Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer-results of a first-in-man dose-escalation study with a fixed-dose extension phase.

BACKGROUND: Objective was to determine maximum tolerated dose (MTD), recommended dose (RD) and schedule, safety, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, and antitumor activity of Debio0932, a new second-generation oral heat shock protein (HSP) inhibitor. PATIENTS AND METHODS: This was a multicenter, uncontrolled, open-label, nonrandomized, dose-escalation study in adults with treatment-resistant advanced cancer. Groups of three patients received oral Debio0932 either daily or every other day. The starting dose of 50 mg was escalated until the MTD was reached, i.e. dose-limiting toxicity (DLT) occurred in ≥2 patients. Further 9 patients and an extension cohort of 30 patients were treated at the next lower dose (=RD). Adverse events (AEs), tumor response, PK, and HSP70 levels in peripheral blood mononuclear cells were recorded over 30 days. RESULTS: Fifty patients were treated with doses up to 1600 mg, at which level three DLT occurred (febrile neutropenia, diarrhea, asthenia). In total, 39 patients were then treated at the RD of 1000 mg daily. Most common drug-related AEs were asthenia and gastrointestinal events. No ocular toxicities were observed. Debio0932 was rapidly absorbed and metabolized. Plasma steady state was reached within 9 days. Volume of distribution was high and elimination half-life was 9-11 h. Food had no effect on PK. PD showed large interpatient variability, but no dose-effect relationship. Partial tumor response was observed in 2 patients (NSCLC and breast cancer), stable disease (SD) in 12 patients (5 of 8 NSCLC patients). In the extension cohort, 9 patients had SD, and 1 patient a partial metabolic tumor response. CONCLUSION: Debio0932 has limited clinical activity, together with manageable toxicity. Further development as adjunct treatment of NSCLC at daily doses of 1000 mg is warranted. CLINICAL TRIAL: NCT01168752.

Takotsubo cardiomyopathy: real life management in the intensive coronary care unit.

AIM: Takotsubo cardiomyopathy is a cardiac syndrome characterized by reversible left ventricular dysfunction, ischemic changes on electrocardiogram, elevation of cardiac biomarkers, absence of obstructive coronary artery disease in the setting of various stressing conditions. To date, little is known on best clinical management of this syndrome in coronary care units. Whe thus aimed to present our experience in a real life takotsubo population. METHODS: We identified all patients with Takotsubo cardiomyopathy at our center Maria Vittoria Hospital, Turin, between October 2006 and February 2012. Patients where considered to have Takotsubo syndrome if they presented chest pain on admission, new elettrocardiographic changes suggestive of myocardial ischemia, evidence of apical balloning with hyperkinesis of basal segments on echocardiography, rise in troponin I and, after coronary angiography, no coronary artery disease. We adjudicated the following clinical events: death and recurrence of ischemic events; we also made a detailed analysis of the stressing conditions leading to clinical syndrome. RESULTS: A total of 26 patients were included, 4 (15%) males and 22 (85%) females; mean age was 71±13. After more than 1 year median follow-up the incidence of death was 7.7% (2 deaths), with all deaths, due to cardiogenic shock, occurring in the first 10 days of hospitalization; 2 patients (8%) experienced recurrence of ischemic event. Leading cause of Takostubo was major depressive episode (16%), followed by mourning (12%), falling down with difficulties in standing up (12%), vomiting (8%) and pulmonary infection (8%). In the coronary care unit major complications of patients with Takotsubo syndrome were acute hearth failure (62%), cardiogenic shock (27%), sepsis (31%), pulmonary aedema (27%) and anemia (12%). Two patients needed non-invasive ventilation support and one intra-aortic balloon conterpulasation. In addition one patient developed rabdomyolysis and one left heart thrombus. Cornerstone drug therapy was as follows: 96% of patients took aspirin, 58% beta blockers, 54% nitroglicerine, 46% intravenous heparin, 27% dopamine. CONCLUSION: Takotsubo syndrome is an important safety issue occurring predominantly in post-menopausal women undergoing specific stressing condition. Heart failure and cardiogenic shock are the most serious clinical complication and leading cause of death in the short period, good prognosis is seen thereafter.

