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More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease.

The aim of this study is to estimate the normal cross-sectional area and diameter of the stellate ganglion (SG) by ultrasound (US) in healthy adults. The study sample included 80 stellate ganglia in 40 participants (15 males, 25 females), mean age 38 years, mean height 162.5 cm, mean weight 67.8 kg, mean body mass index 25.4 kg/m2. Two radiologists separately obtained US images of the bilateral SG. Each participant was scanned 3 times bilaterally to assess for intra-observer reliability. The mean diameter of the SG was 1 mm (range: 0.1-2). The mean CSA of the bilateral SG was 1.3 mm2 (range: 0.6-3.9). The SG diameter positively correlated with age. Our study demonstrates the ability of US to image the SG and estimate its normal diameter and CSA. Knowledge of how to identify and measure the SG during ultrasound-guided procedures would be expected to decrease the risk of associated complications and help establish normal reference values., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, and subverts cell senescence, resulting in unrestricted cell proliferation. HIV structural proteins are present in a soluble form in the lymphoid tissues and blood of infected individuals, even without active viral replication. The HIV matrix protein p17, the envelope glycoprotein gp120, the transenvelope protein gp41, and the capsid protein p24 interact with immune cells and deregulate the biological activity of the immune system. The biological activity of HIV structural proteins is also demonstrated in endothelial cells and some tumor cell lines, confirming the ability of viral proteins to promote cell proliferation and cancer progression, even in the absence of active viral replication. This review corroborates the hypothesis that HIV structural proteins, by interacting with different cell types, contribute to creating a microenvironment that is favorable to the evolution of cancerous pathologies not classically related to AIDS.

Background: Percutaneous CT-guided cryoablation is an emerging technique for treating bone tumors. However, experience with using this procedure for osteoid osteomas in pediatric patients remains limited. Our study aims to assess its technical feasibility, clinical efficacy, and safety in children treated under conscious anesthesia., Methods: We conducted a retrospective study of consecutive pediatric patients who underwent CT-guided percutaneous cryoablation for osteoid osteomas at our institution between September 2017 and March 2021. All patients received conscious anesthesia. Data on peri-procedural VAS scores, post-procedural VAS scores, imaging findings, and nonsteroidal anti-inflammatory drug (NSAID) usage rates were collected for each patient. Technical success was defined as proper cryoprobe placement at the nidus center, while clinical success referred to pain relief without NSAID use. Intra- and post-operative complications were also evaluated., Results: Nine patients underwent CT-guided percutaneous cryoablation for osteoid osteomas under conscious sedation, with a 100% overall success rate with low peri-procedural and median VAS scores ( p < 0.01). No complications were observed during or after the procedure., Conclusions: CT-guided percutaneous cryoablation of pediatric osteoid osteomas is an effective and safe minimally invasive procedure feasible under conscious anesthesia, holding promise as a valuable treatment option.

The aim of this study is to utilize ultrasound to evaluate the normal cross-sectional area (CSA) of the phrenic nerve (PN), at the level of the anterior scalene muscle. The study included 62 PNs in 31 healthy subjects (13 men, 18 women); mean age, 36.6 years; mean height, 161.1 cm; mean weight, 69.6 kg; and mean body mass index 25.8 kg/m2. High-resolution ultrasound images of the bilateral PNs were obtained by a radiologist with 15 years of experience in neuromusculoskeletal ultrasound. Three separate CSA measurements for the bilateral PNs bilaterally were obtained. Images were also reviewed by an experienced neurologist to evaluate for inter-rater variability. The mean CSA of the right PN was 0.54 mm2 ± 0.16. The mean CSA of the left PN was 0.53 mm2 ± 0.18. We believe that the reference values for the normal CSA of the PNs obtained in our study could help in the sonographic evaluation of PN enlargement, as it relates to the diagnosis of various diseases affecting the PN. Furthermore, knowledge of its location and size, at the level of the scalene muscle, could help prevent PN-related complications during interventional procedures in that area. Additionally, for each participant, demographic information of age and gender as well as body mass index, weight, and height were documented., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

(1) Background: to retrospectively evaluate safety and efficacy of combined microwave ablation (MWA) and bilateral expandable titanium SpineJack (SJ) implants followed by vertebroplasty (VP) for the treatment of painful thoracolumbar pathological vertebral compression fracture. (2) Methods: from July 2017 to October 2022, twenty-eight patients (13 women and 15 men; mean age 68 ± 11 years) with a history of primary neoplasm and thirty-six painful vertebral metastases with vertebral compression fracture underwent combined MWA and bilateral expandable titanium SpineJack implants with vertebroplasty. We analyzed safety through complications rate, and efficacy through vertebral height restoration and pain decrease, evaluated using a visual analogue scale (VAS), and Functional Mobility Scale (FMS), and local tumor control. Contrast-enhanced CT scans were performed at 1, 3, and 6 months and a contrast-enhanced spine MRI at 6 months after the procedure. (3) Results: Technical success rate was 100%. No procedure-related major complications or death occurred. Vertebral height restoration was observed in 22 levels (58%), with a mean anterior height restoration of 2.6 mm ± 0.6 and a mean middle height restoration of 4.4 mm ± 0.6 ( p < 0.001). Mean VAS score of pain evaluation on the day before treatment was 6.3 ± 1.5 (range 4-9). At the 6-month evaluation, the median VAS score for pain was 0.4 ± 0.6 (range 0-2) with a mean reduction of 93.65% (6.8 ± 0.7 vs. 0.4 ± 0.6; p < 0.000) compared with baseline evaluation. Contrast-enhanced CT scans were performed at 1, 3, and 6 months and a contrast-enhanced spine MRI was performed at 6 months after the procedure, showing no local recurrence, implant displacement, or new fractures in the treated site. (4) Conclusions: combined microwave ablation and bilateral expandable titanium SpineJack implants with vertebroplasty is a safe and effective procedure for the treatment of pathological compressive vertebral fractures. The vertebral stabilization achieved early and persistent pain relief, increasing patient mobility, improving recovery of walking capacity, and providing local tumor control.

