Targeting Aggressive B-cell Lymphomas through Pharmacological Activation of the Mitochondrial Protease OMA1.

DLBCL are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to adapt to stress caused by uncontrolled growth, such as hypoxia, amino acid deprivation, and accumulation of misfolded proteins. Here, we show that ISR hyperactivation is a targetable liability in DLBCL. We describe a novel class of compounds represented by BTM-3528 and BTM-3566, which activate the ISR through the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest, and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability which is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell, and MYC-rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. BTM-3566 represents a first-of-its kind approach of selectively hyperactivating the mitochondrial ISR for treating DLBCL.

1-Thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives as antitumor agents.

A class of substituted 1-thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives was found to have potent anti-proliferative activity against a broad range of tumor cell lines. A compound from this class (14) was profiled across a broad panel of hematologic and solid tumor cancer cell lines demonstrating cell cycle arrest at the G0/G1 interphase and has potent anti-proliferative activity against a distinct and select set of cancer cell types with no observed effects on normal human cells. An example is the selective inhibition of human B-cell lymphoma cell line (BJAB). Compound 14 was orally bioavailable and tolerated well in mice. Synthesis and structure activity relationships (SAR) in this series of compounds are discussed.

Immune response to sipuleucel-T in prostate cancer.

Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients' own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues.

Preoperative haemodynamic parameters and the immediate outcome after open repair of ruptured abdominal aortic aneurysms.

AIM: The aim of this study was to evaluate the impact of preoperative cardiac function and haemodynamic parameters on the immediate outcome after repair of ruptured abdominal aortic aneurysm (RAAA). METHODS: This is a retrospective review of 68 consecutive patients who underwent emergency repair of RAAA. Baseline pulmonary artery pressure, cardiac index, oxygen saturation and pulse rate were measured and recorded immediately after insertion of a pulmonary artery thermodilution catheter and before anaesthesia induction. RESULTS: The in-hospital mortality rate was 39.7%. The area under the receiver operating characteristic (ROC) curve of cardiac index was 0.74 (95% CI 0.61-0.86), of stroke volume index was 0.78 (95% CI 0.67-0.89) and for oxygen delivery 0.72 (95% CI 0.60-0.84) for prediction of in-hospital death. The best cut-off values of cardiac index was 2.7 l/min/m(2) (18.8% vs. 58.3%, OR 6.07, 95% CI 2.00-18.37), of stroke volume index was 27 ml/m(2) (23.1% vs. 62.1%, OR 5.46, 95% CI 1.90-15.70) and of oxygen delivery was 370 ml/min/m(2) (17.9% vs. 56.4%, OR 5.05, 95% CI 1.87-18.91). Multivariate analysis showed that patient's age (P=0.01, OR 1.23, 95% CI 1.05-1.44), stroke volume index (P=0.018, OR 0.89, 95% CI 0.81-0.98), and shock (P=0.007, OR 14.20, 95% CI 2.09-96.67) were independent predictors of in-hospital death. CONCLUSIONS: This study suggests that impaired cardiac function and suboptimal oxyhaemodynamic parameters are important determinants of death after repair of RAAA.

HRQoL after coronary artery bypass grafting and percutaneous coronary intervention for stable angina.

OBJECTIVES: To assess the health related quality of life (HRQoL) and the change in the NYHA class after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in the management of stable coronary artery disease (CAD). The study was non-randomized. CABG group consisted of 240 patients and 229 patients were treated with PCI. HRQoL was measured prospectively by the 15D instrument. RESULTS: Three-year survival was 95.0 and 95.6% (NS). The HRQoL improved statistically in both groups until 6 months after treatment but deteriorated towards the end of the follow-up of 36 months. Clinically evident improvement of the HRQoL and decrease of the NYHA class took place more frequently among CABG patients. CONCLUSIONS: Despite initially more serious preoperative state and more demanding procedure CABG patients achieve equal level of HRQoL when compared with PCI patients. CABG patients may also obtain better relief from symptoms in mid-term follow-up. HRQoL cannot be the only factor to determine outcome after invasive treatment of CAD but it has to be placed in the context of the overall situation.