Fatigue Threshold R-Curves for Dental Lithium Disilicate Glass-Ceramics.

Chemical and mechanical fatigue degradation in ceramic materials is generally inconspicuous yet ubiquitous, to the effect that clinical fractures still consist of the main cause of failure in all-ceramic restorations. Implications of this span wide, from a reduced survival prognosis for the affected teeth, including more frequent and increasingly invasive procedural interventions, to the financial burden borne by individuals and health care systems. To suffice as an effective corrective, restoration lifetimes need only to be extended so to outlive the patient. That opens a box of problems from a materials science standpoint, entailing inherent deficiencies of brittle materials to resist mechanical and environmental challenges. Efforts in developing more damage-tolerant and fatigue-resistant restoratives go thus hand in hand with understanding intrinsic mechanisms of crack growth behavior under conditions that simulate the oral environment. Here we developed experiments using size-relevant sharp precracked specimens with controlled size and geometry (truncated semielliptical crack in the surface-crack-in-biaxial-flexure method) to establish a relationship between crack size and strength. The tangent method was used to construct envelopes for the quasi-static resistance curves (R-curves), which served as template for deriving residual cyclic R-curve analogs. By means of experimentally obtained stress-cycle curves, lifetime and fatigue parameters were employed within a mechanistic framework to reveal constitutive toughening mechanisms during subcritical growth under cyclic loading in a wet environment. Using 3 modern dental lithium disilicate glass-ceramics, we demonstrate the extent of R-curve degradation up to a threshold of 10 million cycles (~30 y in service) and draw parallels between the scope of fatigue degradation and the size of the microstructural units responsible for toughening mechanisms in glass-ceramic materials. Our results indicate that larger microstructural elements endow glass-ceramics with a higher reaching quasi-static R-curve at the onset but degrading more rapidly to comparable levels of lithium disilicates having submicrometric and nanometric crystal phases.

Epidemiological and molecular characterization of HBV and HCV infections in HIV-1-infected inmate population in Italy: a 2017-2019 multicenter cross-sectional study.

HBV/HCV co-infection is common in HIV-1-infected prisoners. To investigate the characteristics of HIV co-infections, and to evaluate the molecular heterogeneity of HIV, HBV and HCV in prisoners, we carried-out a multicenter cross-sectional study, including 65 HIV-1-infected inmates enrolled in 5 Italian detention centers during the period 2017-2019. HIV-1 subtyping showed that 77.1% of inmates were infected with B subtype and 22.9% with non-B subtypes. Italian nationals were all infected with subtype B (93.1%), except two individuals, one infected with the recombinant form CRF72_BF1, and the other with the HIV-1 sub-subtype A6, both previously not identified in inmates of Italian nationality. Non-Italian nationals were infected with subtype B (52.6%), CRFs (36.8%) and sub-subtypes A1 and A3 (5.2%). HIV variants carrying resistance mutations to NRTI, NNRTI, PI and InSTI were found in 7 inmates, 4 of which were never exposed to the relevant classes of drugs associated with these mutations. HBV and/or HCV co-infections markers were found in 49/65 (75.4%) inmates, while 27/65 (41.5%) showed markers of both HBV and HCV coinfection. Further, Italian nationals showed a significant higher presence of HCV markers as compared to non-Italian nationals (p = 0.0001). Finally, HCV phylogenetic analysis performed in 18 inmates revealed the presence of HCV subtypes 1a, 3a, 4d (66.6%, 16.7% and 16.7%, respectively). Our data suggest the need to monitor HIV, HBV and HCV infections in prisons in order to prevent spreading of these viruses both in jails and in the general population, and to implement effective public health programs that limit the circulation of different genetic forms as well as of viral variants with mutations conferring resistance to treatment.