Objective: To retrospectively evaluate the feasibility and effectiveness of vertebroplasty using Spinejack implantation for the treatment and stabilization of painful vertebral compression fractures, in patients diagnosed with Multiple Myeloma (MM), to allow both an effective pain reduction and a global structural spine stabilization., Materials and Methods: From July 2017 and May 2022 thirty-nine patients diagnosed MM, with forty-nine vertebral compression fractures underwent percutaneous Vertebroplasty using Spinejack Implants. We analyzed the feasibility and complications of the procedure, the decrease in pain using visual analogue scale (VAS) and Functional Mobility Scale (FMS)., Results: The technical success rate was 100%. No procedure-related major complications or death occurred. In the 6-month follow-up, the mean VAS score decreased from 5.4 ± 1.0 to 0.2 ± 0.5 with a mean reduction of 96.3%. FMS decreased from 2.3 ± 0.5 vs. 1.2 ± 0.4 with a mean reduction of -47.8%. There were no major complications related to incorrect positioning of the Expandable Titanium SpineJack Implants. In five patients, a cement leak was observed with no associated clinical manifestations. The average length of hospital stay was 6-8 Hours6.6 ± 1.2 h. No new bone fractures or local disease recurrence occurred during a median contrast-enhanced CT follow-up of 6 months., Conclusions: Our results suggest that vertebroplasty, using Spinejack implantation for the treatment and stabilization of painful vertebral compression fractures, secondary to Multiple Myeloma is a safe and effective procedure with long - term pain relief and restoration of vertebral height., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Pusceddu, Faiella, Derudas, Ballicu, Melis, Zedda, Marsico.)

(1) Background: Cement distribution after radiofrequency ablation of spinal metastases can be unpredictable due to various tumor factors, and vertebral augmentation requires advanced devices to prevent cement leakage and achieve satisfactory filling. The purpose of this study is to evaluate the safety and efficacy of a platform of steerable technologies with an articulating radiofrequency ablation (RFA) probe and targeted cavity creation before vertebral augmentation in the treatment of painful spinal metastases. (2) Methods: Sixteen patients (mean age, 67 years) underwent RFA in conjunction with vertebral augmentation after the creation of a targeted balloon cavity for metastatic spinal disease and were followed up to 6 months. Pain and functional mobility were assessed before treatment and postoperatively using the Visual Analogue Score (VAS) and Functional Mobility Scale (FMS). Complications, predictability of cement distribution, anatomical restoration, and local recurrence were collected. Technical success was defined as successful intraoperative ablation and predictable cement distribution after cavity creation without major complications. (3) Results: Sixteen patients with 21 lesions were treated for tumors involving the thoracolumbar spine. All treatments were technically successful and were followed by targeted cavity creation and vertebral augmentation. A statistically significant reduction in median VAS score was observed before treatment and 1 week after RFA treatment ( p < 0.001). A total of six of the seven patients who reported limited painful ambulation before treatment reported normal ambulation 1 month after treatment, while the remaining patient reported no improvement. Patients who reported wheelchair use before treatment improved to normal ambulation (four/eight) or limited painful ambulation (four/eight). The improvement in mobility before and after treatment was statistically significant ( p = 0.002). Technical success was achieved in all the combined procedures. (4) Conclusions: The combined treatment of RFA and vertebral augmentation with a steerable platform that allows the creation of a targeted cavity prior to cement injection proved to be a safe and effective procedure in our patient sample, resulting in improved quality of life as assessed by the Visual Analogue Score (VAS) and Functional Mobility Scale (FMS).

Background: Breast cancer is the second leading cause of death among women after lung cancer. Despite the improvement in prevention and in therapy, breast cancer still remains a threat, both for pre- and postmenopausal women, due to the development of drug resistance. To counteract that, novel agents regulating gene expression have been studied in both hematologic and solid tumors. The Histone Deacetylase (HDAC) inhibitor Valproic Acid (VA), used for epilepsy and other neuropsychiatric diseases, has been demonstrated a strong antitumoral and cytostatic activity. In this study, we tested the effects of Valproic Acid on the signaling pathways involved in breast cancer cells viability, apoptosis and in Reactive Oxygen Species (ROS) production using ER-α positive MCF-7 and triple negative MDA-MB-231 cells., Methods: Cell proliferation assay was performed by MTT Cell cycle, ROS levels and apoptosis were analyzed by flow cytometry, protein levels were detected by Western Blotting., Results: Cell treatment with Valproic Acid reduced cell proliferation and induced G0/G1 cell cycle arrest in MCF-7 and G2/M block in MDA-MB-231 cells. In addition, in both cells the drug enhanced the generation of ROS by the mitochondria. In MCF-7 treated cells, it has been observed a reduction in mitochondrial membrane potential, a down regulation of the anti-apoptotic marker Bcl-2 and an increase of Bax and Bad, leading to release of cytochrome C and PARP cleavage. Less consistent effects are recorded in MDA-MB-231 cells, in which the greater production of ROS, compared to MCF-7cells, involves an inflammatory response (activation of p-STAT3, increased levels of COX2)., Conclusions: Our results have demonstrated that in MCF-7 cells the Valproic Acid is a suitable drug to arrest cell growth, to address apoptosis and mitochondrial perturbations, all factors that are important in determining cell fate and health. In a triple negative MDA-MB 231 cells, valproate directs the cells towards the inflammatory response with a sustained expression of antioxidant enzymes. Overall, the not always unequivocal data between the two cellular phenotypes indicate that further studies are needed to better define the use of the drug, also in combination with other chemotherapy, in the treatment of breast tumors., (© 2023. The Author(s).)