Repeat intervention after invasive treatment of coronary arteries.

OBJECTIVE: Patients who undergo successful revascularisation either with coronary artery bypass grafting (CABG) or with percutaneous coronary intervention (PCI) may subsequently require repeat invasive procedures. METHODS: A cohort of 662 coronary artery diseased (CAD) patients was retrospectively reviewed. Follow-up was 36 months. RESULTS: Thirty-day mortality was 1.0% in the CABG group (n=302) and 0% in the PCI group (n=360) (p=0.094). Overall 3-year survival for the cohort was 95.0% (NS). In addition to repeat angiographies (cumulative frequency 57.7% for PCI vs 4.3% for CABG, p<0.001) patients underwent both repeat PCI (20.7% vs 3.2%, p<0.001) and repeat CABG (6.9% vs 0.7%, p<0.001) during the follow-up. In Cox regression analysis hazard ratio (HR) for repeat PCI after initial PCI was 8.5, 95% confidence interval (CI) 3.7-19.5, p<0.001 and for repeat CABG 9.5, CI 2.2-40.0, p=0.002 in comparison to initial CABG. In-stent restenosis and progression of atherosclerotic plaques in native vessels were reasons for repeat intervention among the PCI patients. Complications with bypass grafts together with progression of the underlying disease were factors for re-interventions after CABG. CONCLUSIONS: PCI is far less invasive and may have lower in-hospital mortality rates than CABG. However, the highly likely need for repeat invasive procedures and revascularisation has to be taken into consideration when choosing an invasive approach for multi vessel CAD patients.

Postoperative delirium and health related quality of life after coronary artery bypass grafting.

OBJECTIVES: We wanted to identify determinants for postoperative delirium and its influence on health related quality of life (HRQoL) during 36-month follow-up of coronary artery bypass (CABG) patients. DESIGN: A total of 302 patients were retrospectively analyzed. HRQoL was assessed prospectively by the 15D instrument. Delirium was diagnosed clinically. RESULTS: The incidence of delirium was 6.0%. The cumulative survival (all-cause death) in 36 months was 96.1% in patients without delirium and 77.8% in patients with delirium. Age, cerebral disease, chronic heart failure, male gender, postoperative pneumonia and low output syndrome were predictors for delirium. Delirium patients needed more resources i.e. intensive care or total duration of hospitalization and experienced no positive change in HRQoL. Moreover patients with high preoperative 15D score tended to suffer fairly severe but reversible impairment during the first 6 months after the operation. CONCLUSIONS: Preoperatively older and sicker patients with complicated postoperative course are at higher risk of developing delirium after CABG. Preoperative status and operative complications together with delirium may exert negative influence on forthcoming HRQoL, which is seen especially in patients with a relatively high preoperative level of HRQoL.

EuroSCORE predicts health-related quality of life after coronary artery bypass grafting.

Three hundred and two patients were evaluated for the EuroSCORE risk and health-related quality of life (HRQoL) during three years after CABG as assessed by the 15D instrument. Both additive and logistic EuroSCORE correlated significantly with the 15D score at 6, 18 and 36 months. A clinically important increase > or =0.03 in the 15D score was achieved by 50.6% of patients at 6 months, 40.0% at 18 months and 35.9% at 36 months. The rates were similar among patients with increasing EuroSCORE at 6 and 18 months, but tended to decrease at 36 months in the highest EuroSCORE group (EuroSCORE 0-2: 46.8%; 3-5: 34.8%; and 6-14: 33.3%, respectively, P=0.13). Both additive (area under the receiver operating characteristic curve, AUC: 0.582, P=0.024) and logistic EuroSCORE (AUC: 0.575, P=0.039) were predictors of a significant increase of the 15D score. The best cut-off value of the additive EuroSCORE for prediction of a clinically important improvement of the 15D score during 3-year follow-up was 3, as 46.7% of patients with EuroSCORE 0-3 and 30.1% of patients with a score >3 (P=0.006) improved clinically. The present study showed that the EuroSCORE also predicts long-term HRQoL after CABG.

