Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines.

Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting.

The hidden hypothesis: A disseminated tuberculosis case.

Case Presentation: 77-year-old former smoker admitted because of fatigue and abdominal distention. Past medical history positive for two previous hospitalizations for pericardial and pleural effusions (no diagnosis achieved). At admission erythrocyte sedimentation rate was 122mm per hour.

The FDA approved PI3K inhibitor GDC-0941 enhances in vitro the anti-neoplastic efficacy of Axitinib against c-myc-amplified high-risk medulloblastoma.

Aberrant receptor kinase signalling and tumour neovascularization are hallmarks of medulloblastoma development and are both considered valuable therapeutic targets. In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis. Therefore, we have been suggested that the clinically approved multi-kinase angiogenesis inhibitor Axitinib, which specifically targets these kinases, might constitute a promising option for medulloblastoma treatment.

Brentuximab vedotin exerts profound antiproliferative and pro-apoptotic efficacy in CD30-positive as well as cocultured CD30-negative germ cell tumour cell lines.

Prognosis in patients suffering from high-risk, refractory and relapsed germ cell tumours (GCT) often comprising of CD30-positive embryonal carcinoma (EC) components remains poor. Thus, novel treatment strategies are warranted. The antibody-drug conjugate (ADC) brentuximab vedotin delivers the potent antimitotic drug monomethyl auristatin E (MMAE) to CD30-expressing tumour cells.

Clinical and prognostic value of hypertensive cardiac damage in the PAMELA Study.

Because subclinical alterations in cardiovascular structure reflect cumulative damage induced by risk factors and represent an intermediate stage between risk factor exposure and cardiovascular events, this damage is regarded as a marker of increased cardiovascular risk in different clinical settings, including the general population. The Pressioni Monitorate e Loro Associazioni (PAMELA) is an originally designed research study aimed at assessing the normal values and prognostic significance of ambulatory and home blood pressure in a representative sample of the Northern Italian general population. Because the study protocol included the collection of electrocardiographic (ECG) and echocardiographic (ECHO) data, the prevalence and clinical correlates, as well as the prognostic value of subclinical cardiac alterations, have been extensively investigated.

Threshold and Target for Blood Pressure Lowering in the Elderly.

Purpose Of Review: Detection of elevated blood pressure values in elderly patients represents a common clinical condition associated with an increased cardiovascular risk. This has been shown to be the case in both systodiastolic and isolated systolic hypertension as well. However, despite the evidence of the benefits of the blood pressure lowering intervention in terms of reduction of cardiovascular morbidity and mortality, at least two issues related to antihypertensive drug treatment in aged individuals are still undefined: (1) the blood pressure threshold at which antihypertensive drug should be initiated and (2) the blood pressure goals of the therapeutic intervention.

Differential effects of enalapril-felodipine versus enalapril-lercanidipine combination drug treatment on sympathetic nerve traffic and metabolic profile in obesity-related hypertension.

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity.

Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients.

The adoptive transfer of lymphocytes genetically engineered to express tumor-specific antigen receptors is a potent strategy to treat cancer patients. T lymphocyte subsets, such as naïve or central memory T cells, selected in vitro prior to genetic engineering have been extensively investigated in preclinical mouse models, where they demonstrated improved therapeutic efficacy. However, so far, this is challenging to realize in the clinical setting, since good manufacturing practices (GMP) procedures for complex cell sorting and genetic manipulation are limited.

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications.

Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3ε monoclonal antibody (mAb) treatment in RAG2(-/-) mice was previously shown to mimic pre-TCR signaling promoting thymic expansion.

Selective preservation of bone marrow mature recirculating but not marginal zone B cells in murine models of chronic inflammation.

Inflammation promotes granulopoiesis over B lymphopoiesis in the bone marrow (BM). We studied B cell homeostasis in two murine models of T cell mediated chronic inflammation, namely calreticulin-deficient fetal liver chimeras (FLC), which develop severe blepharitis and alopecia due to T cell hyper responsiveness, and inflammatory bowel disease (IBD) caused by injection of CD4(+) naïve T cells into lymphopenic mice. We show herein that despite the severe depletion of B cell progenitors during chronic, peripheral T cell-mediated inflammation, the population of BM mature recirculating B cells is unaffected.