(1) Background: The aim of this study was to retrospectively evaluate the safety and efficacy of a combined CT-guided percutaneous microwave ablation (MWA) and pedicle screw fixation followed by vertebroplasty (MASFVA) for the treatment and stabilization of painful vertebral metastases with vertebral pedicle involvement. (2) Methods: from January 2013 to January 2017 11 patients with 16 vertebral metastatic lesions (7 men and 5 women; mean age, 65 ± 11 years) with vertebral metastases underwent CT-guided microwave ablation and screw fixation followed by vertebroplasty (MASFVA). Technical success, complication rate, pain evaluation using a visual analogue scale (VAS), Oswestry Disability Index (ODI) and local tumor control were examined. (3) Results: Technical success rate was 100%. No procedure-related major complications occurred. VAS score decreased from 6.8 ± 0.7 to 0.6 ± 0.6. ODI score decreased from 3.1 ± 0.7 to 1.2 ± 0.4. All patients could walk independently without neurological complication after one week from the procedure. No new bone fractures or local disease recurrence occurred during a median follow-up of 12 months. (4) Conclusions: Our results suggest that MWA and percutaneous pedicle screw fixation followed by vertebroplasty for the treatment of painful vertebral metastases is a safe and effective procedure for painful vertebral metastases with vertebral pedicle involvement, allowing pain relief and local tumor control.

Background: Radiofrequency ablation (RFA) and cementoplasty, individually and in concert, has been adopted as palliative interventional strategies to reduce pain caused by bone metastases and prevent skeletal related events. We aim to evaluate the feasibility and safety of a steerable RFA device with an articulating bipolar extensible electrode for the treatment of extraspinal bone metastases. Methods: All data were retrospectively reviewed. All the ablation procedures were performed using a steerable RFA device (STAR, Merit Medical Systems, Inc., South Jordan, UT, USA). The pain was assessed with a VAS score before treatment and at 1-week and 3-, 6-, and 12-month follow-up. The Functional Mobility Scale (FMS) was recorded preoperatively and 1 month after the treatment through a four-point scale (4, bedridden; 3, use of wheelchair; 2, limited painful ambulation; 1, normal ambulation). Technical success was defined as successful intraoperative ablation and cementoplasty without major complications. Results: A statistically significant reduction of the median VAS score before treatment and 1 week after RFA and cementoplasty was observed (p < 0.001). A total of 6/7 patients who used a wheelchair reported normal ambulation 1 month after treatment. All patients with limited painful ambulation reported normal ambulation after the RFA and cementoplasty (p = 0.003). Technical success was achieved in all the combined procedures. Two cement leakages were reported. No local recurrences were observed after 1 year. Conclusions: The combined treatment of RFA with a steerable device and cementoplasty is a safe, feasible, and promising clinical option for the management of painful bone metastases, challenging for morphology and location, resulting in an improvement of the quality of life of patients.

Introduction: Psoriasis (PsO), a chronic inflammatory, multisystemic, and multifactorial disease can cause endothelial dysfunction, artery calcification, and atherosclerotic disease. A higher incidence of vascular occlusive events has been observed in psoriatic patients compared to healthy controls, and multiple studies confirm the association between moderate-severe PsO and atherosclerosis, coronary artery calcification, and higher cardiovascular risk., Objective: We sought to analyze atherosclerotic disease prevalence in epiaortic vessels of psoriatic and non-psoriatic patients to understand if PsO could represent an independent risk factor predisposing to atherosclerotic disease., Methods: We evaluated 47 psoriatic patients without cardiovascular risk factors with color Doppler ultrasound (CDUS). If atheromatous plaques were detected, a computed tomography angiography (CTA) was performed. We evaluated 47 non-psoriatic patients without cardiovascular risk factors with CDUS. Atherosclerosis prevalence in both groups were statistically analyzed. CDUS performance was compared to CTA., Results: In the psoriatic group (mean age 50.9 years), 6 had atheromatous plaques and 12 had an intima-media thickness (IMT) > 1 mm (overall prevalence of atherosclerotic disease: 38.2%). All plaques detected with CDUS were confirmed at CTA. In the control group (mean age 51.3 years), CDUS revealed atheromatous plaques in 4 patients and IMT > 1 mm in 4 ones (overall prevalence of 17%). The difference of atherosclerotic disease prevalence between the groups was statistically significant (P < 0.05)., Conclusion: Our results highlight that PsO could be considered a predisposing factor for atherosclerotic disease development in epiaortic vessels, as it causes an increased IMT, that is also considered an independent cardiovascular risk factor., Competing Interests: Competing interests: None., (©2022 Dattola et al.)