Influence of MHC class I and II haplotypes on the experimental infection of Mauritian cynomolgus macaques with SHIVSF162P4cy.

Mauritian cynomolgus macaques (MCM) are widely used in human immunodeficiency virus research because of their restricted major histocompatibility complex (MHC) diversity which provides the opportunity to address the influence of host factors on vaccine studies. We herein report the impact of MHC haplotype on the outcome of 21 MCM infections with the CCR5-tropic simian/human immunodeficiency virus (SHIV)(SF162P4cy). MCM were susceptible to SHIV(SF162P4cy) infection as shown by viremia and loss of CD4+ T cells. A significant association between haplotype M7 (class IA, IB, II) and persistent viremia was observed in chronic phase, whereas recombinant class IA haplotype was associated with a reduction of viral RNA during acute infection. Class IB M4 haplotype displayed significantly lower acute phase provirus copy numbers. In addition, statistical analysis indicated a detrimental effect of haplotype M4 (class IA, IB) on the course of infection as indicated by lower CD4+ T-cell levels during chronic infection. A decrease in post-acute phase CD4+ T-cell numbers was also observed in haplotype M2 animals. This is the first report that documents the effects of host MHC class I and II molecules on the SHIV(SF162P4cy) infection in MCM, particularly with regard to the association between recombinant class IA, M4, and M7 haplotypes and the dynamic of viral replication and level of CD4+ T cells.

A phase II, randomised clinical trial to demonstrate the non-inferiority of low-dose MF59-adjuvanted pre-pandemic A/H5N1 influenza vaccine in adult and elderly subjects.

BACKGROUND: Effective planning and preparedness against a possible future A/H5N1 influenza pandemic is a major global challenge. Because dose sparing strategies are required to meet the global demand for vaccine, efforts have focused on the development of adjuvanted vaccine formulations of relatively lower antigen content. AIM: This study aimed to demonstrate the non-inferiority of a low-antigen-dose (3.75 µ) [DOSAGE ERROR CORRECTED] A/H5N1 pre-pandemic vaccine compared with a licensed, higher-dose (7.5 mg) formulation in adult and elderly subjects. Immunogenicity was assessed according to European and U.S. licensure criteria. METHODS: A total of 722 subjects were randomized in equal numbers to receive either the licensed or low-dose formulation. All subjects received two vaccine doses administered three weeks apart. Immunogenicity was assessed three weeks after the administration of each vaccine dose by hemagglutination inhibition (HI), single radial haemolysis (SRH) and microneutralization assays (MN). Local and systemic reactions were assessed over a seven day period post-vaccination. Adverse events were recorded throughout. RESULTS: The low-dose vaccine was demonstrated to be non-inferior to the licensed formulation in terms of antibody titres against the vaccine strain. All three European licensure criteria were met by adult subjects in response to the low-dose vaccine; two criteria were met by the elderly age group. Cross-reactive antibodies were detected against the heterologous A/H5N1 antigen strains A/Indonesia/05/05 and A/turkeyTurkey/01/05. Both vaccines were generally well tolerated by both age groups. CONCLUSION: These data demonstrate that a low antigen dose in combination with MF59 adjuvant is adequate for the routine pre-pandemic immunization of adult and elderly subjects.

Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine.

Vaccine strategies aimed at blocking virus entry have so far failed to induce protection against heterologous viruses. Thus, the control of viral infection and the block of disease onset may represent a more achievable goal of human immunodeficiency virus (HIV) vaccine strategies. Here we show that vaccination of cynomolgus monkeys with a biologically active HIV-1 Tat protein is safe, elicits a broad (humoral and cellular) specific immune response and reduces infection with the highly pathogenic simian-human immunodeficiency virus (SHIV)-89.6P to undetectable levels, preventing the CD4+ T-cell decrease. These results may provide new opportunities for the development of a vaccine against AIDS.

