Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM-2 trial.

BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response. METHODS: DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL). RESULTS: This final analysis (cutoff date, March 31, 2022), N = 223, with median follow-up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment. CONCLUSIONS: This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile.

Phosphate Toxicity and Epithelial to Mesenchymal Transition.

The underlying role of inadequate or excess intake of phosphate is evident in disease states, including metabolic, skeletal, cardiac, kidney and various cancers. Elevated phosphate levels can induce epithelial to mesenchymal transition (EMT) and cell death. EMT and associated lethal, metastatic or fibrinogenic responses are known to be underlying disease processes in fibrotic diseases and various solid tumors. Studies have shown EMT is regulated by induction of different signaling pathways, including TGF-ß, RTK, SRC, Wnt and Notch signal transduction. However, cross-talk amongst these signaling pathways is less understood. We have shown that elevated phosphate levels enhanced EMT partially through activating ERK1/2 pathway, resulting in massive cell death. We thus proposed excess phosphate-mediated lethal EMT as one of the underlying mechanisms of phosphate-induced cytotoxicity, which could explain high phosphate-associated renal fibrosis and cancer metastasis in preclinical and clinical studies. This chapter provides the overview of EMT with the highlights of its regulation by various signaling pathways induced by phosphate toxicity. We further put lately reported lethal EMT in the context of phosphate toxicity with the intent to explain it to excessive phosphate-associated pathologies.

Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study.

BACKGROUND: On the basis of the DREAMM-2 study (ClinicalTrials.gov identifier NCT03525678), single-agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti-CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM-2 after 13 months of follow-up among patients who received belamaf 2.5 mg/kg. METHODS: DREAMM-2 is an ongoing, phase 2, open-label, 2-arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti-CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee. RESULTS: As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty-one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%-43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression-free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6-3.6 months), respectively. Response and survival outcomes in patients who had high-risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow-up. CONCLUSIONS: Extended follow-up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.

Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study.

BACKGROUND: Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. METHODS: DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0-2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing. FINDINGS: Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8-42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9-46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3-4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort). INTERPRETATION: Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma. FUNDING: GlaxoSmithKline.

AIF promotes a JNK1-mediated cadherin switch independently of respiratory chain stabilization.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein occasionally involved in cell death that primarily regulates mitochondrial energy metabolism under normal cellular conditions. AIF catalyzes the oxidation of NADH in vitro, yet the significance of this redox activity in cells remains unclear. Here, we show that through its enzymatic activity AIF is a critical factor for oxidative stress-induced activation of the mitogen-activated protein kinases JNK1 (c-Jun N-terminal kinase), p38, and ERK (extracellular signal-regulated kinase). AIF-dependent JNK1 signaling culminates in the cadherin switch, and genetic reversal of this switch leads to apoptosis when AIF is suppressed. Notably, this widespread ability of AIF to promote JNK signaling can be uncoupled from its more limited role in respiratory chain stabilization. Thus, AIF is a transmitter of extra-mitochondrial signaling cues with important implications for human development and disease.

Fluidic Microactuation of Flexible Electrodes for Neural Recording.

Soft and conductive nanomaterials like carbon nanotubes, graphene, and nanowire scaffolds have expanded the family of ultraflexible microelectrodes that can bend and flex with the natural movement of the brain, reduce the inflammatory response, and improve the stability of long-term neural recordings. However, current methods to implant these highly flexible electrodes rely on temporary stiffening agents that temporarily increase the electrode size and stiffness thus aggravating neural damage during implantation, which can lead to cell loss and glial activation that persists even after the stiffening agents are removed or dissolve. A method to deliver thin, ultraflexible electrodes deep into neural tissue without increasing the stiffness or size of the electrodes will enable minimally invasive electrical recordings from within the brain. Here we show that specially designed microfluidic devices can apply a tension force to ultraflexible electrodes that prevents buckling without increasing the thickness or stiffness of the electrode during implantation. Additionally, these "fluidic microdrives" allow us to precisely actuate the electrode position with micron-scale accuracy. To demonstrate the efficacy of our fluidic microdrives, we used them to actuate highly flexible carbon nanotube fiber (CNTf) microelectrodes for electrophysiology. We used this approach in three proof-of-concept experiments. First, we recorded compound action potentials in a soft model organism, the small cnidarian Hydra. Second, we targeted electrodes precisely to the thalamic reticular nucleus in brain slices and recorded spontaneous and optogenetically evoked extracellular action potentials. Finally, we inserted electrodes more than 4 mm deep into the brain of rats and detected spontaneous individual unit activity in both cortical and subcortical regions. Compared to syringe injection, fluidic microdrives do not penetrate the brain and prevent changes in intracranial pressure by diverting fluid away from the implantation site during insertion and actuation. Overall, the fluidic microdrive technology provides a robust new method to implant and actuate ultraflexible neural electrodes.