Quality of life during 18 months after coronary artery bypass grafting.

OBJECTIVE: The aim of the present study was to evaluate the change in health related quality of life (HRQoL) among elective coronary artery bypass grafting (CABG) patients. METHODS: A total of 302 CABG patients were included in the study. Complete pre-, peri- and postoperative data were collected comprehensively in a database. HRQoL was measured by the 15D instrument. The 15D is a non-disease-specific, 15-dimensional, standardized and self-administered measure of HRQoL that can be used both as a profile and single index score measure. Baseline assessment was carried out before coronary angiography and assessment was repeated 6 and 18 months after surgery. Data were analysed by gender and in three age groups, i.e. patients <65 years, 65-74 years and > or = 75 years. RESULTS: Thirty day mortality was 1.0%, and the survival rate at 6 and 18 months was 99.0% and 96.7%, respectively. Preoperative HRQoL of CABG patients was lower in comparison to age- and gender-standardized Finnish population (P<0.001). HRQoL of the patients improved significantly after CABG and the positive change lasted over the whole observation period, despite a slight decrease of 15D scores until 18 months. Although male patients had a higher preoperative HRQoL than women (P=0.005), both genders benefited similarly from the operation. In the patients > or = 75 years, the initial improvement of HRQoL returned to the preoperative level 18 months after the surgery. CONCLUSIONS: CABG patients experience a significant improvement in their HRQoL within 6 months after the operation and the effect remains through a mid-term observation time. However, expectations of improved HRQoL may have a limited value in decision making for surgery of coronary artery disease (CAD) for patients more than 75 years old.

Risk-scoring method for prediction of 30-day postoperative outcome after infrainguinal surgical revascularization for critical lower-limb ischemia: a Finnvasc registry study.

BACKGROUND: The aim of the present study was to develop a risk-scoring method for prediction of immediate postoperative outcome after infrainguinal surgical revascularization for critical limb ischemia. METHODS: The Finnvasc registry included data on 3,925 infrainguinal surgical revascularization procedures. This database was randomly divided into a derivation and a validation data set of similar sizes. RESULTS: In the overall series, 30-day postoperative mortality and major amputation rates were 3.1% and 6.3%, respectively. The 30-day postoperative mortality and/or limb-loss rate was 9.2%. Diabetes, coronary artery disease, foot gangrene, and urgent operation were independent predictors of 30-day postoperative mortality and/or major lower-limb amputation. A risk score was developed by assigning 1 point each to the latter risk factors. In the derivation data set, the 30-day postoperative mortality/amputation rates in patients with scores of 0, 1, 2, 3, and 4 were 7.7%, 6.4%, 11.1%, 20.4%, and 27.3%, respectively, (P < 0.0001); mortality rates were 1.3%, 2.3%, 4.1%, 7.7%, and 12.1%, respectively, (P < 0.0001); and major amputation rates were 6.4%, 4.3%, 7.1%, 12.7%, and 18.2%, respectively, (P < 0.0001). In the validation data set, the 30-day postoperative mortality/amputation rates in patients with scores of 0, 1, 2, 3, and 4 were 4.8%, 7.5%, 10.1%, 15.9%, and 22.2%, respectively, (P < 0.0001); mortality rates were 0.7%, 2.3%, 4.2%, 5.5%, and 14.8%, respectively, (P < 0.0001); and major amputation rates were 4.6%, 5.3%, 6.4%, 11.0%, and 14.0%, respectively (P = 0.011). CONCLUSIONS: This simple risk-scoring method can be useful to stratify the immediate postoperative outcome of patients undergoing infrainguinal surgical revascularization for critical lower-limb ischemia.

Adjuvant arteriovenous fistula as means of rescue for infrapopliteal venous bypass with poor runoff.

