CIGB-258, a peptide derived from human heat-shock protein 60, decreases hyperinflammation in COVID-19 patients.

Hyperinflammation distinguishes COVID-19 patients who develop a slight disease or none, from those progressing to severe and critical conditions. CIGB-258 is a therapeutic option for the latter group of patients. This drug is an altered peptide ligand (APL) derived from the cellular stress protein 60 (HSP60). In preclinical models, this peptide developed anti-inflammatory effects and increased regulatory T cell (Treg) activity. Results from a phase I clinical trial with rheumatoid arthritis (RA) patients indicated that CIGB-258 was safe and reduced inflammation. The aim of this study was to examine specific biomarkers associated with hyperinflammation, some cytokines linked to the cytokine storm granzyme B and perforin in a cohort of COVID-19 patients treated with this peptide. All critically ill patients were under invasive mechanical ventilation and received the intravenous administration of 1 or 2 mg of CIGB-258 every 12 h. Seriously ill patients were treated with oxygen therapy receiving 1 mg of CIGB-258 every 12 h and all patients recovered from their severe condition. Biomarker levels associated with hyperinflammation, such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF-α), granzyme B, and perforin, significantly decreased during treatment. Furthermore, we studied the ability of CIGB-258 to induce Tregs in COVID-19 patients and found that Tregs were induced in all patients studied. Altogether, these results support the therapeutic potential of CIGB-258 for diseases associated with hyperinflammation. Clinical trial registry: RPCEC00000313.

Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review.

Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life-threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.

Focusing on Diabetic Ulcers.

Foot ulcers associated with Diabetes mellitus require immediate attention due to risk of amputation if left untreated. Herein we focus on the mitigating risk factors and physiopathology of the diabetic foot, recounting our own surgical approach and revascularization procedures.

Superhydrophobic lab-on-chip measures secretome protonation state and provides a personalized risk assessment of sporadic tumour.

Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at-risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual's diagnosis and/or help clarify risk in healthy populations.

Innate immunity in cutaneous melanoma.

The skin immune system is composed of a vast network of immune cells, including lymphocytes, macrophages, neutrophils, dendritic cells and Langerhans cells, which not only are involved in inflammatory responses but also contribute to homeostatic function and may participate in the various steps of carcinogenesis. Many studies support the notion that innate immunity has a key role in the development, growth and prognosis of cutaneous malignant melanoma (MM), through the release of pro- and/or anti-inflammatory cytokines and tumour growth factors. The tumour environment in a major subset of cutaneous MM shows evidence of a T cell-infiltrated phenotype, but there is less known about the presence and the phenotype of other immune system cells. Response to immunotherapy is largely correlated with the presence of T cells in the tumour microenvironment, while the regulation exerted by stromal components such as macrophages and mast cells has been less investigated. In the current report, we review the recent literature, focusing our attention on the role of macrophages, dendritic cells, mast cells and natural killer cells in orchestrating MM progression, to better understand tumour immunobiology. The identification of new therapeutic targets and the application of approaches aimed at modulating crosstalk between immune and tumour cells, could have a crucial impact on immunotherapy and result in better clinical outcome. We hope this review will be helpful in cutaneous MM research.

Non-invasive real-time biopsy of intracranial lesions using short time expanded circulating tumor cells on glass slide: report of two cases.

BACKGROUND: Circulating Tumor Cells (CTCs) are promising biomarkers for monitoring solid cancer and were used to monitor brain tumors. Here we report two cases in which, for the first time, CTCs were used in cytological diagnostic evaluation to discriminate a space-occupying lesion of the brain. CASE PRESENTATION: Two cases of focal intracranial lesions, unclassified for diagnosis, untreated and apparently symptomatic, were examined after high-contrast resolution Magnetic Resonance Imaging and/or Computed Tomography scans. CTCs were seeded on chamber slides and short-time expanded under the optimized conditions as we previously reported. The first case was a focal lesion localized in the parietal-occipital area in a 67-year-old woman. The second case was a 31-year-old man with an expansive intracerebral lesion localized in the left peri-trigonal area. Both patients underwent excisional biopsy. Histopathological evaluation of the biopsy confirmed the previous cytological diagnoses, and the analysis of the clinical outcomes retrospectively validated both diagnoses. CONCLUSIONS: The cases here reported illustrate the potential for using expanded CTCs as non-invasive, real-time biopsy. Moreover, non-invasive real-time biopsy can represent an alternative diagnostic tool to be used when a functional area of the brain is at risk of injury from excisional biopsy procedures.

Protective T Cell and Antibody Immune Responses against Hepatitis C Virus Achieved Using a Biopolyester-Bead-Based Vaccine Delivery System.