The tensor fascia lata is a muscular structure that forms part of the lateral portion of the pelvis and proximal thigh. Because conditions affecting this muscle have not been widely reported and are relatively unknown, hypertrophy and pseudo-hypertrophy of the tensor fascia lata, although relatively common imaging findings, often go undiagnosed; instead, radiologists perform the differential diagnosis with more complex and more dangerous conditions. This article aims to review the anatomic and functional characteristics of the tensor fascia lata, going into detail about the radiological description of this muscle and pathological conditions that can affect it, as well as reviewing the relevant literature., (Copyright © 2021 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: To describe imaging and laboratory findings of confirmed PE diagnosed in COVID-19 patients and to evaluate the characteristics of COVID-19 patients with clinical PE suspicion. Characteristics of patients with COVID-19 and PE suspicion who required admission to the intensive care unit (ICU) were also analysed., Methods: A retrospective study from March 18, 2020, until April 11, 2020. Inclusion criteria were patients with suspected PE and positive real-time reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2. Exclusion criteria were negative or inconclusive RT-PCR and other chest CT indications. CTPA features were evaluated and severity scores, presence, and localisation of PE were reported. D-dimer and IL-6 determinations, ICU admission, and previous antithrombotic treatment were registered., Results: Forty-seven PE suspicions with confirmed COVID-19 underwent CTPA. Sixteen patients were diagnosed with PE with a predominant segmental distribution. Statistically significant differences were found in the highest D-dimer determination in patients with PE and ICU admission regarding elevated IL-6 values., Conclusion: PE in COVID-19 patients in our series might predominantly affect segmental arteries and the right lung. Results suggest that the higher the D-dimer concentration, the greater the likelihood of PE. Both assumptions should be assessed in future studies with a larger sample size., Key Points: • On CT pulmonary angiography, pulmonary embolism in COVID-19 patients seems to be predominantly distributed in segmental arteries of the right lung, an assumption that needs to be approached in future research. • Only the highest intraindividual determination of d-dimer from admission to CT scan seems to differentiate patients with pulmonary embolism from patients with a negative CTPA. However, interindividual variability calls for future studies to establish cut-off values in COVID-19 patients. • Further studies with larger sample sizes are needed to determine whether the presence of PE could increase the risk of intensive care unit (ICU) admission in COVID-19 patients.

Avian reovirus p17 (ARV p17) is a non-structural protein known to activate autophagy, interfere with gene transcription and induce a significant tumor cell growth inhibition in vitro and in vivo. In this study, we show that ARV p17 is capable of exerting potent antiangiogenic properties. The viral protein significantly inhibited the physiological angiogenesis of human endothelial cells (ECs) by affecting migration, capillary-like structure and new vessel formation. ARV p17 was not only able to suppress the EC physiological angiogenesis but also rendered ECs insensitive to two different potent proangiogenic inducers, such as VEGF-A and FGF-2 in the three-dimensional (3D) Matrigel and spheroid assay. ARV p17 was found to exert its antiangiogenic activity by upregulating transcription and release of the well-known tumor suppressor molecule dipeptidyl peptidase 4 (DPP4). The ability of ARV p17 to impact on angiogenesis is completely new and highlights the "two compartments" activity of the viral protein that is expected to hamper the tumor parenchymal/stromal crosstalk. The complex antitumor activities of ARV p17 open the way to a new promising field of research aimed to develop new therapeutic approaches for treating tumor and cancer metastasis.

Psoriasis (PsO) is a chronic skin disease. This study aims to evaluate clinical and subclinical response to calcipotriol+betamethasone foam, in patients with PsO, comparing, for the first time, data from microvascular ultrasound (MicroV) and shear wave elastography (SWE) with Psoriasis Area and Severity Index (PASI)., Methods: Between November 2018 and April 2019 in Tor Vergata Hospital (Roma, Italy), we enrolled 26 patients with PsO who were ageds 20-75 years, with PASI score ≥4, candidated for calcipotriol+betamethasone foam treatment. They underwent MicroV and SWE evaluation at baseline (T 0 ) and after 4 weeks of treatment (T 4 ). Clinical follow-up was carried on at T 4 , T 8 and T 12 . Student's t-test (p values<0.05 statistically significant) was used to compare SWE and PASI values., Results: At T 0 , SWE stiffness values of target plaques (61.5% on elbows, 23% knees, 7.7% sacrum,7.7% legs) were significantly higher than values under healthy skin. At T 4 , all patients showed a significant reduction of PASI; MicroV showed reduction in vascularisation of responsive plaques in 85% of cases, only in 15%, the vascularisation degree remained stable; and SWE values of target plaques were significantly lower compared with T 0 . Only in 7.7%, there was a relapse at T 12 ., Conclusions: Calcipotriol+betamethasone foam is a very effective topical treatment in a short-medium term follow-up in patients with PsO. MicroV and SWE evaluate response to treatment (in term of plaque vascularisation and stiffness), so they could represent promising early indicators of therapeutic response and help the physician to establish a better clinical-therapeutic management of patients with PsO., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Human Metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, per se , could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment.

