A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/ß-catenin pathway were more frequently mutated and negative regulators of Wnt/ß-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/ß-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Isolation of chlorine-containing antibiotic from the freshwater cyanobacterium Scytonema hofmanni.

Scytonema hofmanni, a filamentous freshwater cyanobacterium (blue-green alga), produces secondary metabolites which inhibit the growth of other cyanobacteria and green algae. A rapid, qualitative assay for this inhibition has been developed with Synechococcus as the test organism. This assay procedure has led to the isolation and characterization of an antibiotic (named cyanobacterin) from Scytonema. The antibiotic has a molecular weight of 430 and an empirical formula of C23H23O6Cl and contains a gamma-lactone and a chlorinated aromatic nucleus. It inhibits the growth of various algae but has limited effect on nonphotosynthetic bacteria or protozoans and thus may have potential use as a specific algicide.

A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity.

Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point for modeling reactive toxicity is the applicability of the general rules of organic chemical reactions and the association of these reactions to cellular targets of importance in toxicology. The identification of plausible "molecular initiating events" based on covalent reactions with nucleophiles in proteins and DNA provides the unifying concept for a framework for reactive toxicity. This paper outlines the proposed framework for reactive toxicity. Empirical measures of the chemical reactivity of xenobiotics with a model nucleophile (thiol) are used to simulate the relative rates at which a reactive chemical is likely to bind irreversibly to cellular targets. These measures of intrinsic reactivity serve as correlates to a variety of toxic effects; what's more they appear to be more appropriate endpoints for QSAR modeling than the toxicity endpoints themselves.

Neutrophil depletion fails to modify myocardial no reflow and functional recovery after coronary reperfusion.

Recent studies suggest that neutrophil accumulation and activation in postischemic myocardium may be responsible for myocardial no reflow, which is characterized by an incomplete restoration of blood flow after reperfusion. To examine this further, 11 open chest, anesthetized dogs received bolus injections of a bovine neutrophil antiserum that produced an average 81 +/- 5% depletion of circulating neutrophils, and 10 control dogs received nonimmune serum. Each animal underwent 2 h of left circumflex artery occlusion followed by 4 h of reperfusion. Simultaneous two-dimensional echocardiography and radioactive microsphere blood flow studies were performed at baseline, 2 h of occlusion and early (approximately 5 min) and 4 h of reperfusion. During occlusion, both groups developed similar reductions in myocardial blood flow and levels of ischemic zone myocardial wall thinning. At early reperfusion, similar levels of hyperemia and regional hypokinesia were observed for both groups. By late reperfusion, both groups experienced significant no reflow in the subendocardium (p less than 0.05) and reduced reflow in the mid-myocardium. Regional depression in ischemic zone function persisted throughout the reperfusion period in both groups. However, infarct size expressed as a percent of left ventricular weight, assessed by triphenyltetrazolium chloride staining, was smaller for the neutrophil depletion group compared with the control group (8.7 +/- 1.3% versus 13.1 +/- 1.8%, p less than 0.05). It is concluded that an 81% neutrophil depletion fails to modify the no reflow phenomenon or improve functional recovery after 2 h of coronary artery occlusion and 4 h of coronary reperfusion despite modification of the ultimate size of necrosis.

Rupture of the left kidney following renosplenic shunt.

Kidney rupture following division of the left renal vein during portal decompression is presented. A review of the renal venous anatomy is described and a possible explanation of this ususual occurrence is offered.

Recurrent variceal hemorrhage following successful Warren shunt.

Recurrent variceal hemorrhages are demonstrated following a technically successful Warren shunt. Serial barium esophagrams show the progressive enlargement of distal esophageal varices. Results of celiac arteriograms and direct examination confirmed the patency of the distal splenorenal shunt. Hemorrhage from varices was shown by fiberoptic esophagoscopy; end-to-side portacaval anastomosis reduced portal pressure and stopped the bleeding.

Innominate artery endarterectomy. A 16-year experience.

Transsternal endarterectomy was performed in 34 of 37 patients with symptomatic atherosclerosis of the innominate artery, with a mortality of 6%. Thirty of the 32 survivors are asymptomatic at an average of 6.1 years postoperatively. Six of these patients who had ulcerated, nonstenotic atherosclerotic lesions have had complete cessation of preoperative transient ischemic attacks. Normal arterial patency has been maintained for follow-up periods varying from seven months to 16 years.

Senile reticular pigmentary degeneration.