Hepatitis C virus (HCV) infection is a major worldwide problem. Chronic hepatitis C is recognized as one of the major causes of cirrhosis, hepatocellular carcinoma, and liver failure. Although new, directly acting antiviral therapies are suggested to overcome the low efficacy and adverse effects observed for the current standard of treatment, an effective vaccine would be the only way to certainly eradicate HCV infection. Recently, polyhydroxybutyrate beads produced by engineered Escherichia coli showed efficacy as a vaccine delivery system. Here, an endotoxin-free E. coli strain (ClearColi) was engineered to produce polyhydroxybutyrate beads displaying the core antigen on their surface (Beads-Core) and their immunogenicity was evaluated in BALB/c mice. Immunization with Beads-Core induced gamma interferon (IFN-γ) secretion and a functional T cell immune response against the HCV Core protein. With the aim to target broad T and B cell determinants described for HCV, Beads-Core mixed with HCV E1, E2, and NS3 recombinant proteins was also evaluated in BALB/c mice. Remarkably, only three immunization with Beads-Core+CoE1E2NS3/Alum (a mixture of 0.1 µg Co.120, 16.7 µg E1.340, 16.7 µg E2.680, and 10 µg NS3 adjuvanted in aluminum hydroxide [Alum]) induced a potent antibody response against E1 and E2 and a broad IFN-γ secretion and T cell response against Core and all coadministered antigens. This immunological response mediated protective immunity to viremia as assessed in a viral surrogate challenge model. Overall, it was shown that engineered biopolyester beads displaying foreign antigens are immunogenic and might present a particulate delivery system suitable for vaccination against HCV.

Abdominal aortic aneurysm.

Endovascular repair of abdominal aortic aneurysm has become a milestone in the treatment of patients with abdominal aortic aneurysm.Technological improvement allows treatment in more and more complex cases. This review summarizes all grafts available in the market. At the best of our knowledge a complete review of most important trial on this topic are provided and at least technical tips and tricks for standard cases are recapitulated.

The risk for type B aortic dissection in Marfan syndrome.

Marfan syndrome is the most prevalent connective tissue disorder, with an autosomal dominant inheritance with variable penetrance. This paper aims to summarize epidemiology and treatment for type B dissection in Marfan patients.

Physician-initiated prospective Italian Registry of carotid stenting with the C-Guard mesh-stent: the IRON-Guard registry. Rationale and design.

According to the World Health Organization, every year, 5 million peoples die for stroke and another 5 million are permanently disabled. Although there are many causes of acute stroke, a common treatable cause of acute stroke is atheromatous narrowing at the carotid bifurcation. Carotid endarterectomy is still the standard of car, even if carotid artery stenting (CAS) has become an effective, less invasive alterantive. Unfortunately, CAS procedure is not yet perfect; regardless the use of an embolic protection device (EPD), percutaneous treatment has been correlated with a risk of cerebral ischemic events related to distal embolization. The objective of the IRON-Guard Registry is to evaluate the clinical outcome of treatment by means of stenting with the C-Guard (InspireMD, Boston, MA, USA) in subjects requiring CAS due to significant extracranial carotid artery stenosis with a physician-initiated, Italian, prospective, multicenter, single-arm study. A total of 200 enrolled subjects divided over different centers are planned to be enrolled. CAS will performed by implanting of C-Guard stent. Procedure will be performed according to the physician's standard of care. Standard procedures will be followed based on the Instructions for Use, for the C-Guard device of Inspire. The primary endpoint of this study is the 30-day rate of major adverse events (MAE), defined as the cumulative incidence of any periprocedural (≤30 days postprocedure) death, stroke or myocardial infarction. Secondary endpoints are rate of late ipsilateral stroke (31 through 365 days), system technical success, device malfunctions, major adverse events (MAEs), serious device-related and procedure-related adverse events, target lesion revascularization, and in-stent restenosis rates.

Endovascular treatment of popliteal aneurysm.

Although traditional surgical repair by aneurysm exclusion and bypass is still considered the gold standard in the treatment of popliteal artery aneurysms (PAAs), the endovascular repair (ER) has been gaining great interest in the last decades. ER offers several advantages over open bypass, including lower morbidity and mortality, and faster functional recovery, but some concerns about migration, occlusion, or fracture remain when a stent graft is deployed across a joint that undergo constant flexion. This review summarizes the current evidence on ER for PAAs. Level I evidence is still very limited, while the majority of published data come from retrospective studies. Moreover the heterogeneity of PAA morphology seems to play a major role in the outcomes after popliteal endografts placement, so that many anatomical criteria should be taken into account to determine which patient is best treated endovascularly. In conclusion, while it is unlike that endovascular treatment may displace open surgical bypass in the near future, it indeed does provide a feasible option for selected patients with high surgical risk and good anatomical features.

