Therapeutic options for patients with multiple myeloma whose disease has relapsed after a prior auto-SCT include novel biologic therapies, traditional chemotherapy or a second transplant, with no ...clear standard of care. Few published studies address the safety and efficacy of a second auto-SCT for relapsed disease. We reviewed the Abramson Cancer Center experience with salvage auto-SCT for relapsed multiple myeloma. Forty-one patients had received a salvage auto-SCT at our institution; the median time between transplants was 37 months (range 3-91). The overall response rate in assessable patients was 55%, and treatment-related mortality was 7%. With a median follow-up time of 15 months, the median PFS was 8.5 months and the median overall survival (OS) was 20.7 months. In a multivariate analysis of OS, independent prognostic factors were >or=5 prior lines of therapy and time to progression after initial auto-SCT of <or=12 months. We conclude that in well-selected patients, salvage auto-SCT is safe and effective for relapsed myeloma.
Summary
In a phase 2 open‐label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to ...receive intravenous 1·0 or 1·3 mg/m2 bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% 90% confidence interval (CI), 15·7–47·1 and 38% (90% CI, 22·6–56·4) in the 1·0 mg/m2 (8 of 27 patients) and 1·3 mg/m2 (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1·0 and 1·3 mg/m2 cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.
Selecting sources with rising flux densities towards longer wavelengths from Herschel/Spectral and Photometric Imaging Receiver (SPIRE) maps is an efficient way to produce a catalogue rich in ...high-redshift (z > 4) dusty star-forming galaxies. The effectiveness of this approach has already been confirmed by spectroscopic follow-up observations, but the previously available catalogues made this way are limited by small survey areas. Here we apply a map-based search method to 274 deg2 of the Herschel Multi-tiered Extragalactic Survey (HerMES) Large Mode Survey and create a catalogue of 477 objects with SPIRE flux densities S
500 > S
350 > S
250 and a 5σ cut-off S
500 > 52 mJy. From this catalogue we determine that the total number of these ‘red’ sources is at least an order of magnitude higher than predicted by galaxy evolution models. These results are in agreement with previous findings in smaller HerMES fields; however, due to our significantly larger sample size we are also able to investigate the shape of the red source counts for the first time. We have obtained spectroscopic redshift measurements for two of our sources using the Atacama Large Millimeter/submillimeter Array. The redshifts z = 5.1 and 3.8 confirm that with our selection method we can indeed find high-redshift dusty star-forming galaxies.
Highlights ► Cell death pathways differ between the sexes. ► Poly(ADP-ribose) polymerase (PARP) gene deletion decreased stroke damage in males and increased damage in females. ► Stroke-induced ...changes in NAD+ differed in the male and female brain. ► Nicotinamide reduced infarct in wild-type males and PARP-1 knockout mice of both sexes but not in wild-type females. ► Energy metabolism may differ between the sexes.
Neutron imaging experiments were carried out to measure the water content of an operating proton exchange membrane fuel cell (PEMFC) under varying conditions of current density and temperature. It ...was found that the water content of the PEMFC is strongly coupled to the current density and temperature of the cell. These measurements indicate that changes in water content lag changes in current density by at least 100s, both when the current density was increased and decreased. Less liquid water was measured in the cells when operating at 80 deg C than at 40 deg C. At 60 deg C cell temperature, a peak in water content was observed around 650mA/cm2 and the water content was found to decrease with increasing current density. This is explained in the context of cell heating by performing a simple thermal analysis of an operating PEMFC so as to yield quantitative information on the waste heat and its effects on the liquid water contained in the cell.
Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and ...secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase‐independent pathway triggered by poly‐ADP‐ribose polymers (PARP) activation. Caspase‐induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase‐independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high‐molecular‐weight (50 kbp) DNA fragmentation. Although caspase‐independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro‐apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly‐ADP‐ribose (PAR) polymers as byproducts of PARP activation. PAR polymers may be directly toxic by triggering mitochondrial AIF release independently of NAD+ depletion. Recently, sex differences have been discovered that illustrate the importance of understanding these molecular pathways, especially as new therapeutics targeting apoptotic cell death are developed. Cell death in females proceeds primarily via caspase activation whereas caspase‐independent mechanisms triggered by the activation of PARP predominate in the male brain. This review summarizes the current literature in an attempt to clarify the roles of NAD+ and PAR polymers in caspase‐independent cell death, and discuss sex specific cell death to provide an example of the possible importance of these downstream mediators.