Sliding contact wear and subsurface damage of CAD/CAM materials against zirconia.

OBJECTIVE: Most previous work conducted on the wear behavior of dental materials has focused on wear rates and surface damage. There is, however, scarce information regarding the subsurface damage arising from sliding contact fatigue. The aim of this study was to elucidate the wear mechanisms and the subsurface damage generated during sliding contact fatigue in 5 contemporary CAD/CAM materials against a zirconia indenter. METHODS: Forty discs (Ø12mm, 1.55mm thick) were cut out of IPS e.max CAD (e.CAD), Suprinity PC (SUP), Enamic (ENA), Vitablocs Mark II (VMII) and Lava Ultimate (LU) blocks and mirror polished. After cementation onto a dentin-like composite, off-axis mouth-motion cycling was conducted with a spherical zirconia indenter (r=3.18mm) in water (200N load, 2Hz frequency) for 5 different cycling periods (102, 103, 104, 105, 106 cycles, n=8). Analysis of the wear scars was conducted using light-microscopy, scanning-electron-microscopy and optical profilometry. Subsurface damage was assessed using sagittal and transverse sections of the samples. RESULTS: Fatigue wear mechanisms predominated in glassy materials (e.CAD, SUP, VMII), accompanied by extensive subsurface damage, whereas abrasive wear mechanisms were responsible for the large wear craters in the resin composite (LU) with an absolute absence of subsurface fracture. A combination of both mechanisms was observed in the polymer-infiltrated reinforced-glass (ENA), displaying large wear craters and severe subsurface damage. SIGNIFICANCE: Well-controlled laboratory simulation can identify wear and subsurface damage susceptibility of various classes of restorative materials. Both wear and subsurface fracture are determining factors for the long-term success of restorations.

Fracture Rates and Lifetime Estimations of CAD/CAM All-ceramic Restorations.

The gathering of clinical data on fractures of dental restorations through prospective clinical trials is a labor- and time-consuming enterprise. Here, we propose an unconventional approach for collecting large datasets, from which clinical information on indirect restorations can be retrospectively analyzed. The authors accessed the database of an industry-scale machining center in Germany and obtained information on 34,911 computer-aided design (CAD)/computer-aided manufacturing (CAM) all-ceramic posterior restorations. The fractures of bridges, crowns, onlays, and inlays fabricated from different all-ceramic systems over a period of 3.5 y were reported by dentists and entered in the database. Survival analyses and estimations of future life revealed differences in performance among ZrO2-based restorations and lithium disilicate and leucite-reinforced glass-ceramics.

Elevated 8-isoprostane levels in basal cell carcinoma and in UVA irradiated skin.

Isoprostanes are prostaglandin isomers produced from the peroxidation of polyunsaturated fatty acids from the cellular membrane. They have been used as a specific index of cellular lipoperoxidation and as an indirect measure of oxidative stress. However, these molecules also present several biological activities. An oxidative environment measured as the presence of other indirect measurements of reactive oxygen species lipoperoxidation has recently been described in basal cell carcinoma, the most frequent type of non-melanoma skin cancer. This study aims to measure the levels of 8-isoprostaglandin F2alpha, an isoprostane widely studied in other models as a by-product of ROS-induced lipid peroxidation, in basal cell carcinoma and in UVA irradiated healthy skin. We found that 8-iso-PGF2 alpha is present in higher levels in BCC specimens compared to healthy non sun-exposed skin, confirming previous studies on the production of lipoperoxidation in this tumor. Moreover, we demonstrated that topical pre-treatment with a compound containing vitamin E is capable of reducing 8-iso-PGF2 alpha formation in UV irradiated skin suggesting a role for isoprostanes in UV induced inflammation and eventually carcinogenesis and confirming the function of vitamin E as an antioxidant in this model.