Elastofibroma dorsi: a histochemical and immunohistochemical study.

Elastofibroma dorsi (ED) is considered a member of a heterogeneous group of benign fibrous (fibroblastic or myofibroblastic) soft-tissue tumors, frequently localized in the periscapular region in middle aged or older individuals. However, the pathogenesis of ED is still unclear and many authors believe that ED results from a reactive hyperproliferation of fibroblastic tissue, while others suggest that it may be a consequence of a mechanical friction. In our study, we examined 11 cases of ED using histochemical and immunohistochemical methods, in order to extend the knowledge about extracellular matrix composition and histopathogenesis of ED. From the results it appeared that stroma and interspersed spindle cells of ED were positive for both periostin and tenascin-C. Mast cells tryptase-positive were also abundant throughout the lesion. The perivascular distribution of periostin and tenascin-C, associated with the CD34 positivity, suggest that endothelial-mesenchymal transition events can account for neovascularization and production of fibroelastic tissue characteristic of elastofibroma. Our data obtained in endothelial cells cultures demonstrated that elastin production is higher when the status of confluence of the cells is low. So, we can assume that such a phenomenon is a characteristic of mesenchymal/endothelial cells CD34 positive, in which elastin production results to be inversely proportional to the vascular differentiation of cellular elements. In the light of these considerations, we think that a cancerous nature of ED is unlikely. Overall, our study report, for the first time, a detailed description of extracellular matrix composition in ED, suggesting that a mechanical strain-dependent reactivation of periostin and tenascin-C expression, as well as of elastin deposition, could be responsible for development of ED.

Detection and quantification of EBV, HHV-6 and CMV DNA in the gastrointestinal tract of HIV-positive patients.

Human herpes viruses (HHVs) have been frequently detected in the gastrointestinal (GI) tract and may contribute to the development of gastric cancer. In the present study, the detection rate and viral load of Epstein Barr virus (EBV), HHV-6 and Cytomegalovirus (CMV) were assessed in the GI tract of human immunodeficiency virus (HIV) positive patients and of uninfected patients. The analysis revealed a significantly higher detection rate of EBV and HHV-6 in HIV-infected individuals than in uninfected subjects (88.5 vs 63%; p = 0.03). Moreover, EBV DNA load was significantly higher in the stomach of HIV patients than in controls. These data suggest that the HIV infection status may increase the persistence of these viruses in the GI compartment. Intriguingly, CMV DNA was undetectable in all biopsy specimens analyzed.

Prosthesis infection: prevention and treatment.

Implantation of a vascular prosthesis increases surgical site infection risk by producing a microenvironment conducive to bacterial attachment and biofilm formation, which sustains bacterial colonization and protects encased organisms from host defenses and antimicrobial therapy. Many maneuvers are used in an attempt to reduce infection in arterial reconstructions, but there are no clear guidelines on the most appropriate or effective. As well, there is no good evidence to guide management. A general principle is that indication for removal of the entire infected graft is mandatory when a suture line is involved in the infectious process, an infected anastomotic aneurism and a suture-line hemorrhage is evident, or when a graft-enteric fistula is diagnosed. Conservative, non-resectional management of graft infection is still a respectable solution for selected patients, as those with significant comorbidities, or those where the implanted aortic graft is in a location that precludes excision without causing a high likelihood of morbidity and/or mortality. Anyway, definitive management depends on the patient's condition and a tailored approach should be always offered. Surgical techniques favor in terms of mortality, patency and reinfection rate the in situ reconstruction. Currently, the choice of the technique used relies on center and operator's experience. This article summarizes the incidence of graft infection, analyze the predisponding factors to graft infection, and review current strategies for prevention and treatment of prosthesis and endograft infection.

Reinterventions in vascular and endovascular carotid surgery.

In recent years the number of carotid revascularization has increased steadily. This increased has inevitably resulted in an increase (relative) in complications, both after carotid endarterectomy (CEA) and carotid stenting (CAS), despite the technical evolutions of new available materials and the expertise of the operators. So, complications which may potentially require operative intervention, although not very frequent, are possible. However, after diagnosis, immediate management should be undertaken in order to avoid sequelae which are often irreversible and potentially fatal. To minimize this risk, it's important that these procedures are performed by skilled operators in high-volume Centers of activity. The aim of this review is to assess local complications which can lead to re-interventions after CEA and CAS.

Ultra-low profile Ovation device: is it the definitive solution for EVAR?