Of 104 consecutive patients with senile reticular pigmentary degeneration (207 eyes), 85 patients (82%) were more than 60 years old (mean age, 69.2 +/- 8.54 years). Forty-nine (47%) were men and 55 (53%) were women. Peripheral visual fields were not characteristically constricted. Although most eyes tested had visual acuities of 20/50 or better, 69 eyes (33%) had visual acuities of 20/100 or worse. A total of 136 eyes (66%) had senile macular degeneration at the time senile reticular pigmentary degeneration was first diagnosed, whereas only 43 control eyes (21%) from the same referral population also had senile macular degeneration (P less than .001). Macular degeneration was the primary cause for reduced vision when it was noted. In no instance could reduced visual acuity or constricted visual fields be attributed to the senile reticular pigmentary degeneration alone. Senile reticular pigmentary degeneration on routine ophthalmoscopy should alert the clinician to the possibility of co-existing macular degenerative disease.

Tumor reactive cis-aconitylated monoclonal antibodies coupled to daunorubicin through a peptide spacer are unable to kill tumor cells.

Antibody-drug conjugates containing a linkage susceptible to lysosomal hydrolases were constructed by coupling peptide-daunorubicin (DNR) derivatives to MAb. Using a modification in the method of Trouet et al, peptide derivatives of DNR containing the sequences Ala-Leu and Ala-Leu-Ala-Leu linked to drug via their carboxy terminus were prepared. Cleavage of these derivatives by lysosomal enzymes resulting in the release of free DNR was demonstrated. Human antitumor MAb were derivatized with either succinic anhydride or cis-aconitic anhydride to introduce spacer arms for coupling. Binding studies showed that MAb with a decrease of 12-20 amino groups retained greater than 70% of their immunoreactivity, a level deemed acceptable for constructing conjugates. Derivatized and native MAb were conjugated to peptide-DNR via a carbodiimide mediated reaction. None of the conjugates displayed cytotoxicity toward target tumor cell lines in vitro.

An immunoassay for TEQ screening of dioxin/furan samples: current status of assay and applications development.

A simple and easy to use system has been developed for rapid screening of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in a variety of situations. The system uses a competitive inhibition Enzyme ImmunoAssay (EIA) based on a previously described mouse monoclonal antibody which is specific for 2,3,7,8-TCDD and related congeners. Two formats have been developed, a rapid tube test and a microplate test. Respective sensitivities are 100 pg/tube and 25 pg/well of 2,3,7,8-TCDD. Congener specificity of the tube test roughly correlates with 1-TEF. The concept of TEQ screening is validated by comparing TEQ values for a set of soil samples to the EIA responses predicted for those samples. Actual analysis of crude extracts of some of the same soils indicated some clean-up is required to remove interferences. Rapid extraction and sample clean-up methods for soil and other matrices are being developed. Potential implementation of the EIA in a fixed lab is discussed. The EIA system offers significant improvements in speed, sample throughput, and cost compared to GC-MS. This system should be useful for screening environmental samples in many situations.

Treatment of hallux valgus with an increased distal metatarsal articular angle: evaluation of double and triple first ray osteotomies.

During a 12-year period in which 878 hallux valgus corrections were performed, 18 patients (21 feet) with symptomatic hallux valgus deformity and an increased distal metatarsal articular angle (DMAA) underwent periarticular osteotomies (double or triple first ray osteotomies). They were studied retrospectively at an average follow-up of 33 months. The surgical technique comprised a closing wedge distal first metatarsal osteotomy combined with either a proximal first metatarsal osteotomy or an opening wedge cuneiform osteotomy (double osteotomy). When a phalangeal osteotomy was added, the procedure was termed a "triple osteotomy." The average age of the patients at the time of surgery was 26 years. At final follow-up, the average hallux valgus correction measured 23 degrees and the average 1-2 intermetatarsal angle correction was 9 degrees. The DMAA averaged 23 degrees preoperatively and was corrected to an average of 9 degrees postoperatively. One patient developed a postoperative hallux varus deformity, and one patient developed a malunion, both of which required a second surgery. A hallux valgus deformity with an increased DMAA can be successfully treated with multiple first ray osteotomies that maintain articular congruity of the first metatarsophalangeal joint.

The biomechanical relationship between the tendoachilles, plantar fascia and metatarsophalangeal joint dorsiflexion angle.