Dental materials for primary dentition: are they suitable for occlusal restorations? A two-body wear study.

AIM: This was to evaluate the wear resistance of different materials, compomers, resin-modified glass ionomer cements (RMGICs), glass ionomer cements (GICs), used for posterior restorations in primary teeth and to compare the results with the reference material, amalgam. STUDY DESIGN: Eight specimens of each material were subjected to two-body wear test, using a chewing simulator. The wear region of each material was examined under a profilometer, measuring the vertical loss (µm) and the volume loss (mm(3)) of the materials. RESULTS: The results showed significant differences of vertical loss and volume loss of the test materials (p < 0.001). Amalgam had the highest wear resistance. Twinky Star (compomer) had the lowest vertical loss and volume loss. There was no significant difference of vertical loss among compomers, Dyract Extra, Dyract Flow and Dyract Posterior. Riva Self Cure (GIC) had no statistically significant difference compared with the compomers (except Twinky Star). No statistically significant difference was found also between Equia (GIC) and Ketac Moral (GIC) with Dyract Extra (Compomer). RMGICs were found to have the lowest wear resistance. STATISTICS: For the statistical analysis, the PASW 20.0 (SPSS Statistics, IBM, Chicago) package was used. Means and standard deviations were measured with descriptive statistics and analyzed using one-way ANOVA. CONCLUSION: Compomers and some GICs, that have moderate wear resistance, may be sufficient for occlusal restorations in primary dentitions.

Influences of misleading postevent information: misinformation interference and acceptance.

Because of the biasing nature of retrieval tests, evidence that the introduction of misleading postevent information will impair the memory for an original event has recently been in dispute. In two experiments, a retrieval test sensitive to both biasing effects of misinformation (misinformation acceptance) and influences of the misinformation on memory (misinformation interference) was used. Both experiments demonstrated misinformation acceptance, and one of the experiments suggested that misinformation interferes with the ability to remember the original event. Two misinformation interference hypotheses are evaluated; they suggest that the misinformation may have either impaired memory or led to confusion regarding what had occurred during the event.

Incongruous item generation effects: a multiple-cue perspective.

In a series of studies, generation effects were obtained under encoding conditions designed to induce incongruous, unrelated item generation. Experiments 1 and 2, using free- and cued-recall measures, respectively, provided evidence that this unrelated generation effect was due to response-specific processing. Experiment 3 demonstrated a lack of relation between free recall and indices of clustering. A preliminary protocol study suggested that Ss generate multiple items in their search for appropriate unrelated responses. In Experiments 4 and 5, conditions designed to produce more extensive multiple generations demonstrated enhanced free recall. These results supported a multiple-cue account of facilitated recall for incongruous item generation. The multiple-cue perspective is consistent with traditional conceptualizations of memory, such as the principle of congruity, and contemporary distinctions between cue-target relational and item-specific processing.

[Isolated infarction of the right ventricle caused by occlusion of the non-dominant right coronary artery. Role of sequential atrioventricular stimulation]. / Infarto isolato del ventricolo destro da occlusione di un'arteria coronaria destra non dominante. Ruolo della stimolazione atrioventricolare sequenziale.

AIM: Description of a case report. PATIENT: The case of a 66-year old woman with cardiogenic shock due to isolated acute right ventricular infarction caused by occlusion of a diminutive right coronary artery is described. RESULTS: Her ECG showed the presence of junctional rhythm and ST elevation in V1-V2 and right precordial leads. Despite infusion of plasma expanders, atropine and inotropic agents, clinical conditions did not improve, but success was only achieved by means of atrioventricular (AV) sequential pacing which allowed good hemodynamic stabilization of the patient. CONCLUSIONS: It is noteworthy that occlusion even of a diminutive right coronary artery can induce cardiogenic shock, and that restoration of the physiological AV synchrony--although somewhat impaired by prolonged atrial stunning--has a markedly positive effect on the hemodynamic balance.