This study consists of an elastosonography evaluation of both eyes of 40 glaucomatous patients and 40 healthy subjects. We used shear wave elastography with a one-dimensional-array probe to capture two-dimensional images in order to study the optic nerve near the papilla, chorioretinal complex, lateral rectus muscle, and periorbital fat tissue. Furthermore, we used a two-dimensional array probe to capture three-dimensional images to study the optic nerve in toto with multilevel sampling. We obtained qualitative and quantitative data ("absolute" stiffness values). Then, we have investigated these tissue also measuring the "stiffness ratio" values. Statistically significant differences (p < 0.05), between glaucomatous patients and healthy patients, were noted in "absolute" stiffness values in the two-dimensional analysis at the emergence of the optic nerve and chorioretinal complex, and in the three-dimensional analysis at the emergence of the optic nerve (level I°). This result was supported by the statistically significant differences in the "stiffness ratio" values between the optic nerve and the adjacent adipose tissue, obtained both in two- and three-dimensional analyses. Data were subsequently compared with diagnostic tests currently used for glaucoma, which showed a sensitivity of 83% and specificity of 80% relative to those of elastosonography. We propose the use of elastosonography to verify the existence of pathological changes in the mechanical and elastic properties of peri-ocular structures and their variations as a complementary tool in the diagnosis of glaucoma and for follow-up during treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women., Competing Interests: The authors declare no conflict of interest.

Although the advent of combined antiretroviral therapy has substantially improved the survival of HIV-1-infected individuals, non-AIDS-related diseases are becoming increasingly prevalent in HIV-1-infected patients. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications. Alterations in coagulation biology in the context of HIV infection seem to be largely a consequence of a chronically inflammatory microenvironment leading to endothelial cell (EC) dysfunction. A possible direct role of HIV-1 proteins in sustaining EC dysfunction has been postulated but not yet investigated. The HIV-1 matrix protein p17 (p17) is secreted from HIV-1-infected cells and is known to sustain inflammatory processes by activating ECs. The aim of this study was to investigate the possibility that p17-driven stimulation of human ECs is associated with increased production of critical coagulation factors. Here we show the involvement of autophagy in the p17-induced accumulation and secretion of von Willebrand factor (vWF) by ECs. In vivo experiments confirmed the capability of p17 to exert a potent pro-coagulant activity soon after its intravenous administration.

The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5's role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor-stroma interactions in both 'in vitro' and 'in vivo' models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients., Competing Interests: The authors declare no conflicts of interest.

Background: Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis., Methods: Cell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT-PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA., Results: Here we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E 2 -induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter., Conclusions: Taken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.

In recent years immunomodulators have gained a strong interest and represent nowadays an active expanding area of research for the control of microbial diseases and for their therapeutic potential in preventing, treating and reducing the morbidity and mortality of different diseases. Pidotimod (3-L-pyroglutamyl-L-thiaziolidine-4carboxylic acid, PDT) is a synthetic dipeptide, which possesses immunomodulatory properties and exerts a well-defined pharmacological activity against infections, but its real mechanism of action is still undefined. Here, we show that PDT is capable of activating tyrosine phosphorylation-based cell signaling in human primary monocytes and triggering rapid adhesion and chemotaxis. PDT-induced monocyte migration requires the activation of the PI3K/Akt signaling pathway and chemokine receptor CXCR3. Indeed, a mAb to CXCR3 and a specific receptor inhibitor suppressed significantly PDT-dependent chemotaxis, and CXCR3-silenced primary monocytes lost responsiveness to PDT chemoattraction. Moreover, our results highlighted that the PDT-induced migratory activity is sustained by the CXCR3A isoform, since CXCR3-transfected L1.2 cells acquired responsiveness to PDT stimulation. Finally, we show that PDT, as CXCR3 ligands, is also able to direct the migration of IL-2 activated T cells, which express the highest levels of CXCR3 among CXCR3-expressing cells. In conclusion, our study defines a chemokine-like activity for PDT through CXCR3A and points on the possible role that this synthetic dipeptide may play in leukocyte trafficking and function. Since recent studies have highlighted diverse therapeutic roles for molecules which activates CXCR3, our findings call for an exploration of using this dipeptide in different pathological processes.

Iodine, a micronutrient that plays a pivotal role in thyroid hormone synthesis, is essential for proper health at all life stages. Indeed, an insufficient iodine intake may determine a thyroid dysfunction also with goiter, or it may be associated to clinical features such as stunted growth and mental retardation, referred as iodine deficiency disorders (IDDs). Iodine deficiency still remains an important public health problem in many countries, including Italy. The effective strategy for the prevention and control of IDDs is universal salt iodization, which was implemented in Italy in 2005 as a nationwide program adopted after the approval of an Italian law. Despite an improvement in the iodine intake, many regions in Italy are still characterized by mild iodine deficiency. In this review, we provide an overview of the historical evolution of the iodine status in the Calabria region, located in the South of Italy, during the past three decades. In particular, we have retraced an itinerary from the first epidemiological surveys at the end of the 1980s to the establishment of the Regional Observatory of Endemic Goiter and Iodine Prophylaxis, which represents an efficient model for the surveillance of IDDs and monitoring the efficacy of iodine prophylaxis., Competing Interests: The authors declare no conflict of interest.

