GDF 15 - A Novel Biomarker in the Offing for Heart Failure

Background:

Several diagnostic and prognostic biomarkers are being explored in heart failure. GDF-15 belongs to the transforming growth factor β (TGF-β) cytokine family that is highly up regulated in inflammatory conditions. We undertook this systematic review to summarize the current evidence on the utility of GDF-15 as a biomarker in heart failure.

Design and Methods:

Multiple electronic databases for studies that reported the association between GDF- 15 and heart failure were searched using different electronic databases such as MEDLINE, Science Direct, Springer Link, Scopus, Cochrane Reviews, and Google Scholar using pre-defined inclusion- exclusion criteria.

Results:

Twenty one original studies were identified that included data from 20,920 study participants. GDF 15 was found to be a strong prognosticator of all-cause mortality in heart failure patients. Several studies found the benefit of using GDF-15 as a component of a multi-biomarker strategy in prognosticating patients with heart failure.

Conclusion:

More studies are warranted to elucidate the molecular pathways involving GDF-15 and to see how knowledge about GDF-15 can be used to make therapeutic decisions in the clinic.     

Lipopolysaccharide-induced diaphragmatic contractile dysfunction in mice lacking the inducible nitric oxide synthase.

The goal of this study was to evaluate the importance of the inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced diaphragmatic contractile dysfunction. Many investigators have proposed that iNOS induction in the ventilatory and limb muscles of animals injected with Escherichia coli LPS leads to impaired muscle contractility and increased fatigability. We tested this proposal by examining wild-type mice and iNOS-deficient (iNOS knockout) mice. Both types of mice were injected with either saline (control) or E. coli LPS and killed after 12 h. Diaphragm nitric oxide synthase (NOS) activity, NOS expression, and muscle contractility were assessed with L-citrulline assay, immunoblotting, and in vitro bath preparation, respectively. LPS injection in wild-type mice induced iNOS protein expression and augmented total diaphragmatic NOS activity, which coincided with impaired muscle force generated at frequencies higher than 30 Hz. In iNOS knockout mice, injection of LPS augmented constitutive muscle NOS activity, upregulated the expression of the neuronal NOS (nNOS), but elicited a significantly greater decline in force generated in response to high frequency of stimulation compared with wild-type animals. We conclude that iNOS may play a protective role in attenuating the inhibitory influence of LPS on muscle contractility.     

IgM myeloma: A multicenter retrospective study of 134 patients

IgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL^?1 with 19% of patients presenting with levels >6,000 mg dL^?1. International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t (11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes.     

Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes

Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management.     

Specific congenital malformations after exposure to cyclophosphamide, epirubicin and 5-fluorouracil during the first trimester of pregnancy

Minimal deviation adenocarcinoma (MDA) is a very rare variant of cervical adenocarcinoma, this pathological entity is composed of mucinous very-well-differentiated glands deeply invading cervical stroma, and often surrounded by a desmoplastic reaction. Despite its benign histological appearance, MDA is typically characterized by aggressive clinical behavior and by relevant difficulties in achieving a final diagnosis. Moreover, the intrinsic chemotherapy resistance, as well as the frequent failure of radiotherapy approaches has raised the need to investigate the efficacy of multimodal strategies for the treatment of MDA patients. Here, we report a case of locally advanced MDA of the uterine cervix in a very young woman, who was successfully treated with concomitant chemoradiation followed by radical surgery.     

Current and emerging strategies for the management of acute myeloid leukemia in the elderly

Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemias diagnosed in adults. The elderly are disproportionately affected by AML, as 35% of newly diagnosed patients are aged >or=75 and the median age at diagnosis is 67. Elderly individuals also respond less well to standard chemotherapy than do younger individuals, as reflected by lower complete remission and relapse-free survival rates in major clinical trials. A higher prevalence of comorbid conditions as well as the unique biological features of elderly AML patients account for the relatively poor response to therapy observed in this population. Compared with AML in younger individuals, for example, AML in the elderly more often emerges from a preceding myelodysplastic syndrome and is more frequently associated with poor-prognosis karyotypes such as 5q- or 7q-. The introduction of novel therapies over the past decade has already altered the treatment paradigm of elderly individuals with AML. The first of these to emerge was gemtuzumab ozogamicin. Other agents are currently under evaluation in clinical trials, including inhibitors of multidrug resistance, farnesyltransferase inhibitors, novel nucleoside analogues, and inhibitors of the FMS-like tyrosine kinase-3. This review describes the biological features of AML in the elderly and summarizes both the current and emerging strategies for the treatment of this disease in older individuals.