Failure of interpolated tests in inducing memory impairment with final modified tests: evidence unfavorable to the blocking hypothesis.

Whether interpolated recall or recognition tests will enhance the impairing influence of postevent misinformation on a final modified recognition test of original event information was examined in two experiments. Both used short retention intervals. Postevent information led to differences between control and misled conditions on interpolated tests, but no differences were found on modified tests. Arguments are presented that discredit the blocking hypothesis as a potential mechanism responsible for impairment found with postevent misinformation experiments that use short retention intervals. Instead, various rejection mechanisms are favorably assessed.

Factors involved in mechanical fatigue degradation of dental resin composites.

The design of clinical trials allows for limited insights into the fatigue processes occurring in resin composites and the factors involved therein. In vitro studies, in contrast, can fundamentally narrow study interests to focus on particular degradation mechanisms and, to date, represent the major contributors to the state of knowledge on the subject. These studies show that microstructural features are important in determining strength and fracture toughness, whereas fatigue resistance is mainly related to the susceptibility of the matrix and the filler/matrix interface to mechanical and chemical degradation. In this review, we focus on fracture mechanisms occurring during fatigue, on the methods used to assess them, and on additional phenomena involved in the degradation of initial mechanical properties of resin composites.

Clinical effectiveness of a hydrophobic coating used in conjunction with a one-step self-etch adhesive: an 18-month evaluation.

The purpose of this randomized clinical trial was to evaluate the clinical performance of a one-step self-etch adhesive in noncarious cervical lesions with inclusion of a hydrophobic bonding layer not included in the original bonding system as a test of potentially improved bonding. Patients with noncarious cervical lesions received two or four restorations after being randomly assigned to two adhesive technique protocols (n=32): EB, application of Adper Easy Bond (3M ESPE) following manufacturer's instructions; and EB+B, application of Adper Easy Bond, immediately followed by the application of a hydrophobic resin coat (Scotchbond Multi-Purpose Bonding Agent, 3M ESPE). All restorations were restored with a microhybrid composite (Filtek Z250, 3M ESPE). Clinical effectiveness was recorded in terms of retention, marginal discoloration, marginal integrity, postoperative sensitivity, recurrent caries, periodontal health, and pulpal vitality, according to the modified USPHS criteria, for 18 months. Data were analyzed using chi-square, Fisher exact, and McNemar tests at α=0.05. Two restorations of each group were debonded after six months, leading to an overall clinical success rate of 93.8% for both groups. At the 18-month evaluation period, no new restoration was debonded. However, one restoration of the EB group displayed recurrent caries at the dentin margin, decreasing the overall success rate to 90.6% in comparison to 93.8% of EB+B. The success rate between EB and EB+B was not statistically significant (p=0.5). The application of a hydrophobic resin coat over EB did not increase bonding effectiveness in noncarious cervical lesions after 18 months.

A photoelastic assessment of residual stresses in zirconia-veneer crowns.

Residual stresses within the veneer are linked to the high prevalence of veneer chipping observed in clinical trials of zirconia prostheses. We hypothesized that the thermal mismatch between the zirconia infrastructure and the veneer porcelain, as well as the rate used for cooling zirconia-veneer crowns, would be directly proportional to the magnitude of residual stresses built within the veneer layer. Two porcelains with different coefficients of thermal expansion were used to veneer zirconia copings, to create high or low thermal mismatches. The crowns were cooled according to a fast- or a slow-cooling protocol. The retardation of polarized light waves was used to calculate the residual stress magnitude and distribution across the veneer, according to the photoelasticity principle, in 1.0-mm-thick crown sections. While thermal mismatch was an important factor influencing the maximum stress development in the veneer, cooling rate had a minor role. Curved surfaces were preferential sites for stress concentration regardless of thermal mismatch or cooling rate.