Progesterone-Receptor (PR) positivity is related with an enhanced response to breast cancer therapy, conversely cyclin D1 (CD1) is a retained marker of poor outcome. Herein, we demonstrate that hydroxyprogesterone (OHPg) through progesterone receptor B (PR-B) reduces breast cancer cell aggressiveness, by targeting the cytoplasmic CD1. Specifically, OHPg diminishes CD1 expression by a transcriptional regulation due to the recruitment of PR-B at a canonical half-PRE site of the CD1 promoter, together with HDAC1, determining a chromatin conformation less prone for gene transcription. CD1, together with its kinase partner Cdk4, regulates cell migration and metastasis, through the association with key components of focal adhesion, such as Paxillin (Pxn). Kaplan-Meier analysis shows that low Pxn expression was associated with increased distant metastasis-free survival in luminal A PR+ breast carcinomas. Interestingly, OHPg treatment reduced Pxn content in T47-D and MCF-7 cells; besides, the interaction between endogenous cytoplasmic CD1/Cdk4 with Pxn was reduced. This was consistent with the reduction of p -Ser83Pxn levels, crucially causing the delay in cell migration and a concomitant inhibition of Rac1 activity and p -PAK. Collectively, these findings support the role of PR-B in breast epithelial cell integrity and reinforce the importance in targeting PR-B as a potential strategy to restrict breast tumor cell invasion and metastasis.

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. In spite of initial good response to chemotherapy, the prognosis of TNBC remains poor and no effective specific targeted therapy is readily available. Recently, we demonstrated the ability of U94, the latency gene of human herpes virus 6 (HHV-6), to interfere with proliferation and with crucial steps of the metastatic cascade by using MDA-MB 231 TNBC breast cancer cell line. U94 expression was also associated with a partial mesenchymal-to-epithelial transition (MET) of cells, which displayed a less aggressive phenotype. In this study, we show the ability of U94 to exert its anticancer activity on three different TNBC cell lines by inhibiting DNA damage repair genes, cell cycle and eventually leading to cell death following activation of the intrinsic apoptotic pathway. Interestingly, we found that U94 acted synergistically with DNA-damaging drugs. Overall, we provide evidence that U94 is able to combat tumor cells with different mechanisms, thus attesting for the great potential of this molecule as a multi-target drug in cancer therapy.

Background: HIV-1 matrix protein p17 variants (vp17s) detected in HIV-1-infected patients with non-Hodgkin's lymphoma (HIV-NHL) display, differently from the wild-type protein (refp17), B cell growth-promoting activity. Biophysical analysis revealed that vp17s are destabilized as compared to refp17, motivating us to explore structure-function relationships., Methods: We used: biophysical techniques (circular dichroism (CD), nuclear magnetic resonance (NMR) and thermal/GuHCL denaturation) to study protein conformation and stability; Surface plasmon resonance (SPR) to study interactions; Western blot to investigate signaling pathways; and Colony Formation and Soft Agar assays to study B cell proliferation and clonogenicity., Results: By forcing the formation of a disulfide bridge between Cys residues at positions 57 and 87 we obtained a destabilized p17 capable of promoting B cell proliferation. This finding prompted us to dissect refp17 to identify the functional epitope. A synthetic peptide (F1) spanning from amino acid (aa) 2 to 21 was found to activate Akt and promote B cell proliferation and clonogenicity. Three positively charged aa (Arg15, Lys18 and Arg20) proved critical for sustaining the proliferative activity of both F1 and HIV-NHL-derived vp17s. Lack of any interaction of F1 with the known refp17 receptors suggests an alternate one involved in cell proliferation., Conclusions: The molecular reasons for the proliferative activity of vp17s, compared to refp17, relies on the exposure of a functional epitope capable of activating Akt., General Significance: Our findings pave the way for identifying the receptor(s) responsible for B cell proliferation and offer new opportunities to identify novel treatment strategies in combating HIV-related NHL., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Human metapneumovirus (hMPV) has been identified as a major cause of lower respiratory tract infection in children. Epidemiological and molecular evidence has highlighted an association between severe childhood respiratory viral infection and chronic lung diseases, such as asthma and chronic obstructive pulmonary disease. Currently, animal models have demonstrated the ability of hMPV to persist in vivo suggesting a role of the virus in asthma development in children. However, mechanisms involved in hMPV persistence in the respiratory tract are not yet understood. In the present study we monitored hMPV infection in human alveolar epithelial A549 cells in order to understand if the virus is able to persist in these cells upon acute infection. Our data show that hMPV initially induces an apoptotic process in A549 cells through poly (ADP-ribose) polymerase 1 cleavage, caspase-3/7 activation and Wee1 activity. The hMPV-infected cells were then able to overcome the apoptotic pathway and cell cycle arrest in G2/M by expressing B-cell lymphoma 2 and to acquire a reservoir cell phenotype with constant production of infectious virus. These findings provide evidence of the ability of hMPV to persist in alveolar epithelial cells and help in understanding the mechanisms responsible for hMPV persistence in the human respiratory tract.

