < 0.05). Conclusions: This study seems to confirm that pulmonary endarterectomy (PEA) can provide an improvement in functional tests in CTEP