Experiments using purified recombinant human NAD(P)H:quinone oxidoreductase 1 (NQO1) revealed that the auto-oxidation of fully
reduced protein resulted in a 1:1 stoichiometry of oxygen consumption to ...NADH oxidation with the production of hydrogen peroxide.
The rate of auto-oxidation of fully reduced NQO1 was markedly accelerated in the presence of superoxide ( ), whereas the addition of superoxide dismutase greatly inhibited the rate of auto-oxidation. The ability of reduced NQO1
to react with suggested a role for NQO1 in scavenging , and this hypothesis was tested using established methods for production and detection. The addition of NQO1 in combination with NAD(P)H resulted in inhibition of dihydroethidium oxidation,
pyrogallol auto-oxidation, and elimination of a potassium superoxide-generated ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide: adduct signal (electron spin resonance). Kinetic parameters for the reduction of by NQO1 were estimated using xanthine/xanthine oxidase as the source of and after NQO1-dependent NADH oxidation at 340 nm. The ability of NQO1 to scavenge was also examined using cell sonicates prepared from isogenic cell lines containing no NQO1 activity (NQO1 - ) or very high levels of NQO1 activity (NQO1 + ). We demonstrated that addition of NAD(P)H and cell sonicate from NQO1 + but not NQO1 - cells resulted in an increased level of scavenging could be inhibited by 5-methoxy-1,2-dimethyl-3-(4-nitrophenoxy)methylindole-4,7-dione (ES936), a mechanism-based
inhibitor of NQO1. NQO1 can generate hydroquinones that are redox active, and the scavenging activity of NQO1 may allow protection against at the site of hydroquinone generation. In addition, the scavenging activity of NQO1 may provide an additional level of protection against induced toxicity.
Bortezomib, a member of a novel class of boronic acid dipeptides with the ability to inhibit the proteasome, was tested in patients with multiple myeloma whose condition was refractory to ...conventional chemotherapy. The drug induced responses in 35 percent of patients and was relatively nontoxic.
Encouraging results with a new drug.
Multiple myeloma accounts for approximately 14,600 new cases of cancer and 10,800 deaths annually in the United States.
1
Although conventional chemotherapy and high-dose therapy
2
with hematopoietic stem-cell rescue can prolong survival, few, if any, patients are cured. Salvage therapies for relapsed disease are equally disappointing,
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,
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and although thalidomide has shown promise,
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,
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new treatments are urgently needed.
We report here the effects of bortezomib (Velcade Millenium Pharmaceuticals, formerly known as PS-341), a selective inhibitor of the proteasome, in patients with multiple myeloma. The proteasome is a multi-enzyme complex that is present in all cells. It degrades proteins that regulate . . .
Domestic wells serve as the primary drinking-water source for rural residents in the northern Appalachian Basin (NAB), despite a limited understanding of contaminant distributions in groundwater ...sources. We employ a newly collected dataset of 216 water samples from domestic wells in Ohio and West Virginia and an integrated contaminant-source attribution method to describe water quality in the western NAB and characterize key agents influencing contaminant distributions. Our results reveal arsenic and nitrate concentrations above federal maximum contaminant levels (MCLs) in 6.8 and 1.3% of samples and manganese concentrations above health advisory in 7.3% of samples. Recently recharged groundwaters beneath upland regions appear vulnerable to surface-related impacts, including nitrate pollution from agricultural activities and salinization from road salting and domestic sewage sources. Valley regions serve as terminal discharge points for long-residence-time groundwaters, where mixing with basin brines is possible. Arsenic impairments occurred in alkaline groundwaters with major-ion compositions altered by ion exchange and in low-oxygen metal-rich groundwaters. Mixing with as much as 4–10% of mine discharge-like waters was observed near coal mining operations. Our study provides new insights into key agents of groundwater impairment in an understudied region of the NAB and presents an integrated approach for contaminant-source attribution applicable to other regions of intensive resource extraction.
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