Novel biomaterials are of paramount importance for bone regrowth. In this study, we investigated human adipose stem cells (hASCs) for osteogenic, osteoconductivity, and osteoinductivity effects of an innovative collagen/hydroxylapatite hybrid scaffold. In hASCs that were grown on this scaffold, osteogenic genes were analyzed for their expression profiles, together with adhesion and extracellular matrix genes. In hASC integrins, basement membrane constituents and collagens were up-regulated, together with cell proliferation. In addition, expression of osteopontin and activated focal adhesion kinase was studied at the protein level. Our in vitro data indicate that hASCs, together with hybrid biomaterial, is an important model of study to investigate in vitro bone induction.-Mazzoni, E., D'Agostino, A., Manfrini, M., Maniero, S., Puozzo, A., Bassi, E., Marsico, S., Fortini, C., Trevisiol, L., Patergnani, S., Tognon, M. Human adipose stem cells induced to osteogenic differentiation by an innovative collagen/hydroxylapatite hybrid scaffold., (© FASEB.)

Background: The introduction of cART has changed the morbidity and mortality patterns affecting HIV-infected (HIV + ) individuals. The risk of breast cancer in HIV + patients has now approached the general population risk. However, breast cancer has a more aggressive clinical course and poorer outcome in HIV + patients than in general population, without correlation with the CD4 or virus particles count. These findings suggest a likely influence of HIV-1 proteins on breast cancer aggressiveness and progression. The HIV-1 matrix protein (p17) is expressed in different tissues and organs of successfully cART-treated patients and promotes migration of different cells. Variants of p17 (vp17s), characterized by mutations and amino acid insertions, differently from the prototype p17 (refp17), also promote B-cell proliferation and transformation., Methods: Wound-healing assay, matrigel-based invasion assay, and anchorage-independent proliferation assay were employed to compare the biological activity exerted by refp17 and three different vp17s on the triple-negative human breast cancer cell line MDA-MB 231. Intracellular signaling was investigated by western blot analysis., Results: Motility and invasiveness increased in cells treated with both refp17 and vp17s compared to untreated cells. The effects of the viral proteins were mediated by binding to the chemokine receptor CXCR2 and activation of the ERK1/2 signaling pathway. However, vp17s promoted MDA-MB 231 cell growth and proliferation in contrast to refp17-treated or not treated cells., Conclusions: In the context of the emerging role of the microenvironment in promoting and supporting cancer cell growth and metastatic spreading, here we provide the first evidence that exogenous p17 may play a crucial role in sustaining breast cancer cell migration and invasiveness, whereas some p17 variants may also be involved in cancer cell growth and proliferation.

Background: Psoriasis (PsO) is a multifactorial chronic and relapsing skin disease that affects about 125 million people in the world. Several studies have demonstrated the link between adipose tissue, inflammation, and PsO. The purpose of our study is to evaluate hypodermal adipose tissue inflammation underneath PsO plaques quantifying tissue elasticity with sonoelastography before and after treatment. The study was conducted at the Department of Dermatology of the University of "Rome Tor Vergata" and Department of Radiology of the University of "Rome Tor Vergata.", Methods: We enrolled 60 patients with plaque PsO and a PASI score of ≥5 divided in three groups of treatment: biologic drugs therapy (Group A), systemic therapy with DMARDS (Group B), and topic therapy (Group C). Each Patient underwent sonoelastography examination (TE: transient elastography) at baseline (T0) and after 1 month (T1) of treatment. The region of interest (ROI) 5 × 5 mm area and the strain ratio was obtained dividing muscular elasticity (referral tissue) by hypodermal elasticity., Results: The difference between T0 and T1 was referred as Δ strain. Sonoelastography is able to identify hypodermal adipose tissue involvement in plaque PsO and on the basis of our experience it could represent a valid method to assess early therapy response in patient with plaque PsO., Conclusions: This is the first report regarding the use of sonoelastography in psoriatic patients. Sonoelastography is easy to use, rapid, and is a portable technique that does not use ionizing radiation. The result showed the mean lesional strain ratio significantly higher than the nonlesional one at baseline examination. In the future, the role of ultrasound sonoelastography is likely to be complementary to conventional imaging techniques in providing an additional tool.

AIDS-related lymphomas (ARLs) are expected to increase in the future since combined antiretroviral therapy (cART) enhances the life expectancy of HIV-1-infected (HIV + ) patients but does not affect the occurrence of ARLs to the same extent as that of other tumors. Lymphangiogenesis is essential in supporting growth and metastatic spreading of ARLs. HIV-1 does not infect the neoplastic B cells, but HIV-1 proteins have been hypothesized to play a key role in sustaining a prolymphangiogenic microenvironment in lymphoid organs. The HIV-1 matrix protein p17 is detected in blood and accumulates in the germinal centers of lymph nodes of HIV + patients under successful cART. The viral protein displays potent lymphangiogenic activity in vitro and in vivo This is, at least in part, mediated by the secretion of the lymphangiogenic factor endothelin-1, suggesting that activation of a secretory pathway sustains the lymphangiogenic activity of p17. Here, we show that the p17 lymphangiogenic activity occurs on human lymph node-derived lymphatic endothelial cells (LN-LECs) under stress conditions only and relies entirely on activation of an autophagy-based pathway. In fact, induction of autophagy by p17 promotes lymphangiogenesis, whereas pharmacological and genetic inhibition of autophagy inhibits p17-triggered lymphangiogenesis. Similarly, the vasculogenic activity of p17 was totally inhibited in autophagy-incompetent mice. Our findings reveal a previously unrecognized role of autophagy in lymphangiogenesis and open the way to identify novel treatment strategies aimed at inhibiting aberrant tumor-driven lymphangiogenesis in HIV + patients. IMPORTANCE AIDS-related lymphomas (ARLs) are the most common malignancies in HIV-1-infected (HIV + ) patients after the introduction of combined antiretroviral therapy (cART). Lymphangiogenesis is of critical importance in sustaining growth and metastasis of ARLs. Indeed, enhanced lymphangiogenesis occurs in the lymph nodes of HIV + patients under successful cART. The HIV-1 matrix protein p17 is detected in blood and accumulates in the lymph node germinal centers even in the absence of virus replication. Several findings suggest a key role for p17 as a microenvironmental factor capable of promoting lymphangiogenesis. Here, we show that p17 promotes lymphangiogenesis of human lymph node-derived lymphatic endothelial cells (LN-LECs). The lymphangiogenic activity of p17 is sustained by an autophagy-based pathway that enables LN-LECs to release prolymphangiogenic factors into the extracellular microenvironment. Our findings indicate that specific targeting of autophagy may provide an important new tool for treating ARLs., (Copyright © 2017 American Society for Microbiology.)

Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.

I prophylaxis is the most effective strategy to eradicate I deficiency disorders, but it has been shown to affect the thyroid disease pattern. In this study, we assessed the frequency of thyroid disorders in an adult population living in two areas of southern Italy after implementing I prophylaxis. To this aim, a cross-sectional, population-based study including 489 subjects from an I-deficient rural and an I-sufficient urban area of southern Italy was conducted. Thyroid ultrasound was performed on all participants, and urine and blood samples were collected from each subject. The levels of thyroid-stimulating hormone (TSH), thyroglobulin (TgAb) and thyroperoxidase antibodies (TPOAb), urinary I excretion (UIE), and thyroid volume and echogenicity were evaluated. We found that the median UIE was higher in the urban than in the rural area (P=0·004), whereas the prevalence of subjects affected by goitre was higher in the rural compared with the urban area (P=0·003). Positive TgAb rather than TPOAb were more frequent in subjects from the urban area compared with the rural area (P=0·009). The hypoechoic pattern at thyroid ultrasound (HT-US) was similar between the two areas, but TgAb were significantly higher (P=0·01) in HT-US subjects from the urban area. The frequency of elevated TSH did not differ between the two screened populations, and no changes were found for TgAb positivity in subjects with high TSH in the urban compared with the rural area. Our findings support that the small risks of I supplementation are far outweighed by the substantial benefits of correcting I deficiency, although continued monitoring of populations is necessary.

Local estrogen production from aromatase-mediated conversion of androgens is an important mechanism of autocrine growth stimulation in hormone-dependent breast cancers. The control mechanism of aromatase enzymatic activity in recent years has been demonstrated to be more complex than previously identified. Indeed, it is well known that aromatase expression is regulated at the transcriptional level through the alternative use of tissue-specific promoters, whereas it has become clear that the activity of this enzyme is also controlled by post-transcriptional modifications, such as phosphorylation processes. This paper presents a selective review of the novel findings in this area showing phosphorylation/dephosphorylation of aromatase as a switch to rapidly modulate its enzymatic activity. Particularly, we describe studies conducted in our laboratories, focusing on the role of estrogens in modulating aromatase activity in estrogen-dependent breast cancer cells. Two separate mechanisms are described. First, 17β-estradiol (E2), through c-Src kinase, is able to enhance tyrosine phosphorylation levels of aromatase protein and increases its enzymatic activity and estrogen biosynthesis. Secondly, E2, through the activation of PI3K/Akt pathway, impairs the ability of the tyrosine phosphatase PTP1B to dephosphorylate aromatase, resulting in a consequent enhanced phosphorylation and activity of the aromatase protein itself. These new controls of aromatase function provide insights into the mechanisms through which local estrogen production can be altered in breast cancer tissues. They also offer a vast array of possibilities for identifying different cell signalings that should be targeted in novel therapeutic strategies for breast cancer treatment.

The HIV-1 matrix protein p17 (p17) plays a crucial role in the virus life cycle. It is released in the extracellular space from HIV-1-infected cells and accumulates in the tissues of patients, even in those successfully treated with highly active antiretroviral therapy. Extracellular p17 deregulates the biological functions of many different cells that are directly or indirectly implicated in AIDS pathogenesis. All p17 actions depend on interaction between its functional epitope (AT20), located at the protein N-terminal region, and different receptors expressed on target cells. This finding corroborates the importance of impeding p17/p17 receptors interaction as a contribution to block AIDS. In this article we review the interaction of p17 with heparan sulfate proteoglycans (HSPGs) and with the chemokine (C-X-C motif) receptor 1 (CXCR1) and 2 (CXCR2). We provide details on how p17 interacts with its receptors and how these interactions are central to the p17 biological activities. Moreover, we highlight the existence of a p17 variant, named S75X, which displays opposite effects on B-cell proliferation as compared to p17. A two-site model for p17 interaction with G-coupled receptors provides a possible explanation on how mutations naturally occurring within the primary amino acid structure can lead S75X to activate the Akt signaling pathway and to promote B-cell growth and transformation. Identification of p17 interaction with HSPGs, CXCR1 and CXCR2 as a fundamental event in supporting its activity could help to find new treatment approaches aimed at blocking all p17/p17 receptors interactions and, consequently, p17 detrimental activities.

Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.