OBJECTIVE: The aim of this study was to assess the outcome of infrapopliteal bypass when an adjuvant arteriovenous (AV) fistula was reconstructed as means of rescue as a result of poor runoff. The design was a retrospective multicenter case-control study. METHODS: Seventy-seven infrapopliteal vein bypasses required an adjuvant AV fistula among 1813 patients operated on for critical leg ischemia in 3 vascular centers between 1996 and 2003. The mean age was 74 years (range, 39-90 years). A total of 70% of the patients had diabetes, and 24% had undergone previous vascular surgery. In 25% of the bypasses, the distal anastomosis was in a crural artery, in 55% it was in the dorsal pedal artery, and in 20% it was in a plantar artery. An adjuvant AV fistula was reconstructed in all cases because of poor intraoperative arterial status, intraoperative angiography, or low intraoperative flow. A control group was retrieved that matched the study group according to the recipient artery and runoff score. RESULTS: The primary and secondary patency were 61% and 75%, respectively, at 1 year in the AV fistula group and 57% and 71% in the control group. The 3-year patency rates were 49% and 62% for the AV fistula group and 46% and 71% for the control group, respectively. There was a 76% leg-salvage rate at 3 years in the study group, compared with 87% in the control group. There were no major complications related to the AV fistula. Intraoperative flow was increased from a median of 20 mL/min to 115 mL/min by the AV fistula (P = .003). The graft flow was significantly higher in the AV fistula group than in the control group (P = .001). CONCLUSIONS: The adjuvant AV fistula increased graft flow significantly in a poor-outflow venous bypass. In this extreme patient group, acceptable patency and leg salvage was achieved without adverse effects. Despite this, the AV fistula did not improve the outcome.

Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram.

Phosphodiesterase catalyzes the hydrolysis of the intracellular second messenger 3',5'-cyclic AMP (cAMP) into the corresponding 5'-nucleotide. Phosphodiesterase 4 (PDE4), the major cAMP-specific PDE in inflammatory and immune cells, is an attractive target for the treatment of asthma and COPD. We have determined crystal structures of the catalytic domain of PDE4B complexed with AMP (2.0 A), 8-Br-AMP (2.13 A) and the potent inhibitor rolipram (2.0 A). All the ligands bind in the same hydrophobic pocket and can interact directly with the active site metal ions. The identity of these metal ions was examined using X-ray anomalous difference data. The structure of the AMP complex confirms the location of the catalytic site and allowed us to speculate about the detailed mechanism of catalysis. The high-resolution structures provided the experimental insight into the nucleotide selectivity of phosphodiesterase. 8-Br-AMP binds in the syn conformation to the enzyme and demonstrates an alternative nucleotide-binding mode. Rolipram occupies much of the AMP-binding site and forms two hydrogen bonds with Gln443 similar to the nucleotides.

Urokinase, tissue-type plasminogen activator and plasminogen activator inhibitor-1 expression in severely stenosed and occluded vein grafts with thrombosis.

Intimal hyperplasia and subsequent thrombotic occlusions limit the success of vascular reconstructive procedures. Plasminogen activation in situ may be an important factor affecting re-stenosis of the graft. Tissue specimens from eight patients with failing or failed infra-inguinal vein bypasses and three specimens from normal veins were harvested to study urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) by in situ hybridization and immunohistochemistry. The possible presence of thrombi was monitored by platelet and fibrin-specific stainings. In occluded grafts, platelet endothelial cell adhesion molecule (PECAM-1) antibody stained the thrombi but not the endothelial area, indicating the absence of endothelium. Platelet glycoprotein (GP) IIb/IIIa co-localized with PECAM-1 and, furthermore, GP IIb/IIIa staining was positive on the vein walls with thrombi and to some extent in the grafts without thrombi. PAI-1 and u-PA were uniformly upregulated in intimal thickening in grafts without thrombus. In organized thrombi, enhanced u-PA, t-PA and PAI-1 reactivity was detected in the ingrowing subendothelium. In non-occluded grafts with small thrombi, u-PA expression was enriched beneath microthrombi co-localizing with the graft wall injury, while PAI-1 was scattered in the (sub)endothelium. We conclude that fibrinolytic system is upregulated at sites of graft stenosis, and local proteolytic degradation of the graft wall associates with thrombus formation.