Apoptosis Inducing Factor Binding Protein PGAM5 Triggers Mitophagic Cell Death That Is Inhibited by the Ubiquitin Ligase Activity of X-Linked Inhibitor of Apoptosis.

Apoptosis inducing factor (AIF) plays a well-defined role in controlling cell death but is also a critical factor for maintaining mitochondrial energy homeostasis; how these dueling activities are balanced has remained largely elusive. To identify new AIF binding partners that may define the continuum of AIF cellular regulation, a biochemical screen was performed that identified the mitochondrial phosphoglycerate mutase 5 (PGAM5) as an AIF associated factor. AIF binds both the short and long isoforms of PGAM5 and can reduce the ability of PGAM5 to control antioxidant responses. Transient overexpression of either PGAM5 isoform triggers caspase activation and cell death, and while AIF could reduce this caspase activation neither AIF expression nor caspase activity is required for PGAM5-mediated death. PGAM5 toxicity morphologically and biochemically resembles mitophagic cell death and is inhibited by the AIF binding protein X-linked inhibitor of apoptosis (XIAP) in a manner that depends on the ubiquitin ligase activity of XIAP. The phosphatase activity of PGAM5 was not required for cell death, and comparison of phosphatase activity between short and long PGAM5 isoforms suggested that only the long isoform is catalytically competent. This property correlated with an increased ability of PGAM5L to form dimers and/or higher order oligomers in intact cells compared to PGAM5S. Overall this study identifies an AIF/PGAM5/XIAP axis that can regulate PGAM5 activities related to the antioxidant response and mitophagy.

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis.

Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi and the causative agents of coccidioidomycosis, a mycosis endemic to certain semiarid regions in the Americas. The most common route of infection is by inhalation of airborne Coccidioides arthroconidia. Once a susceptible host inhales the conidia, a transition to mature endosporulated spherules can occur within the first 5 days of infection. For this study, we examined the host response in a murine model of coccidioidomycosis during a time period of infection that has not been well characterized. We collected lung tissue and bronchoalveolar lavage fluid (BALF) from BALB/c mice that were infected with a C. immitis pure strain, a C. immitis hybrid strain, or a C. posadasii strain as well as uninfected mice. We compared the host responses to the Coccidioides strains used in this study by assessing the level of transcription of selected cytokine genes in lung tissues and characterized host and fungal proteins present in BALF. Host response varied depending on the Coccidioides strain that was used and did not appear to be overly robust. This study provides a foundation to begin to dissect the host immune response early in infection, to detect abundant Coccidioides proteins, and to develop diagnostics that target these early time points of infection.

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models.

Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 µg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.

Fibronectin-binding protein of Borrelia hermsii expressed in the blood of mice with relapsing fever.

To identify and characterize surface proteins expressed by the relapsing fever (RF) agent Borrelia hermsii in the blood of infected mice, we used a cell-free filtrate of their blood to immunize congenic naive mice. The resultant antiserum was used for Western blotting of cell lysates, and gel slices corresponding to reactive bands were subjected to liquid chromatography-tandem mass spectrometry, followed by a search of the proteome database with the peptides. One of the immunogens was identified as the BHA007 protein, which is encoded by a 174-kb linear plasmid. BHA007 had sequence features of lipoproteins, was surface exposed by the criteria of in situ protease susceptibility and agglutination of Vtp(-) cells by anti-BHA007 antibodies, and was not essential for in vitro growth. BHA007 elicited antibodies during experimental infection of mice, but immunization with recombinant protein did not confer protection against needle-delivered infection. Open reading frames (ORFs) orthologous to BHA007 were found on large plasmids of other RF species, including the coding sequences for the CihC proteins of Borrelia duttonii and B. recurrentis, but not in Lyme disease Borrelia species. Recombinant BHA007 bound both human and bovine fibronectin with Kd (dissociation constant) values of 22 and 33 nM, respectively, and bound to C4-binding protein with less affinity. The distant homology of BHA007 and its orthologs to BBK32 proteins of Lyme disease species, as well as to previously described BBK32-like proteins in relapsing fever species, indicates that BHA007 is a member of a large family of multifunctional proteins in Borrelia species that bind to fibronectin as well as other host proteins.

The enzymatic activity of apoptosis-inducing factor supports energy metabolism benefiting the growth and invasiveness of advanced prostate cancer cells.