When Juan Parodi implanted an endograft in a human body for the first time on September 7, 1990 in Buenos Aires, Argentina, the delivery system of the handmade device was primitive, extremely rigid, and had a bulky profile of 27 French (F). Since then, stent-graft technology has evolved rapidly, limitations of earlier-generation devices have been overtaken, and endovascular aneurysm repair (EVAR) eligibility has increased enormously. Nevertheless (still) challenging aortoiliac anatomy such as short and complex proximal aortic neck seal zones and narrow access vessels are responsible for EVAR ineligibility in up to 50% of cases. The Ovation Prime abdominal stent-graft system (TriVascular, Inc., Santa Rosa, CA, USA) is a trimodular device designed with the aortic body delivered via a flexible, hydrophilic-coated, ultra-low profile catheter (14-F outer diameter - OD). The aortic body is provided with a suprarenal nitinol stent with anchors that provide active fixation, while a network of rings and channels that are inflated with a low-viscosity radiopaque polymer during stent-graft deployment, provides effective sealing. The previous EVAR technology aimed to both anchor and seal using stents combined with fabric, with neither optimized for their roles and each forced to compete for the same space within their delivery catheters, which inevitably led to larger profile of the delivery system. The technical revolution of the Ovation endograft includes the idea to truly uncouple the stages of stent-graft fixation and seal during the procedure. In the Ovation endograft platform, stent and fabric are not competing the same space within the delivery system and an ultra-low profile delivery can be achieved without compromise. With such a low-profile delivery catheter, approximately 90% of men and 70% of women with abdominal aortic aneurysm have access vessel diameters considered fit for endovascular repair. The aim of this review paper was to analyze the main properties of Ovation endograft, to emphasize the advantage of the ultra-low profile device, and to sum up current literature.

Two-year-results of Endurant stent-graft in challenging aortic neck morphologies versus standard anatomies.

AIM: The aim of this paper was to evaluate the influence of a challenging neck on mid-term results using the Endurant I stent-graft system in high risk patients. METHODS: A retrospective study was conducted on a prospectively compiled database of 72 elective patients with challenging neck treated with the Endurant I system (Endurant Stent Graft, Medtronic AVE, Santa Rosa, CA, USA). These patients were compared to a control group (65 patients) without significant neck problems. The endpoints were mid-term 2-years technical, clinical success and the event free survival of all treated patients. RESULTS: Mean age was 76.12 years; 76.6% of patients were males. Risk factors and preoperative variables did not differ significantly between the two groups. Only 4 (5.5%) patients of the study group vs. 2 (3.1%) in the control group developed type I endoleak during the follow-up. Three (4.1%) study group patients developed type III endoleak vs. 2 (3.1%) in the control group. All these patients required an adjunct procedure of relining with a new endograft. No type II endoleaks requiring adjunctive endovascular procedures were detected in our series. The 2-year event free survival rate did not differ statistically between the two groups (P=0.425). CONCLUSION: Treatment with the Endurant stent-graft is technically feasible and safe, yielding satisfactory results even in challenging anatomies. Mid-term results are promising and challenge current opinion concerning the negative influence of challenging neck anatomy on EVAR especially after a longer follow-up.

Diabetic foot: surgical approach in emergency.

Introduction. Critical limb lschemia (CLI) and particularly diabetic foot (DF) are still considered "Cinderella" in our departments. Anyway, the presence of arterial obstructive disease increases the risk of amputation by itself; when it is associated with foot infection, the risk of amputation is greatly increased. Methods. From January 2007 to December 2011, 375 patients with DF infection and CLI have been admitted to our Unit; from 2007 to 2009, 192 patients (Group A) underwent surgical debridement of the lesion followed by a delayed revascularization; from 2010 to 2011, 183 patients (Group B) were treated following a new 4-step protocol: (1) early diagnosis with a 24 h on call DF team; (2) urgent treatment of severe foot infection with an aggressive surgical debridement; (3) early revascularization within 24 hours; (4) definitive treatment: wound healing, reconstructive surgery, and orthesis. We reported rates of mortality, major amputation, and foot healing at 6 months of followup. Results. The majority of patients in both groups were male; no statistical differences in medical history and clinical condition were reported at the baseline. The main difference between the two groups was the mean time from debridement to revascularization (3 days in Group A and 24 hours in Group B). After 6 months of follow-up, mortality was 11% in Group A versus 4.4% in Group B. Major amputation rate was 39.6% and 24.6% in Groups A and B, respectively. Wound healing was achieved in 17.8% in Group A and 20.8% in Group B. Conclusions. This protocol requires a lot of professional skills that should to reach the goal to avoid major amputations in patients with DF. Only an interdisciplinary integrated DF team and an early intervention may significantly impact the outcome of our patients: "Time is Tissue"!