We carried out an experiment to measure the relationship between tensile force in the tendoachilles and plantar fascia strain, and how this relationship is affected by the metatarsophalangeal joint dorsiflexion angle. Eight cadaver lower extremity specimens underwent biomechanical testing. Using a servo-hydraulic testing machine, a tensile force up to 500 N was applied to the tendoachilles while the strain on the plantar fascia was measured using an extensometer. The experiment was repeated at four different metatarsophalangeal joint dorsiflexion angles (0 degrees, 5 degrees, 30 degrees, and 45 degrees). Measurements and calculations showed that dorsiflexion of the toes tightens the plantar fascia (the windlass effect) and increases the effect that a tensile force in the tendoachilles has on the tensile strain and tensile force in the plantar fascia.

Editor's Mail.

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An exploratory study of life-change events, social support and pregnancy decisions in adolescents.

This exploratory, descriptive study investigated the relationship of life-change events and family and social support to decision making in pregnant adolescents. The convenience sample consisted of 43 subjects aged 14 to 18 years coming to two midwestern clinics for pregnancy testing. Instruments were the Adolescent Life Change Event Questionnaire and the Demographic and Social Support Questionnaire. Data analysis involved three groups: continue the pregnancy (N = 30); abort (N = 9); and undecided (N = 4). Kruskal-Wallis one-way analysis of variance by ranks was used to test for differences between groups on overall life-change unit (LCU) scores and social support scores. Chi square, Fisher Exact Tests and step method multiple discriminant analysis were used to determine if specific life changes were more associated with particular outcome decisions. While not statistically significant, the overall LCU scores were higher and the social support scores lower for the continue group than for the abortion group. Subjects in the abortion group were younger, more likely to have experienced "getting grounded," and more involved in school and social activities. More subjects in the continue group reported personal and family health problems.

PIP: This exploratoy study investigats the relationship of life-change events and family and social support to decision making in pregnant adolescents. The convenience sample consisted of 43 subjects aged 14 to 18 years coming to 2 midwestern, urban American clinics for pregnancy testing. Instruments were the Adolescent Life Change Event Questionnaire and the Demographic and Social Support Questionnaire. Data analysis involved 3 groups: continue the pregnancy (N=30); abort (N=9); and undecided (N=4). Kurskal-Wallis 1-way analysis of variance by ranks was us%ed to test for differences between groups on overall life-change unit (LUC) scores ans social support scores. Chi-square, Fisher Exact Tests and step method multiple discriminant analysis were used to determine if specific life changes were more associated with particular outcome decisions. While not statistically significant, the overall LCU scores were higher and the social support scores lower for the continue group than for abortion group. Subjects in the abortion group were younger, were more likely to have experienced getting grounded, and more involved in school and social activities. More subjects in the continue group reported personal and family health problems.

Breaking the incest cycle: the group as a surrogate family.

1. Adult women who are survivors of incest can work on healing issues during long-term group therapy sessions. 2. Group therapy sessions can assist survivors to deal with unresolved family issues. 3. Group therapy sessions can be facilitated by psychiatric nurses who are college faculty when a nursing center is affiliated with a college of nursing.

Obese men have more advanced and more aggressive prostate cancer at time of surgery than non-obese men after adjusting for screening PSA level and age: results from two independent nested case-control studies.

BACKGROUND: It remains unclear whether the hemodilution effect of body mass index (BMI) on PSA levels translates to inappropriate prostate cancer (PCa) screening in obese men. To address this, we conducted two nested case-control studies within prospective cohorts of men undergoing radical prostatectomy for newly diagnosed PCa. METHODS: We identified 1817 men with BMI 30 kg m(-2) (cases) and 1244 men with BMI <25 kg m(-2) (controls) who underwent surgery to treat PCa at Mayo Clinic in Rochester between 2000 and 2009. Cases and controls were frequency matched on age and PSA level. In a similar manner, we identified 206 cases and 133 controls treated at Mayo Clinic in Florida between 2006 and 2011. We employed logistic regression models to evaluate the association of pathologic features of aggressiveness with obesity status. RESULTS: After adjusting for age and PSA level, we noted that obese men in the Rochester population are more likely to present with Gleason grade 8-10 tumors (OR= 1.50; 95% CI 1.14-1.96; P=0.003) and pT3, pT4, pTxN+ stage disease (OR=1.30; 95% CI 1.05-1.62). We noted a similar association seminal vesicle involvement (OR= 1.41; 95% CI 1.03-1.92; P=0.03). Results from the smaller Florida population supported these same associations but did not achieve conventional statistical significance. CONCLUSIONS: Obese men present with more aggressive PCa tumors compared with non-obese men of similar age and PSA screening values. If confirmed, this would support the need to explore PSA-based screening in obese men to possibly account for a hemodilution effect.