Apoptosis-inducing factor (AIF) promotes cell death yet also controls mitochondrial homeostasis and energy metabolism. It is unclear how these activities are coordinated, and the impact of AIF upon human disease, in particular cancer, is not well documented. In this study we have explored the contribution of AIF to the progression of prostate cancer. Analysis of archival gene expression data demonstrated that AIF transcript levels are elevated in human prostate cancer, and we found that AIF protein is increased in prostate tumors. Suppression of AIF expression in the prostate cancer cell lines LNCaP, DU145, and PC3 demonstrated that AIF does not contribute to cell toxicity via a variety of chemical death triggers, and growth under nutrient-rich conditions is largely unaffected by AIF ablation. However, under growth stress conditions, AIF depletion from DU145 and PC3 cell lines led to significant reductions in cell survival and growth that were not observed in LNCaP cells. Moreover AIF-deficient PC3 cells exhibited substantial reduction of tumorigenic growth in vivo. This reduced survival correlated with decreased expression of mitochondrial complex I protein subunits and concomitant changes in glucose metabolism. Finally, restoration of AIF-deficient PC3 cells with AIF variants demonstrated that the enzymatic activity of AIF is required for aggressive growth. Overall these studies show that AIF is an important factor for advanced prostate cancer cells and that through control of energy metabolism and redox balance, the enzymatic activity of AIF is critical for this support.

Quantitative analysis of torsional stiffness in supplemental one-third tubular plate fixation in the management of isolated syndesmosis injuries: a biomechanical study.

BACKGROUND: Disruption of the distal tibia and fibula articulation or syndesmosis can occur without fracture, and isolated syndesmotic disruption is often treated operatively. Following syndesmotic screw removal, a period of protected weight-bearing usually follows to allow the screw holes to heal. Our hypothesis was that supplementing transsyndesmotic fixation with a one-third tubular plate would potentially increase the torsional stiffness about the ankle, thus reducing the risk of fracture after screw removal and potentially allowing a faster return to weight-bearing and sport. METHODS: Ten pairs of fresh frozen cadaveric specimens were divided into 2 groups. In group 1 (7 pairs), each left extremity underwent the placement, and subsequent removal, of a 4.5-mm transsyndesmotic screw in a tricortical fashion. The matching right extremity underwent the same procedure but with the addition of a one-third tubular plate, which remained in situ after screw removal. In group 2 (3 pairs), the left specimens had a screw placed and removed while the right limbs remained intact. All specimens were tested under an axial preload and a torsional load until failure. RESULTS: In group 1, the results demonstrated an increase in torsional stiffness in 5 of 7 specimens with supplemental fixation of a one-third tubular plate. In group 2, the presence of the screw hole alone reduced the torsional stiffness in all specimens tested when compared with intact specimens. However, neither of these differences were statistically significant. CONCLUSION: From this study, we can conclude that the use of supplementary one-third tubular plate fixation demonstrated a trend toward increasing the torsional stiffness following transsyndesmotic screw removal. CLINICAL RELEVANCE: We believe the trend toward improved stiffness justifies the continued use of our technique, although further studies are necessary to confirm it.

Using integrated data to examine the effects of summer youth employment program completion on educational and criminal justice system outcomes: Evidence from Cuyahoga County, Ohio.

The current study builds the evidence base on the effects of Summer Youth Employment Programs (SYEP) both geographically and methodologically by linking SYEP participant records to a comprehensive integrated longitudinal database to better understand programmatic impacts on youth who completed participation in an SYEP in Cleveland, Ohio. The study matches SYEP participants and unselected applicants on various observed covariates using the Child Household Integrated Longitudinal Data (CHILD) System and relies upon propensity score matching techniques to estimate program completion impacts on educational and criminal justice system involvement outcomes. SYEP completion is associated with a lower prevalence of juvenile offense filings and incarceration events, better school attendance, and improved graduation rates 1-2 years following program participation.

Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation.

Apoptosis inducing factor (AIF) is a mediator of caspase-independent cell death that is also necessary for mitochondrial energy production. How these seemingly opposite cellular functions of AIF are controlled is poorly understood. X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of caspases that also regulates several caspase-independent signaling pathways. The RING domain of XIAP possesses E3 ubiquitin ligase activity, though the importance of this function to signal regulation remains incompletely defined. XIAP binds and ubiquitinates AIF, and in this study, we determined the functional consequences of XIAP-mediated AIF ubiquitination. Unlike canonical ubiquitination, XIAP-dependent AIF ubiquitination did not lead to proteasomal degradation of AIF. Experiments using ubiquitin mutants demonstrated that the XIAP-dependent ubiquitin linkage was not formed through the commonly used lysine 48, suggesting a noncanonical ubiquitin linkage is employed. Further studies demonstrated that only lysine 255 of AIF was a target of XIAP-dependent ubiquitination. Using recombinant AIF, we determined that mutating lysine 255 of AIF interferes with the ability of AIF not only to bind DNA but also to degrade chromatin in vitro. These data indicate that XIAP regulates the death-inducing activity of AIF through nondegradative ubiquitination, further defining the role of XIAP in controlling AIF and caspase-independent cell death pathways.

Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding.

NADPH oxidase comprises both cytosolic and membrane-bound subunits, which, when assembled and activated, initiate the transfer of electrons from NADPH to molecular oxygen to form superoxide. This activity, known as the respiratory burst, is extremely important in the innate immune response as indicated by the disorder chronic granulomatous disease. The regulation of this enzyme complex involves protein-protein and protein-lipid interactions as well as phosphorylation events. Previously, our laboratory demonstrated that the small membrane subunit of the oxidase complex, p22(phox), is phosphorylated in neutrophils and that its phosphorylation correlates with NADPH oxidase activity. In this study, we utilized site-directed mutagenesis in a Chinese hamster ovarian cell system to determine the phosphorylation sites within p22(phox). We also explored the mechanism by which p22(phox) phosphorylation affects NADPH oxidase activity. We found that mutation of threonine 147 to alanine inhibited superoxide production in vivo by more than 70%. This mutation also blocked phosphorylation of p22(phox) in vitro by both protein kinase C-alpha and -delta. Moreover, this mutation blocked the p22(phox)-p47(phox) interaction in intact cells. When phosphorylation was mimicked in vivo through mutation of Thr-147 to an aspartyl residue, NADPH oxidase activity was recovered, and the p22(phox)-p47(phox) interaction in the membrane was restored. Maturation of gp91(phox) was not affected by the alanine mutation, and phosphorylation of the cytosolic component p47(phox) still occurred. This study directly implicates threonine 147 of p22(phox) as a critical residue for efficient NADPH oxidase complex formation and resultant enzyme activity.

Troponin measurements during drug development--considerations for monitoring and management of potential cardiotoxicity: an educational collaboration among the Cardiac Safety Research Consortium, the Duke Clinical Research Institute, and the US Food and Drug Administration.

Drug-induced cardiac toxicity is a recognized challenge in development and implementation of pharmacotherapy. Appropriate biomarkers are needed to detect these abnormalities early in development and to manage the risk of potentially cardiotoxic drugs or biologic agents. Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury. Although most commonly used to detect myonecrosis in the setting of ischemia, cTns are also elevated with other acute and chronic disease processes, including heart failure, renal failure, sepsis, pulmonary embolic disease, and many others. High-sensitivity assays for both cTnI and cTnT are now available that achieve acceptable imprecision (coefficient of variation <10%) at the 99th percentile of a normal reference population. Even more sensitive assays are being developed that detect cTn in ranges that are near the level of normal cellular turnover (apoptosis). These properties of cTn and the continuing evolution of highly sensitive assays position cTn as a potentially uniquely informative marker for early detection of cardiac toxicity. This article summarizes collaborative discussions among key stakeholders in the Cardiac Safety Research Consortium about the use of cTn monitoring in drug development.

Effects of the HEET garment in the prevention of hypothermia in a porcine model.

BACKGROUND: Hypothermia is a common battlefield trauma occurrence. This study compared the effectiveness of the hypothermia, environmental, exposure, and trauma (HEET) garment (Trident Industries, Beaufort, SC) with and without thermal inserts with a control group of two wool blankets in the prevention of hypothermia in a treated hypovolemic porcine model. MATERIALS AND METHODS: Five female swine (Sus scrofa-Yorkshire cross) were assigned to each of three groups: HEET with thermal inserts (n=5); HEET without thermal inserts (n=5); or control (n=5). After the animals were anesthetized and stabilized for 30 min, the swine were hemorrhaged to a mean arterial pressure (MAP) of 30 mm Hg, simulating a battlefield injury. Hetastarch 6% (500 mL) was rapidly administered, simulating initial field resuscitation. One hour later, the animals' shed blood was reinfused, simulating transfusion at a field medical facility. The investigators moved the animal into a cooler set at 10°C ± 0.5°C. A pulmonary artery catheter was used to monitor core body temperature over a 6-h period. RESULTS: A repeated measures ANOVA and Tukey's post hoc test were used to analyze the data. There was a significant difference between the groups. At the end of 6h, the mean core temperature for the HEET with inserts group was 32.69°C ± 1.5; the HEET without inserts, 31.02°C ± 1.8; and control, 34.78°C ± 1.2 (P<0.05). While all groups became hypothermic, the wool blanket group was most effective in maintaining body temperature closer to normothermia. CONCLUSION: The HEET garments with and without heaters are ineffective in preventing hypothermia.