Impact of different definitions of the metabolic syndrome on the prevalence of organ damage, cardiometabolic risk and cardiovascular events.

Objectives: We compared definitions of metabolic syndrome performed by ATPIII [the National Cholesterol Education Program Adult Treatment Panel III; three criteria of the following: systolic blood pressure >or=130 mmHg and/or diastolic blood pressure >or=85 mmHg, fasting serum glucose >or=110 mg/dl, high-density lipoprotein plasma cholesterol or=150 mg/dl, waist circumference >or=102 cm (men) or 88 cm (women)], AHA (the American Heart Association; same cut-off of ATPIII except serum glucose >or= 100 mg/dl) and IDF [the International Diabetes Federation; mandatory criteria of visceral obesity with reduced cut-off of 94 cm (men) or 80 cm (women), and at least two criteria with the same cut-off as in AHA] for their impact on metabolic syndrome prevalence, cardiac organ damage, long-term risk of cardiovascular events and death for any cause and risk of developing diabetes mellitus, in-office and out-of-office hypertension and left ventricular hypertrophy (LVH).

Methods: In 2051 participants, we measured office, home and ambulatory blood pressure as well as metabolic, anthropometric and echocardiographic variables. Measurements were performed between 1990 and 1992 and repeated 10 years later.

Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF.

CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8+ T-cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.

Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels.

T cell receptor (TCR) stimulation results in the influx of Ca(2+), which is buffered by mitochondria and promotes adenosine triphosphate (ATP) synthesis. We found that ATP released from activated T cells through pannexin-1 hemichannels activated purinergic P2X receptors (P2XRs) to sustain mitogen-activated protein kinase (MAPK) signaling. P2XR antagonists, such as oxidized ATP (oATP), blunted MAPK activation in stimulated T cells, but did not affect the nuclear translocation of the transcription factor nuclear factor of activated T cells, thus promoting T cell anergy.

Tumors hamper the immunogenic competence of CD4+ T cell-directed dendritic cell vaccination.

Dendritic cells loaded with tumor-derived peptides induce protective CTL responses and are under evaluation in clinical trails. We report in this study that prophylactic administration of dendritic cells loaded with a MHC class II-restricted peptide derived from a model tumor Ag (Leishmania receptor for activated C kinase (LACK)) confers protection against LACK-expressing TS/A tumors, whereas therapeutic vaccination fails to cure tumor-bearing mice. Although CD4+ T cell-directed dendritic cell vaccination primed effector-like (CD44(high)CD62L(low), IL-2(+), IFN-gamma(+)) and central memory-like lymphocytes (CD44(high)CD62L(high), only IL-2(+)) in tumor-free mice, this was not the case in tumor-bearing animals in which both priming and persistence of CD4+ T cell memory were suppressed.

A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome.

Rag enzymes are the main players in V(D)J recombination, the process responsible for rearrangement of TCR and Ig genes. Hypomorphic Rag mutations in humans, which maintain partial V(D)J activity, cause a peculiar SCID associated with autoimmune-like manifestations, Omenn syndrome (OS). Although a deficient ability to sustain thymopoiesis and to produce a diverse T and B cell repertoire explains the increased susceptibility to severe infections, the molecular and cellular mechanisms underlying the spectrum of clinical and immunological features of OS remain poorly defined.

The immunogenicity of dendritic cell-based vaccines is not hampered by doxorubicin and melphalan administration.

Immunization of cancer patients is most effective in tumor-free conditions or in the presence of minimal residual disease. In the attempt to develop new strategies able to control tumor recurrence while allowing the development of protective immunity, we have investigated the immunogenic potential of two distinct vaccine formulations when provided alone or upon single and repeated treatment with chemotherapeutics drugs. Vaccine-induced T cell responses were first investigated by tracing Ag-specific T cell responses in mice bearing detectable frequencies of Ag-specific TCR transgenic CD4 and CD8 T cells.