In vitro antitumor activity of MIC2 protein-doxorubicin conjugates

The pseudoautosomal encoded MIC2 glycoprotein is a tumor-associated antigen of Ewing's sarcoma (ES) and closely related tumors of unknown function. To investigate the use of this protein as selective drug carrier recombinant MIC2 was coupled to doxorubicin by a two step glutaraldehyde method (molar ratio DOX/MIC2 of 32 and 16). The conjugates showed dose-dependent cytostatic activity against the ES cell line SK-ES1, the peripheral neuroectodermal line KAL and the prostate cancer cell line PC-3 concurrent with reduced toxicity against normal lymphoblasts. In comparison to free doxorubicin the MIC2-doxorubicin conjugates exhibited highest activity against the PC-3 cell line. Confocal microscopy showed intracellular accumulation of MIC2 conjugates.     

Inhibitory effect of antagonists of bombesin and growth hormone-releasing hormone on orthotopic and intraosseous growth and invasiveness of PC-3 human prostate cancer in nude mice.

PURPOSE: To determine whether antagonists of growth hormone-releasing hormone (GHRH) and bombesin/gastrin-releasing peptide (BN/GRP) can inhibit the orthotopic and metastatic growth of PC-3 human androgen-independent prostate cancers. EXPERIMENTAL DESIGN: The effects of administration of GHRH antagonist MZ-J-7-118, BN/GRP antagonist RC-3940-II, and their combination on the growth and metastatic spread of PC-3 tumors implanted orthotopically into nude mice were evaluated. The efficacy of this treatment on PC-3 tumors implanted intratibially and s.c. was also determined. RESULTS: Treatment with MZ-J-7-118, RC-3940-II, or their combination significantly inhibited the growth of PC-3 tumors implanted orthotopically, intraosseously, and s.c. The combination of the two antagonists had the greatest effect, inhibiting orthotopic tumor growth by 77%, intratibially implanted tumors by 86%, and s.c. tumors by 86%. The therapy with BN/GRP and GHRH antagonists, especially in combination, also reduced the local tumor spread and distant metastases in animals bearing orthotopic tumors. Combination therapy was likewise the most effective in reducing the incidence and severity of tibial osteolytic lesions and pathologic fractures in intraosseously implanted tumors. High-affinity binding sites for BN/GRP and GHRH were found in s.c. and orthotopic PC-3 tumor samples. MZ-J-7-118, RC-3940-II, and the combination of both compounds inhibited in vitro growth of PC-3 cells. CONCLUSIONS: Our findings show the efficacy of BN/GRP antagonists and GHRH antagonists for the treatment of advanced prostate cancer in preclinical metastatic models. As BN/GRP antagonists are already in clinical trials and GHRH antagonists are effective in androgen-independent prostate cancer models, these analogues could be considered for the management of advanced prostate carcinoma.     

Cardiovascular Efficacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis Including the ODYSSEY OUTCOMES Trial

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are efficacious lipid-lowering agents, but more precise estimates of their effects on major adverse cardiovascular events (MACE), mortality, and safety are needed. We systematically reviewed and meta-analyzed randomized controlled trials with durations ≥ 6 months comparing MACE, mortality, and safety with PCSK9 inhibitors vs control. We searched CENTRAL, Embase, MedLine and the grey literature to November 7, 2018. From 2048 articles, we included 23 trials (n = 60,723). PCSK9 inhibitors reduced MACE (relative risk, 0.83; 95% confidence interval, 0.78-0.88), but did not clearly reduce mortality (relative risk, 0.93; 95% confidence interval, 0.85-1.02) or increase adverse events. In conclusion, PCSK9 inhibitors reduce nonfatal MACE, are well tolerated, but effects on mortality remain unclear.     

The Story of the Texas Pain Society: Formation and Function of a Regional Pain Society

Abstract: The idea of forming a Texas Pain Society came to the Founders in 1987 due to disparity and deficiencies in the practice of pain management in the United States and, in particular, the State of Texas. The Founders considered very carefully the implication of forming such a society. They diligently mapped out the mission and goals of the Texas Pain Society in those early formative years. This report is the history of Texas Pain Society as the activities unfolded from 1989 to 2011. The reader may question why there is a need to tell such a story. We believe strongly that, with disparities of standards of practice in pain medicine and poor recognition of advances in pain management, this scenario is quite common in many states and countries. The practitioners of pain management in these regions certainly must have considered getting together and forming a consensus on the standards of practice in their communities. This historical report of the Texas Pain Society provides the relevant information necessary and the efforts to be made for a society’s mission to achieve its goals and have an ongoing impact in its own region. We hope that we have shed some light on a process for the formation of a regional pain society such as ours. ?     

Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

Open in a separate window     

Open hemiarch versus clamped ascending aorta replacement for aortopathy during initial bicuspid aortic valve replacement

BackgroundThere is controversy regarding the extent of aortic resection necessary in patients with aortopathy related to bicuspid aortic valve disease. To address this issue, we reviewed our experience in patients undergoing ascending aorta replacement during bicuspid aortic valve replacement.MethodsWe reviewed 702 patients who underwent ascending aorta replacement at the time of initial nonemergent native bicuspid aortic valve replacement at our institution between January 2000 and June 2017. Treatment cohorts included an open hemiarch replacement group (n = 225; 32%) and a clamped ascending aorta replacement group (n = 477; 68%).ResultsMedian patient age was 60 years (interquartile range [IQR], 51-67 years), female sex was present in 113 patients (16%), ejection fraction was 62% (IQR, 56%-66%), and aortic arch diameter was 33 mm (IQR, 29-36 mm). Cardiopulmonary bypass time was longer in the hemiarch replacement group (188 minutes vs 97 minutes; P < .001). Procedure-related complications (36%) and mortality (<1%) were similar in the 2 groups; however, the hemiarch group had an increased odds of blood transfusion (odds ratio, 1.62; 95% confidence interval [CI], 1.15-2.28; P = .006). The median duration of follow-up was 6.0 years (95% CI, 5.3-6.8 years). Overall survival was 94 ± 1% at 5 years and 80 ± 2% at 10 years. Multivariable analysis demonstrated similar survival in the 2 groups (hazard ratio, 0.83; 95% CI, 0.51-1.33; P = .439). No repeat aortic arch operations were done for aortopathy over the duration of clinical follow-up.ConclusionsCompared with patients in the clamped ascending aorta replacement group, patients in the hemi-arch replacement group had longer cardiopulmonary bypass and aortic cross-clamp times, along with an increased risk of blood transfusion, but similar freedom from repeat aortic arch operation and survival. We identified no advantage of performing hemiarch replacement in the absence of aortic arch dilation.     

Corneal Manifestations of Systemic Sclerosis

Purpose: Corneal involvement in systemic sclerosis (SSc) is rare, but due to rich collagen composition cornea is especially vulnerable to connective tissue diseases. Therefore, our aim was to evaluate corneal parameters of SSc patients.

Methods: The study included 32 SSc patients and 39 control subjects with no ocular symptoms or ocular surface disorders. All study participants underwent Pentacam evaluation and objective signs of dry eye disease (DED), and clinical parameters were evaluated.

Results: All pachymetric values, most of the corneal front surface, corneal volume, as well as anterior chamber depth measurements were significantly lower in the SSc group than in the control group (p < 0.05). Significant negative correlation was found between corneal parameters and age on the one hand, and disease duration on the other.

Conclusions: Early recognition of corneal impairment, a possible extraintestinal manifestation of SSc, should be included in the check-up of the disease in order to reduce sight-threatening complications.     

The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

Despite the fact that lysophosphatidic acid (LPA) has been identified as a main platelet-activating lipid of mildly oxidized low-density lipoprotein (LDL) and human atherosclerotic lesions, it remains unknown whether it is capable of activating platelets in blood. We found that LPA at concentrations slightly above plasma levels induces platelet shape change, aggregation, and platelet-monocyte aggregate formation in blood. 1-alkyl-LPA (16:0 fatty acid) was almost 20-fold more potent than 1-acyl-LPA (16:0). LPA directly induced platelet shape change in blood and platelet-rich plasma obtained from all blood donors. However, LPA-stimulated platelet aggregation in blood was donor dependent. It could be completely blocked by apyrase and antagonists of the platelet adenosine diphosphate (ADP) receptors P2Y1 and P2Y12. These substances also inhibited LPA-induced aggregation of platelet-rich plasma and aggregation and serotonin secretion of washed platelets. These results indicate a central role for ADP-mediated P2Y1 and P2Y12 receptor activation in supporting LPA-induced platelet aggregation. Platelet aggregation and platelet-monocyte aggregate formation stimulated by LPA was insensitive to inhibition by aspirin. We conclude that LPA at concentrations approaching those found in vivo can induce platelet shape change, aggregation, and platelet-monocyte aggregate formation in whole blood and suggest that antagonists of platelet P2Y1 and P2Y12 receptors might be useful preventing LPA-elicited thrombus formation in patients with cardiovascular diseases.